Assessment of Innovative Approaches to Cervical Cancer Screening by gxr14046

VIEWS: 33 PAGES: 230

									                          ALLIANCE FOR CERVICAL CANCER PREVENTION

                               International Agency for Research in Cancer (IARC), Lyon
                               John Hopkins Program for International Education of Gynecologists
 Scientific Institute          and Obstetricians (JHPIEGO Corporation), Baltimore
                               Program for Appropriate Technology in Health (PATH), Seattle
 of Public Health


                          Funded by the Bill & Melinda Gates Foundation




 Assessment of Innovative Approaches to
 Cervical Cancer Screening, Follow-Up and
  Treatment of Screen Detected Cervical
      Lesions in Developing Countries

 A Pooled Analysis of ACCP Study Results




            Marc ARBYN1, Lynne GAFFIKIN2,
Rengaswamy SANKARANARAYANAN3, Richard MUWONGE3,
      Namory KEITA4, Ramani WESLEY5, Vivien TSU6

               1. Scientific Institute of Public Health, Brussels, Belgium
                      2. JHPIEGO Corporation, Baltimore, USA
            3. International Agency for Research in Cancer, Lyon, France
   4. Service de Gynécologie/Obstétrique, Université de Conakry, Guinée-Conakry
        5. Medicine, Regional Cancer Center, Trivandrum, Kerala State, India
                                  6. PATH, Seattle, USA




                  IPH/EPI REPORTS Nr. 2006–002


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2
Epidemiology, January 2006; Brussels (Belgium)
Scientific Institute of Public Heatlh, IPH/EPI REPORTS 2006 - 002
Depotnumber: D/2006/2505/002
File: ACCP_Meta9a.doc.

Funded by the Bill & Melinda Gates Foundation

ALLIANCE FOR CERVICAL CANCER PREVENTION
IARC, Lyon (France)
JHPIEGO Corporation, Baltimore (USA)
PATH, Seattle (USA)



  Assessment of Innovative Approaches to Cervical Cancer
  Screening, Follow-Up and Treatment of Screen Detected
         Cervical Lesions in Developing Countries

             A Pooled Analysis of ACCP Study Results

              Marc ARBYN1, Lynne GAFFIKIN2,
  Rengaswamy SANKARANARAYANAN3, Richard MUWONGE3,
        Namory KEITA4, Ramani WESLEY5, Vivien TSU6

                    1. Scientific Institute of Public Health, Brussels, Belgium
                           2. JHPIEGO Corporation, Baltimore, USA
                 3. International Agency for Research in Cancer, Lyon, France
        4. Service de Gynécologie/Obstétrique, Université de Conakry, Guinée-Conakry
             5. Medicine, Regional Cancer Center, Trivandrum, Kerala State, India
                                       6. PATH, Seattle, USA




                                                           Scientific Institute of Public Health
                                                                              J. Wytsmanstr. 14
                                                                                 B1050 Brussels
                                                                                        Belgium

                                                              e-mail: marc.arbyn@iph.fgov.be
                                          http://www.iph.fgov.be/epidemio/epien/PROG2.HTM

                        IPH/EPI REPORTS Nr. 2006 – 002



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1. Table of contents
1.          TABLE OF CONTENTS.................................................................................5
2.          EXECUTIVE SUMMARY..............................................................................8
     2.1.     BACKGROUND ................................................................................................8
     2.2.     MATERIAL AND METHODS ..............................................................................8
        2.2.1. Conducted studies .....................................................................................8
        2.2.2. Statistical analyses ....................................................................................9
     2.3.     RESULTS .......................................................................................................10
        2.3.1. Prevalence of cervical disease ................................................................10
        2.3.2. Test characteristics of the evaluated screening tests...............................10
        2.3.3. Influence of study characteristics on test accuracy.................................12
        2.3.4. Triage of VIA-positive cases ..................................................................13
        2.3.5. Cryotherapy: compliance, acceptability and safety ................................13
     2.4.     CONCLUSIONS ..............................................................................................13
3.          INTRODUCTION..........................................................................................15
4.          MATERIAL AND METHODS.....................................................................17
     4.1.     CONDUCTED STUDIES ...................................................................................17
        4.1.1. Cross-sectional multi-center study of the test accuracy of VIA, VIAM,
                VILI, cytology and the HC2 assay..........................................................18
        4.1.2. Cross-sectional study on the test accuracy of VIA, cytology and the HC2
                assay in Zimbabwe..................................................................................19
        4.1.3. Randomized trial: VIA screening versus no screening in rural South
                India ........................................................................................................20
        4.1.4. Western Kenya Cervical Cancer Prevention Project ..............................21
        4.1.5. Safety, acceptability, and feasibility of a single-visit approach to cervical
                cancer prevention in rural Thailand ........................................................23
        4.1.6. Safety, acceptability, and feasibility of a single-visit approach to
                cervical-cancer prevention in Ghana ......................................................23
     4.2.     METHODS .....................................................................................................25
     4.3.     STATISTICAL ANALYSES ...............................................................................27
5.          RESULTS OF THE SEPARATE STUDIES ...............................................29
     5.1.     CROSS-SECTIONAL MULTI-CENTER STUDY ON THE TEST ACCURACY OF
              VIA, VIAM, VILI, CYTOLOGY AND THE HC2 ASSAY ..................................29
        5.1.1. Test accuracy of VIA and VILI for CIN2+ ............................................29
        5.1.2. Pooled relative accuracy of the screening tests.......................................32
     5.2.     CROSS-SECTIONAL STUDY ON THE TEST ACCURACY OF VIA, CYTOLOGY
              AND THE HC2 ASSAY IN ZIMBABWE .............................................................33
     5.3.     RANDOMIZED TRIAL OF VIA SCREENING IN RURAL SOUTH INDIA ................35
     5.4.     WESTERN KENYA CERVICAL CANCER PREVENTION PROJECT (WKCCPP)..37
       5.4.1. Positive predictive value and approximated specificity of VIA .............37
       5.4.2. Performance of triage methods ...............................................................38
       5.4.3. Combination of VIA screening with subsequent triage ..........................41
       5.4.4. Experience of women in the 1-3 month period after cryotherapy ..........42
       5.4.5. Follow-up 1 year after cryotherapy.........................................................46



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     5.5.       SAFETY, ACCEPTABILITY, AND FEASIBILITY OF A SINGLE-VISIT APPROACH
                TO CERVICAL-CANCER PREVENTION IN RURAL THAILAND ............................48
     5.6.       SAFETY, ACCEPTABILITY, AND FEASIBILITY OF A SINGLE-VISIT APPROACH
                TO CERVICAL CANCER PREVENTION IN GHANA .............................................54

6.          POOLED ANALYSES...................................................................................59
     6.1.     META-ANALYSIS OF TEST CHARACTERISTICS OF APPLIED SCREENING
              METHODS ......................................................................................................59
        6.1.1. Test characteristics of VIA .....................................................................59
        6.1.2. Test characteristics of VILI ....................................................................70
        6.1.3. Test characteristics of VIAM..................................................................80
        6.1.4. Test characteristics of HPV DNA detection by HC2..............................90
        6.1.5. Test characteristics of cervical cytology...............................................100
        6.1.6. Summary of the meta-analyses of the accuracy for CIN1+..................127
        6.1.7. Summary of the meta-analyses of the accuracy for CIN2+..................129
        6.1.8. Summary of the meta-analyses of the accuracy for CIN3+..................131
        6.1.9. Summary of the meta-analyses of the accuracy for cancer...................133
     6.2.     META-ANALYSES OF THE RELATIVE SENSITIVITY AND SPECIFICITY OF
              CERVICAL CANCER SCREENING TESTS .........................................................135
        6.2.1. Relative sensitivity and specificity of VILI compared to VIA .............135
        6.2.2. Relative sensitivity and specificity of VIAM compared to VIA ..........138
        6.2.3. Relative sensitivity and specificity of HC2 compared to VIA .............140
        6.2.4. Relative sensitivity and specificity of cervical cytology (at ASCUS+)
                compared to VIA...................................................................................142
        6.2.5. Relative sensitivity and specificity of cervical cytology (at LSIL+)
                compared to VIA...................................................................................144
        6.2.6. Relative sensitivity and specificity of cervical cytology (at HSIL+)
                compared to VIA...................................................................................146
        6.2.7. Relative sensitivity and specificity of VIAM compared to VILI .........148
        6.2.8. Relative sensitivity and specificity of HC2 compared to VILI.............150
        6.2.9. Relative sensitivity and specificity of cytology (at ASCUS+) compared
                to VILI ..................................................................................................152
        6.2.10. Relative sensitivity and specificity of cytology (at LSIL+) compared to
                VILI.......................................................................................................154
        6.2.11. Relative sensitivity and specificity of cytology (at HSIL+) compared to
                VILI.......................................................................................................156
        6.2.12. Relative sensitivity and specificity of HC2 compared to VIAM ..........158
        6.2.13. Relative sensitivity and specificity of cytology at (ASCUS+) compared
                to VIAM................................................................................................160
        6.2.14. Relative sensitivity and specificity of cytology (at LSIL+) compared to
                VIAM ....................................................................................................162
        6.2.15. Relative sensitivity and specificity of cytology (at HSIL+) compared to
                VIAM ....................................................................................................164
        6.2.16. Relative sensitivity and specificity of cytology (at ASCUS+) compared
                to HC2...................................................................................................166
        6.2.17. Relative sensitivity and specificity of cytology (at LSIL+) compared to
                HC2 .......................................................................................................168
        6.2.18. Relative sensitivity and specificity of cytology (at HSIL+) compared to
                HC2 .......................................................................................................170




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        6.2.19. Summary of the meta-analyses of the relative accuracy of screening tests
                 ...............................................................................................................172
     6.3.     SUMMARY ROC CURVES ............................................................................174
     6.4.     INFLUENCE OF STUDY CHARACTERISTICS ON THE PREVALENCE OF
              DISEASE ......................................................................................................178
     6.5.        INFLUENCE OF STUDY COVARIATES ON TEST CHARACTERISTICS ............180
        6.5.1. Variation of the test positivity rate by age group..................................180
        6.5.2. Variation of the test positivity rate by time period ...............................183
        6.5.3. Influence of age, period and study setting on the PPV .........................185
        6.5.4. Influence of study characteristics on the sensitivity and specificity of
                 screen tests ............................................................................................189
        6.5.5. Influence of study characteristics on the diagnostic odds ratio using
                 multi-variate SROC-regression analysis...............................................192
     6.6.     CORRELATIONS BETWEEN TESTS ................................................................194
     6.7.     PPV OF COLPOSCOPY TRIAGE .....................................................................194
     6.8.     TREATMENT OF VIA-POSITIVE CASES.........................................................198
7.          DISCUSSION ...............................................................................................202
8.          ACKNOWLEDGEMENTS.........................................................................206
9.          ABBREVIATIONS ......................................................................................208
10.         REFERENCES.............................................................................................209
11.         ANNEXES.....................................................................................................213
     11.1. DATA FILES AND STATISTICAL SYNTAX FILES .............................................213
     11.2. ABSTRACTS FROM THE INCLUDED SEPARATE PUBLISHED STUDIES..............214
       11.2.1. Cross-sectional multi-country study (5 publications) ...........................214
       11.2.2. Zimbabwe study (3 publications)..........................................................216
       11.2.3. Ambilikai RCT (2 publications) ...........................................................218
       11.2.4. Kenya study ..........................................................................................219
       11.2.5. Thailand demonstration project ............................................................219
       11.2.6. Ghana demonstration project ................................................................220
     11.3. COMPREHENSIVE TABLE WITH CHARACTERISTICS OF THE INCLUDED
            STUDIES ......................................................................................................221




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2. Executive summary


2.1. Background

Cervical cancer is the most common female cancer in developing counties. Cervical
cancer has a long detectable preclinical phase and this makes it particularly
preventable by screening. The incidence of and mortality from this disease has fallen
dramatically in western countries where the use of the Pap smear was well established
and quality could be assured. By lack of financial and technical resources it is
unrealistic to introduce similar screening policies in developing countries. Therefore
new screening methods, applicable in resource-poor settings, are currently being
investigated. The Bill & Melinda Gates Foundation has made it possible for the
Alliance for Cervical Cancer Prevention to set up large-scale studies, which in the
long run may result in the development of appropriate health policies using effective
and affordable technologies to prevent cervical cancer.



2.2. Material and methods
2.2.1. Conducted studies
Five operational partners in the Alliance for Cervical Cancer Prevention (ACCP)--
PATH (Seattle), IARC (Lyon), JHPIEGO (Baltimore), EngenderHealth (New York)
and PAHO (Washington)--conducted several trials in Africa, Asia and Latin America
between 1999 and 2004. At an intermediate evaluation that took place in Geneva in
April 2004, experts suggested that a pooled analysis of available data be performed.
Data from six different studies were obtained.

One research project was conducted by the International Agency for Research in
Cancer (IARC, Lyon). It was a cross-sectional multi-center study set up in 11
locations, in five African countries and India, where in total 58 000 women were
screened with naked-eye visual inspection after application of 3 to 5% acetic acid
(VIA). In several settings other screening tests were performed as well. In three
locations, the cervix was inspected with a magnifying device (VIAM); in 10 locations
Lugol’s iodine was used to identify suspect yellow non-iodine uptake areas. At five
places a Pap smear was taken and in four settings the Hybrid Capture II (HC2) assay
was used to detect presence of high-risk HPV DNA. The gold standard verification
consisted of a colposcopic exploration of the cervix, offered to all women,
irrespective of the screen test result and performed during the same visit. Biopsies
were taken from colposcopically suspect areas. The histological result or, if histology
was absent, the negative colposcopy result was considered as the outcome. Women
with CIN or more serious cervical disease received adequate treatment.

A similar study was conducted by JHPIEGO (Baltimore) in collaboration with the
University of Zimbabwe. Here more than 2000 enrolled women were tested with
VIA, a Pap smear and the Hybrid Capture II assay. The gold standard verification
was as described for the first study.



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A third study was a cluster-randomized controlled trial conducted by IARC in
Ambilikai in the Dindigul District (India). In study arm A, VIA screening was
offered to voluntary participating women whereas in the second group no screening
took place. VIA-positive women, in group A, were verified with colposcopy and
biopsies from colposcopically suspect areas. Women with colposcopically localized
cervical intra-epithelial neoplasia were treated on the spot with cryotherapy. Women
with more advanced disease were referred for appropriate treatment. Cancer and
mortality surveillance is organized similarly in both groups, by the Ambilikai Cancer
Register and mortality registries. The cumulative incidence of and mortality from
cervical cancer over ten years will be compared for the two study arms. The VIA
results and colposcopy and histology results of VIA-positive women enrolled in arm
A are already available and included in this meta-analysis. The Ambilikai study is the
first randomized trial ever conducted which will document effectiveness of cervical
cancer screening directly.

A fourth study was conducted by PATH (Seattle) in the Busia district, within the
Western Kenya Cervical Cancer Prevention Project. More than 2000 women were
screened at the local health center with VIA, and screen-positive women were referred
to the district hospital where two alternative triage methods were tested in parallel:
cytology and visual inspection with acetic acid using the Aviscope for magnification
(VIAM). All women presenting for triage were colposcoped as well. Women with a
colposcopy-based diagnosis of localized CIN were treated with cryotherapy. Treated
women were followed at 1-3 months and at 12 months after treatment to verify
secondary effects of cryotherapy and occurrence of residual/recurrent CIN. Outcomes
of the study were: positive predictive value of the screen test, performance of VIAM
and cytology to triage VIA-positive women; compliance of treated women with
follow-up procedures and the safety of VIA treatment. At the end of the study, VILI
was evaluated as well in a small subset of women as a screening test (at the health
center) and as a triage test (at the referral hospital).

The fifth and sixth studies were demonstration projects, conducted by JHPIEGO,
which were purposefully set up not to measure test accuracy parameters but safety,
acceptability and feasibility of cryotherapy offered to VIA-positive eligible women in
a single visit. Almost 6000 and 4000 women from Roi-et Province (Thailand) and
from Accra (Ghana), respectively, were screened with VIA. Non eligible women
were referred for further examination. VIA-positive women having received treatment
were interviewed about their experience and possible side-effects at and after
cryotherapy and were followed at 3 and 12 months after treatment.

We obtained the individual anonymized data files of all six studies described above.


2.2.2. Statistical analyses
The main test accuracy parameters – sensitivity, specificity, positive and predictive
value, prevalence of disease, detection rate of disease – could be evaluated for the first
two studies where all screened women were verified with a gold standard, assuming
that colposcopy followed by the histological examination of colposcopically oriented
biopsies provided perfect ascertainment of the cervical status.



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From the Ambilikai RCT and the Busia study, we could derive the positive predictive
value of VIA, the detection rate of disease and an approximated specificity. From all
six studies the test-positivity rate for the VIA-test could be evaluated.
Four levels of disease outcome were discerned: CIN I or worse (CIN1+), CIN2+,
CIN3+ and invasive cervical cancer.
Compliance with treatment recommendations could be addressed in the last four
studies and the occurrence of side-effects and the acceptability of cryotherapy can be
analyzed from the studies conducted in Kenya, Thailand and Ghana. In first set of
meta-analyses, data documenting the test characteristics of each separate test were
pooled and analyzed. Subsequently we computed the relative sensitivity and
specificity of each test compared to the other study tests. Random effect models were
used for pooling and forest plots were produced for all meta-analyses of test
parameters of all tests and outcomes. The simultaneous variation of sensitivity and
specificity was addressed by constructing summary ROC curves (sROC) and
computing the area under this sROC curve. The influence of study covariates on test
characteristics was studied graphically and by logistic regression using the individual
patient data and using age group, study phase and study location as co-variates.
Finally the multi-variate variation of the overall accuracy was analyzed using sROC-
regression analyses.


2.3. Results


2.3.1. Prevalence of cervical disease
The prevalence of cervical intra-epithelial neoplasia (CIN) could be assessed in the
first two studies. The prevalence of high-grade cervical disease (CIN2+) was
exceptionally high in Zimbabwe: 9.7% for CIN2+, whereas in the cross-sectional
multi-center study the prevalence of CIN2+ ranged only from 0.8% to 3.3%. In
general the prevalence increased slightly until the age of 50-54 and increased with a
steeper slope thereafter.


2.3.2. Test characteristics of the evaluated screening tests

Accuracy of VIA
The pooled sensitivity of VIA to detect presence of CIN2+ and CIN3+ was
respectively 79% (CI: 74% to 84%) and 83% (CI: 77% to 89%). Its specificity was
83% (CI: 79% to 87%) for CIN2+ and 84% (CI: 80% to 88%) for CIN3+. The pooled
predictive value of a positive VIA test was 12% (CI: 9% to 15%) if CIN2+ was the
considered outcome and 8% (CI: 5% to 9%)) if CIN3+ was the considered outcome.
The pooled predictive value of a negative VIA result was higher than 99% for both
outcomes. Important statistically significant inter-study variation was observed.
Visual inspection after application of Lugol’s iodine solution was 11% (CI: 5% to
17%) more sensitive to detect CIN2+ than after application of diluted acetic acid. For
CIN3+, VILI was 7% (CI: 4% to 11%) more sensitive than VIA.
VIA had a similar sensitivity and specificity as inspection assisted with a magnifying
device (VIAM). In these studies, VIA showed a higher sensitivity overall than the
HC2 for CIN2+ and CIN3+, but the difference was not statistically significant. On



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the other hand, the HC2 was 6% (CI: 3% to 9%) more specific for excluding CIN2+
and 8% (CI: 5% to 10%) more specific for excluding CIN3+ than VIA. It must be
remarked that these findings were dominated by results observed in India. In
Zimbabwe, HC2 showed an almost significantly higher sensitivity and lower
specificity for CIN2+ than VIA.
VIA was always more sensitive than the conventional Pap smear but this latter test, in
turn, was more specific. Accuracy differences between VIA and cytology (higher
sensitivity and lower specificity of VIA) were significant, with the exception of the
sensitivity when the cytological cutoff was ASCUS+ and the outcome was CIN3+.

Accuracy of VILI
The sensitivity and specificity of VILI as a screening test was only assessed by the
IARC. Of all evaluated tests, VILI showed the highest sensitivity: the pooled value
was 91% (CI: 88% to 95%) for CIN2+ and 94% (91% to 97%) for CIN3+. The
specificity of VILI was 85% (CI: 81% to 88%) when CIN2+ was the outcome and
84% (CI: 81% to 87%) when CIN3+ was the outcome. The PPV and NPV for the
same outcomes were respectively 13% (CI: 8% to 18%) and 99.8% (CI: 99.7% to
99.9%).
As mentioned above, VILI is more sensitive but equally specific compared to VIA.
VILI was more sensitive than the HC2 (ratio = 1.20; CI: 1.06-1.35) for CIN2+. There
was no statistically significant difference between VILI and HC2 when CIN3+ was
considered in the three Indian settings where both screening tests were performed.
The specificity of VILI was significantly lower than that of HC2 for both CIN2+ and
CIN3+. VILI always was more sensitive but less specific than cytology at whatever
cytological cutoff.

Accuracy of VIAM
As mentioned VIAM showed accuracy values which did not differ from those of VIA.

Accuracy of the Hybrid Capture II assay
The pooled sensitivity for high-grade CIN was unexpectedly low compared to
previously published studies [summarized by Lorincz, 2003 and Franco, 2003]. It
was 66% (CI: 62% to 77%) for CIN2+ and 68% (CI: 62% to 75%) for CIN3+. The
sensitivity for CIN2+ was homogeneously low in the four Indian settings where the
HC2 was evaluated (62%; CI: 56% to 68%), whereas, in Harare, it was 80% (CI:
74.1% to.85.4%). The specificity of HC2 for CIN2+, pooled for the four Indian
settings, was 94% (CI: 92% to 95%). In Harare, it was only 61% (CI: 59% to 63%).
The PPV of HC2 varied between minimally 9% (in Kolkata 1) and maximally 18%
(in Zimbabwe). The range of the NPV was situated between 96.7% and 99.7%.
HC2 showed a higher pooled sensitivity for CIN2+ than cytology, even at cutoff
ASCUS+. In the four Indian settings this difference was insignificant, but in Harare it
was significant. HC2 showed a significantly higher pooled specificity than cytology.
In Zimbabwe, HC2 showed a significantly lower specificity.

The accuracy of the Pap smear
The pooled sensitivity of the Pap smear changed by cytological cut-off: at ASCUS+ it
was 58% (CI: 44% to 73%) for CIN2+ and 63% (CI: 38% to 88%) for CIN3+; at
LSIL it was 50% (CI: 33% to 67%) for CIN2+ and 56% (CI: 33% to 80%) for CIN3+,
at HSIL it was substantially lower: 38% (CI: 22% to 54%) for CIN2+ and 52% (CI:
32% to 71%). Due to large interstudy heterogeneity, these differences were


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insignificant. On the contrary, the specificity increased significantly by cytological
cut-off: at ASCUS+ it was 90% (CI: 86% to 94%) and at HSIL it was 99.1% (98.6%
to 99.5%) for the outcome of CIN2 or worse. The specificity for CIN3+ did not
change by cytological cut-off.
The pooled positive predictive value of the Pap smear for the outcome CIN2+ using
the cut-off HSIL (56%, 35% to 77%) was higher than when the cut-off ASCUS (21%,
CI: 13% to 29%) was used.
The NPV always was higher than 98% in spite of the rather low sensitivity.
Among all evaluated screening tests, cytology had the lowest sensitivity for all
degrees of CIN. Only for the comparison with HC2 assay was the difference not
significant. On the other hand, cytology was the most specific test. Only when
ASCUS was the cut-off, and when compared with the HC2 test, was the difference in
specificity not significant.

Test positivity rate
The range of variation in VIA test positivity rate was wide: from 6% in Amasaman
(Ghana) to 40% in Harare (Zimbabwe). The VILI test positivity rate ranged from 9%
to 29%. The HPV test positivity rate varied between 6% and 9% in the Indian settings
but was 43% in Harare. The test positivity rate of all visual tests varied considerably
by age group, study phase and setting. The variation in VIA test positivity by age
group was inconsistent: it increased significantly in certain settings, whereas in others
it decreased or remained rather constant, or changed following a "V" or inversed-"V"
shape curve. Three periods were defined using tertiles of the screening dates.
Important period effects were observed for the visual inspection methods, in particular
for VIA and for cytology. Remarkable was the absence of a period effect in the HPV-
test positivity rate.

Summary ROC curve (sROC)
An overall summary measure of test accuracy, the area under the sROC curve, was
not different for VIA and VILI. However, given the restricted range of VILI points,
the sROC curve could not describe VILI accuracy appropriately. No sROC curves
could be constructed for the other tests because of insufficient points.


2.3.3. Influence of study characteristics on test accuracy
By logistic regression the multivariate effects of age group, study period and setting
on the PPV (14 locations) and on sensitivity and specificity (12 settings) for CIN2+
were analyzed. In general, the PPV increased with age and period and varied further
by location. The PPV of HC2 did not vary by period.
Age did not influence the sensitivity for CIN2+ of the screening tests, with the
exception of the Pap smear. Period had an effect only on the sensitivity of VIA. The
sensitivity always varied by study setting. The sensitivity of VILI was lower in the
Indian settings, compared to the African settings.
Age, period and setting always influenced the specificity for CIN2+, with the
exception of the HC2 assay, which was not influenced by period. For all other tests,
the specificity increased by period.
The influence of study characteristics on the diagnostic odds ratio, an accuracy
measure that integrates sensitivity and specificity, was assessed by sROC regression.
The S term always was significantly different from zero, indicating change of
accuracy by degree of positivity of the screen test. Age never was influential. The


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diagnostic odds ratio (DOR) always was higher in the second or third period
compared with the first, with the exception of the HC2 test. High DOR-values for
VIA (considering CIN2+ as outcome) were observed in Conakry and Bamako, where
at the same time high sensitivities and specificities were found. Visual screening
methods (VIA, VIAM, VILI) always had higher DOR values in Kolkata 2 and
Trivandrum 2 compared to Kolkata 1 and Trivandrum 1.


2.3.4. Triage of VIA-positive cases
One of the purposes of colposcopy triage is to reduce the number of women needing
treatment. The low-grade colposcopy rate among VIA-positive women varied widely
from 40% to 93%. Its pooled value was 65% (CI: 54% to 76%). This means that, on
average, the number of treated women could be decreased by 35% in a "see-triage-
treat" strategy compared with a "see & treat" strategy. The pooled PPV of VIA
testing could be increased by adding colposcopy triage by a factor 1.59 (CI: 1.48-
1.64) when CIN2+ was the outcome, but only by a factor of 1.13 (CI: 1.03 to 1.18)
when CIN3+ was the outcome.
Only in Busia (Kenya) were alternative triage methods evaluated. Cytology appeared
to be unacceptable, because it showed, at cutoff ASCUS+, only a moderate sensitivity
(72%) and low specificity (49%) for the outcome CIN2+. VIAM had a higher
sensitivity (92%) but a lower specificity (40%). VILI showed the best triage results
(100% sensitivity and 76% specificity), but this was evaluated only on a small group.
Triage was offered only at the referral hospital, which yielded a drop out of 36% of
VIA+ cases.


2.3.5. Cryotherapy: compliance, acceptability and safety
More than 80% of women with known CIN2+ status in Ambilikai and Busia got
treatment. In Thailand and Ghana more than 90% of VIA-positive women were
treated. Ninety-one percent of treated women in Ambilikai were treated with
cryotherapy. Among women receiving cryotherapy, between 71% and 82% were
treated on the same day.

Cryotherapy offered to VIA-positive women immediately after screening is highly
accepted and quite safe. Pain during or just after cryotherapy was the most noticed
secondary effect (40% in Thailand, 23% in Ghana), which was most often mild (79%
in Roi-Et and 86% in Accra), and only in 2% (Roi-Et) and 3% (Accra) was it severe.
In 2% of treated women some minor blood loss occurred. In Thailand, 83% and 93%
of treated women presented at the follow-up visits at respectively 3 and 12 month
after treatment. In Ghana these proportions were 77% and 55%.


2.4. Conclusions
An enormous quantity of new information has now become available from the ACCP
research projects analyzed in this report, which provides insight into two important
aspects of cervical cancer screening in developing countries: the cross-sectional test-
accuracy of five screening tests and the feasibility, acceptability and safety of
immediate treatment of women who are positive at visual cervical inspection. Meta-
analytical pooling allowed us to formulate the following conclusions:



                                                                                    13
•   Direct visual inspection of the cervix after application of acetic acid solution
    or Lugol’s iodine allows detection of cervical cancer precursors with an
    accuracy that is as good as or even better than the standard Pap smear or
    testing for presence of DNA from high-risk human papillomaviruses with the
    Hybrid Capture II assay.
•   Direct visual inspection of the cervix after application of Lugol’s-iodine
    (VILI) is 10 % more sensitive but equally specific in detecting high-grade
    cervical intra-epithelial lesions as application of dilute acetic acid (VIA). The
    test characteristics varied widely between the settings and between the start
    and end phase of the studies, which might reflect low reproducibility and
    which underlines the need for training and continuous supervision.
•   The use of a magnifying device does not improve the accuracy of the visual
    interpretation.
•   The Hybrid Capture II assay (HC2) showed an unexpectedly low sensitivity,
    which is in conflict with previously published results. Nevertheless, the
    variability of the test results between the study locations and the study periods
    was limited, suggesting high reproducibility. The reason for its low sensitivity
    must be explored before conclusions can be drawn concerning the
    performance of the HC2 test.           Currently existing HPV DNA detection
    methods are nowadays still expensive and require laboratory infrastructure and
    appropriate logistics.
•   Among all evaluated tests, cytology showed the lowest sensitivity, which is in
    agreement with the documented very wide variation of the accuracy of this
    test. Moreover, cytology is not highly reproducible, it does not allow an
    instantaneous diagnosis, and it requires important resources for training and
    logistics.
•   By colposcopy or other visual triage, the number of women needing treatment
    can be reduced and targeted biopsies can be taken for a definitive diagnosis.
    Nevertheless, throughout the ACCP studies, the triaging performance varied
    widely. When triage is only available at distance from the screening place, an
    important drop out of patients can be expected.
•   Therefore "see and treatment" options are important to maximize treatment
    compliance. The experiences from the demonstration projects in Thailand and
    Ghana indicate that immediate cryotherapy of VIA-positive women is
    accepted by women and their partners and only causes limited side effects.




                                                                                  14
3. Introduction
Cervical cancer is the second most common cancer in women worldwide and is the
most common female cancer in Central America, Sub-Saharan Africa, South-Central
Asia and Melanesia. It is estimated that, in 2002, approximately 493,000 women
developed cervical cancer and that 273,000 died from the disease [Ferlay, 2004].
83% of all cervical cancers occur in developing countries. The disease primarily
affects younger women with the majority of cases appearing between the ages of 30
and 50, an age when many women are actively involved in their careers or caring for
their families [Yang, 2004]. Nevertheless, among all malignant tumors, cervical
cancer is the one that is most easily preventable by screening. The detection of
cytological abnormalities by microscopic examination of Pap smears, and the
subsequent treatment of women where cytological abnormalities are high-grade,
avoids development of cancer [Miller, 1993]. Through well-organized cytological
screening at the population level, every three to five years, the incidence can be
reduced up to 80% [Expert team cervical cancer screening, 2005]. In industrial
countries, incidence of and mortality from cervical cancer dropped dramatically, most
probably as a consequence of cytological screening [Bray, 2005; Devesa, 1987].
However, in only a few of them-such as the Nordic countries, the United Kingdom
and the Netherlands--is cytological screening well organized [Anttila, 2004]. In most
other countries, screening is opportunistic, depending on the initiative of the
individual woman or her doctor. Such opportunistic screening is most often
characterized by a high coverage in selected parts of the population with screening
done too frequently, coexisting with a low coverage in lower socio-economic groups
and heterogeneous quality, which results in poor cost-effectiveness [van Ballegooijen,
2000; van den Akker-van Marle, 2002; Miller 2002].

It is nowadays widely recognized that policies calling for repetitive cytological
screening and prolonged surveillance of screen-positive women are difficult to realize
in developing countries, because of financial, technical and human constraints.
Therefore alternative test methods are being investigated which might perform as well
as or even better than the Pap smear but be more affordable, applicable and acceptable
in wide ranges of settings in the low-resource countries [Miller, 2000]. Swabbing the
cervix with 3 to 5% acetic acid (VIA) turns cervical intra-epithelial abnormalities
white, and detection of such aceto-white lesions by visual inspection might be a useful
alternative screening test. It is cheap and can be applied by local health workers after
a few weeks of training. Visual inspection with Lugol’s iodine (VILI) can be used as
well [Sankaranarayanan, 2003c]. In this case yellow non-iodine uptake areas are
indicative of cervical lesions. The cervix can be inspected with the naked eye or
using a low-level magnifying device (VIAM). The establishment of the evidence that
oncogenic types of the human papillomavirus are a necessary but insufficient
condition for the development of virtually all cervical cancers has resulted in the
development of HPV DNA detection methods [Bosch, 2002; 2003]. The Hybrid
Capture II assay (Digene Corp., Gaithersburg, MD, USA) is, nowadays, the only
USFDA approved commercially available HPV DNA detection test applicable in
cervical cancer screening [Lörincz, 1997].
In order to avoid development of cancer, screen-detected intra-epithelial lesions with
potential of progression must be treated. Several excisional or ablative techniques
exist, and all are believed to be equally effective in treatment of localized CIN


                                                                                     15
[Mitchell, 1998; Martin-Hirsh, 2000]. Among all, cryotherapy appears the most
appropriate method for treatment of localized cervical lesions in low-resource
settings, since it requires only limited equipment and is easy to handle by mid-level
health workers.

In 1999, the Bill & Melinda Gates Foundation awarded US$50 million to a group of
international research organizations through the Alliance for Cervical Cancer
Prevention (ACCP). A series of large-scale studies were set up between 1999 and
2004 to assess new screening and treatment approaches and technologies appropriate
to low-resource settingsa.

The current report pools the study results obtained from three ACCP partners: IARC,
JHPIEGO and PATH.
The main aims of the current pooled analysis are the estimation of the test accuracy of
five cervical cancer screening techniques: the visual inspection methods (VIA, VILI
and VIAM), the cytological examination of the conventional Pap smear and HPV
DNA detection using the Hybrid Capture II (HC2) test; the evaluation of alternative
triage options for management of screen-positive women; and finally the assessment
of the feasibility, acceptability and safety of immediate cryotherapy offered to women
with a positive VIA test.




a
    ACCP (Alliance for Cervical Cancer Prevention): see http://www.alliance-cxca.org/


                                                                                        16
4. Material and methods

4.1. Conducted studies

We obtained data files including the individual records of more than 106,000 women,
from six studies conducted at 19 settings in 10 countries in Asia and Africa (see map
in Table 1 and Figure 1).

Table 1. Study size, location of settings and coordinating agency of the six studies included in the
pooled analysis.
     Study                      Location               Country                       N    Coordinating
                                                                                          agency
1.   Multi-center cross-        11 urban settings      Burkina-Faso,            58,679    IARC
     sectional study                                   Congo, Guinea, Mali,
                                                       Niger, India
2.   Zimbabwe cross-            Chitungwiza &          Zimbabwe                  2,206    JHPEIGO
     sectional study            greater Harare
                                area
3.   Ambilikai RCT              Rural area in          India                    31,317    IARC
                                Dindigul district
4.   WKCCPPa                    5 rural divisions      Kenya                     2,295    PATH
                                in Busia district
5.   Thai demonstration         4 rural districts in   Thailand                  5,999    JHPEIGO
     project                    Roi-Et Province
6.   Ghanaian                   Accra                  Ghana                     3,665    JHPEIGO
     demonstration project      Metropolitan area
7.   Amansaman                  Amansaman, rural       Ghana                     3,206    JHPEIGO
     demonstration projectb
     Total                                             10 countries            106,626

Throughout the meta-analysis we will rank the study settings by study and within the
study by alphabetic order of the setting, as following:
    • Multi-center study: (1) Bamako, (2) Brazzaville, (3) Conakry,
       (4) Jaipur, (5) Kolkata-1, (6) Kolkata-2, (7) Mumbai, (8) Niamey,
       (9) Ouagadougou, (10) Trivandrum 1, (11) Trivandrum 2
    • Zimbabwe study: (12) Harare
    • Ambilikai RCT: (13) Ambilikai
    • WKCCSP: (14) Busia
    • Thai demonstration project: (15) Chaturapakpiman ,(16) Kasetwisai,
          (17) Pathumrat, (18) Phanomphrai
    • Ghanaian demonstration project: 19) Accra.

The six studies are described separately in the following subchapters.




a
 WKCCPP: Western Kenya Cervical Cancer Prevention Project.
b
 The Amansanan data file will be included a posteriori once the completed cleaned data file will
become available.


                                                                                                       17
                                                                           Jaipur
                                                                                    Calculta

            Bamako
                      Niamey
                                                                           Dindigul            Roy Et
                 Ouagadougou
                                                                   Trivandrum
 Conakry

             Accra
                                              Busia

                 Brazzaville




                                     Harare




Figure 1. Study locations in 10 countries where the ACCP studies were conducted included in this
pooled analysis. In red: studies coordinated by IARC: Bamako (Mali), Brazzaville (Congo), Conakry
(Guinea), Niamey (Niger), Ouagadougou (Burkina Faso), Calcutta, Dindigul [Ambilikai], Jaipur and
Trivandrum (India); in green: study conducted by PATH: Busia (Kenya); in blue: studies conducted by
JHPIEGO: Harare (Zimbabwe), Accra (Ghana) and Roi-Et (Thailand).




4.1.1. Cross-sectional multi-center study of the test accuracy of
       VIA, VIAM, VILI, cytology and the HC2 assay

Study design:
A cross-sectional study was conducted in 11 centers and consisted of concomitant
testing with VIA, VILI, VIAM, the Pap smear and the Hybrid Capture II Assay. VIA
was evaluated in all centers, VILI in 10 centers, VIAM in 3, conventional cytology in
5 and the HC2 assay in 4 centers. Screening tests were followed by colposcopy in all
women. Punch biopsies were taken from colposcopically suspect areas. The
histological result of the biopsy or, if absent, the colposcopic interpretation was
considered as a combined gold standard (assuming 100% accurate). Different health
workers, blinded to the results of the other tests, performed all tests. Since the gold
standard is applied to all study subjects, the accuracy for CIN or cancer can be
evaluated without verification bias.




                                                                                                        18
Sample size:
Table 2. Tests evaluated and sample size by setting involved in the multi-center cross-sectional study.

                                                                    Number of
Center              Country        Tests evaluated                women included
Bamako              Mali           VIA, VILI                          5552
Brazzaville         Congo          VIA, VILI                          6935
Calcutta 1a         India          VIA, VIAM, Cytology, HC2           5894
Calcutta 2          India          VIA, VILI, VIAM, HC2               8080
Conakry             Guinea         VIA, VILI                          8627
Jaipur              India          VIA, VILI, Cytology                5786
Mumbai              India          VIA, VILI, VIAM, Cytology, HC2     4004
Niamey              Niger          VIA, VILI                          2534
Ouagadougou         Burkina Faso   VIA, VILI                          2051
Trivandrum 1        India          VIA, VILI, Cytology                4457
Trivandrum 2        India          VIA, VILI, Cytology, HC2           4759
Total                                                                58,679

Time period:
Between 1999 and 2003.

Setting and characteristics of the study population:
Unscreened population from urban areas in India and five African countries (see
Table 2). Women were between 25 and 65 years old.

For more details on the study population, the health workers performing the tests and
the technical aspects of the tests, we refer to a series of previous publications
[Sankaranarayanan 2003b, 2004a, 2004c, 2004d, 2004e].




4.1.2. Cross-sectional study on the test accuracy of VIA, cytology
       and the HC2 assay in Zimbabwe
Study design:
Participants in this cross-sectional study were invited to a health education talk on
cervical cancer and were screened with three tests: VIA, the Pap test and the Hybrid
Capture II assay. In Phase II of the study all women were examined by colposcopy
and biopsies were taken in colposcopically suspect areas, so that sensitivity and
specificity could be evaluated without verification bias, assuming 100% accuracy for
the applied gold standard. The outcome thresholds were CIN1+ and CIN2+. Data
from phase I of the study were not included in this meta-analysis, because of the
occurrence of verification bias. In phase I, diagnosis was supposed to be conducted
for all screen-positives and a random fraction of screen-negatives, but due to
circumstances the fraction of screen-negative women being verified was not random.

a
    Throughout the study we use the Indian name for Calcutta: "Kolkata".


                                                                                                     19
Sample size:
2205 women in phase II of the study.

Time period:
The study took place between October 1995 and August 1997.

Setting and characteristics of the study population:
The participants were women, 25-55 years old, consulting at one of 15 primary health
care clinics in Chitungwiza and greater Harare area. Pregnant women, women having
a history of cervical cancer and hysterectomized women were excluded. More details
can be found in four publications from the University of Zimbabwe/JHPIEGO [1999],
Blumenthal [2001] and Womack [2000a; 2000b].




4.1.3. Randomized trial: VIA screening versus no screening in rural
       South India

Study design: cluster-randomized screening trial
Villages were randomized into two arms: women in villages of group A were offered
VIA testing, followed by verification of VIA+ cases with colposcopy and punch
biopsies if colposcopically suspect. Women with localized CIN were offered
cryotherapya, and women with more extended disease were referred to the hospital for
treatment with LEEP or cold knife conization; specific oncological treatment was
provided in case of cancer. No screening was given to women in villages from group
B.
Incidence of invasive cervical cancer and mortality from cervical cancer are the final
outcomes of the study. Cancer and mortality surveillance is organized similarly in
both groups, by the Ambilikai Cancer Register and mortality registers.

VIA screening, colposcopy and biopsies were performed by nurses trained to perform
the examinations under the supervision of physicians. Histological examination of the
punch biopsies was performed by pathologists.

Process indicators in group A:
   - Participation rate among the eligible population
   - Follow-up compliance of screen positives
   - Treatment compliance among women referred for treatment.
   - Compliance with post-treatment follow-up at 1 year after treatment.

Intermediate outcomes in group A are:
    - Test positivity rate
    - Detection rate of confirmed CIN or cancer at screening


a
 Local CIN: <3/4 of the TZ involved; not extending to endocervical canal or vaginal wall, whole lesion
could be covered by the nipple of the cryoprobe.


                                                                                                   20
    -   Program sensitivity (proportion of cancers detected at screening among all
        cancers detected in the whole follow-up period).

Intermediate outcomes in group A and B are:
    - Stage distribution at diagnosis of cancer.
    - Survival from cancer.

Initial available results concern the screen test results, the colposcopic and
histological verification of VIA+ cases, and the incidence of cervical cancer in the
short-term follow-up period.
This trial will be the first randomized study ever conducted that will yield a direct
estimate of the reduction in incidence of and mortality from cervical cancer as a
consequence of screening and management of screen-positive women.

Sample size:
Group A: 57 clusters, 48 225 women included among whom 30 577 were screened.
Group B: 56 clusters, 30 167 women

Time period:
Recruitment: 1999-2003.
Follow-up: 2003-2012.

Characteristics of the study population:
Age: 30-59 years.
Location: Ambilikai area in Dindigul District (South India).
Rural never screened population.

For more details, we refer to a publication in the International Journal of Cancer
[Sankaranarayanan, 2004c].



4.1.4. Western Kenya Cervical Cancer Prevention Project
Study design:
Women were screened at the health center with VIAa. Screen-positive women were
referred to the district hospital, where they received 3 triage tests: VIAM with the
AviScope, a Pap test and colposcopy. Different providers performed VIAM and
colposcopy. The providers were family planning nurses or clinical officers previously
trained in both visual cervical inspection techniques. Punch biopsies were taken,
when there was a colposcopic impression of CIN. Endocervical curettage was
performed when it was difficult to see the upper border of the cervical lesion.
Immediate cryotherapy was offered to colpo-positive cases. Pap smears were
processed in the district hospital and along with the biopsies were sent initially to the
provincial hospital of Kisumu for interpretation by cytotechnicians and pathologists
and later to a private pathologist in Nairobi. The pathologists were blinded to
screening tests results. The Bethesda System (version 1991) was used for reporting
the Pap smear results and the CIN classification was used for reporting the

a
 At the end of the study, a group of women was also screened with VILI and the VILI results were
used to determine referral to the district hospital.


                                                                                                   21
histological results. Women treated with cryotherapy were invited to return for
follow-up at 1-3 months (when cytology and biopsy results were available) and for a
final visit at 12 months. The main outcomes were:
    • Accuracy of VIA for different degrees of CIN in a small subset of 133 women
        receiving all expert colposcopy (by Dr. E. Kauffman) irrespective of screen
        test results.
    • PPV of the screen test for different degrees of CIN.
    • Differences in accuracy of triage methods, using the biopsy result and, if
        colposcopy was negative, the colposcopy result as gold standard.a
    • Compliance of screen positives with referral and follow-up
    • Safety of cryotherapy and outcome of treated lesions.

Sample size:
2295 were screened with VIA and 137 among them also with VILI. 116 women
received cryotherapy.

Time period:
Screening took place between November 2000 and March 2004. Before Spring 2005
all treated women could be expected to have undergone follow-up visit.

Setting and characteristics of the study population:
Women from a rural area, in the Busia District (Western Kenya), in the age range 29-
40 years.




a
    Expert colposcopy results were used as gold standard if available.


                                                                                 22
4.1.5. Safety, acceptability, and feasibility of a single-visit approach
       to cervical cancer prevention in rural Thailand

Study design:
Enrolled women were tested by VIA. VIA-positive women were offered immediate
cryotherapy, if eligible, after counseling about the benefits, potential risks, and
probable side-effects. Treated women were followed at 3 and 12 months after
treatment to assess safety, acceptability of cryotherapy. Compliance with hygiene and
follow-up instructions was an additional outcome measure. The test positivity rate
and the proportion of test-positives that are not eligible for treatment are also
documented.

Sample Size:
5999 women were tested by VIA. 756 women received cryotherapy.

Time period:
Women were enrolled in the period February – November 2000; treated women were
followed at 12 months.

Setting and characteristics of the study population:
Twelve trained nurses provided services in mobile (village health center-baseda) and
fixed (hospital-based) teams in four rural districts of Roi-et Province (Thailand)
Women were in the age range 30-45 years.



4.1.6. Safety, acceptability, and feasibility of a single-visit
      approach to cervical-cancer prevention in Ghana
Study design:
The study enrolled women, consulting at the hospital. They were tested with VIA by
trained health workers. Many came to the facility specifically for testing based on
word of mouth information from family members or friends. VIA-positive cases were
offered immediate cryotherapy or referral if indicated. The study design was similar
to that of the Thai demonstration project (see 4.1.5) and is further explicated in the
flow chart in Figure 2 [Gaffikin, 2004].
Contra-indications for immediate treatment were: suspicion of cancer, large lesions
extending onto the vaginal wall or occupying >3/4 of the cervix, extending 2mm or
more beyond the cryoprobe, cervicitis, polyps.
Women with cervicitis were reassessed after antibiotic treatment. Women suspect for
having cervical cancer or with large lesions were referred for evaluation with biopsies
and were offered appropriate treatment. Women, receiving cryotherapy were amply
informed about expected side effects and alarm signals requiring further care. They
were counseled to abstain from sexual relations for 1 month. If sexual abstinence was
not possible, condom use was recommended and a supply of condoms was offered.




a
    Mobile teams: services provided by a trained team from the fixed site.


                                                                                    23
Figure 2. Flow chart diagram applied in the SAFE project (extracted from Gaffikin, 2004).


Sample Size:
3665 women were tested with VIA.a




a
 A second similar study was conducted in the rural Health Centre of Amansaman. Three thousand two
hundred and six were tested with VIA. The Amasaman data files could not be analysed as the data had
not been fully cleaned at the time of this analysis.


                                                                                                24
Time period:
Women were enrolled during an 18-month period (March 2001-August 2002); treated
women were followed at 12 months.

Setting and characteristics of the study population:
The target population was restricted to women in the age range 25-45 years.
Enrolment took place in the family planning clinic in the Ridge Hospital, an urban
regional hospital located in the Accra Metropolitan Area of the Greater Accra Region
in Ghana. Total hysterectomy, history of cervical cancer and pregnancy (based on
clinical examination) were exclusion criteria for participation.


4.2. Methods

Addressed study questions
What is the accuracy of five cervical cancer screening tests to detect different degrees
of cervical cancer or cervical cancer precursors? This question was the focus of the
first two studies. The evaluated tests were: VIA (naked eye visual inspection after
application of 3-5% acetic acid); VIAM (visual inspection after application of acetic
acid solution using a magnifying instrument); VILI (naked eye visual inspection of
the cervix after application of Lugol’s iodine); cytological examination of a Pap
smear; high-risk HPV DNA detection using the Hybrid Capture II assay [Lörincz,
1997].

What is the test positivity rate and does this vary through the different studies? This
question could be addressed in all included studies.

How accurate are triage tests applied to VIA-positive women? The evaluated triage
methods were: cytological examination of a Pap smear, VIAM, VILI, and colposcopy.

What was the treatment compliance of women referred for treatment?

What is the safety and acceptability of cryotherapy applied to VIA-positive women or
women with colposcopic confirmation of CIN?

Definition of disease
Four levels of prevalent disease are distinguished throughout this pooled analysis:
cervical intra-epithelial neoplasia grade I (CIN 1), CIN 2, CIN 3, and invasive
cervical cancer [Richart, 1973]. High-grade CIN is used for the lumping of CIN2 and
CIN3.

Definition of test positivity
VIA or VIAM positivity is defined as: presence of opaque, dull, well-defined
confluent acetowhite lesions touching the squamo-columnar junction (SCJ) or close to
the external ostium uteri or surrounding the os; presence of warts and leukoplakia
turning acetowhite. Dense, opaque aceto-white visible ulceroproliferative growth
indicates lesions that are compatible with suspicion of cervical cancer. VILI positivity
was defined as: presence of well-defined, dense, yellow non-iodine uptake areas in the
transformation zone touching the SCJ, or, circumorificial area occupying a large
portion of the cervix, or ulceroproliferatrive growth on the cervix turning yellow after


                                                                                     25
application of Lugol’s iodine [Sankarananarayan, 2003b; Sankarananarayan, 2004c;
Sankaranarayanan, 2000].
For cytology, the three-tier classification of Bethesda (1991) was applied: atypical
squamous cells of unspecified significance (ASCUS), low-grade squamous intra-
epithelial lesion (LSIL) and high-grade squamous intra-epithelial lesion (HSIL)
[Lundberg, 1989; Luff, 1992].
For the detection of DNA of 13 high-risk human papillomaviruses, the Hybrid
Capture II assay was used. Positivity in all included studies was defined as RLU
(relative light units)>1, which is the standard criterion proposed by the manufacturer.
This cut-off corresponds with presence of more than 1pg of HPV DNA/pg.

We always dichotomized test results in our statistical analysis. For instance: "LSIL+"
means: a cytological result compatible with LSIL, HSIL or cancer.

Evaluated test parameters
We have assumed that colposcopy followed by the histological examination of punch
biopsies provided complete ascertainment of the true cervical status. We did not deal
with potential misclassification due to potential imperfect gold standard verification.

Under this assumption we were able to compute the following test characteristics for
the two first studies (the cross-sectional multi-center and the Zimbabwean trials):
sensitivity, specificity, the negative and predictive values. We refer to previous work
[Arbyn, 2002] and standard epidemiology handbooks for the definition of these
parameters. Further, for these studies, we can compute: the test positivity rate, the
prevalence of disease and the detection rate of disease. The detection rate of disease
is the proportion of the true positives among all tested subjects, which equals the
product of the test sensitivity and the prevalence of disease.

An overall test accuracy parameter, integrating sensitivity and specificity, is the
diagnostic odds ratio (DOR).
         OddsTPR       Sensi (1 − Sensi )         Sensi * Speci
DOR =                =                    =                           .
         OddsFPR       (1 − Speci) Speci    (1 − Sensi) * (1 − Speci)
The logarithm of the DOR is the outcome of summary ROC-curve regression analysis
[Moses, 1993; Pepe, 2003].


In the Ambilikai trial and the Kenya study, verification was limited to VIA-positive
cases. In this circumstance we can only compute the test positivity rate, the positive
predictive value and the detection rate of disease. In this situation, sensitivity and
specificity cannot be computed anymore, since it requires verification of at least a
random sample of test negative subjects. Nevertheless, an approximated specificity
can be computed. The approximated specificity is defined as the number of test-
negatives divided by the total number of tested cases from which the number of true
positive cases is subtracted.
                    # negative cases
Specificityapprox =                  . Using the conventional 2x2 contingency table,
                         N - # TP
where a = #TP, b = #FP, c = #FN and d = # TN, the approximated specificity
=(c+d)/(c+b+d); whereas the real specificity = d/(b+d). This approximated specificity
is an acceptable proxy for the real specificity when the prevalence of disease is low



                                                                                    26
(<10%a), the sensitivity is high and/or the specificity is high. In these situations the
value of "c" becomes so small that it can be ignored.

The demonstration projects conducted in Thailand and Ghana, were not set up to
study test accuracy. Nevertheless, information of the VIA-test positivity rates can be
derived from both studies.



4.3. Statistical analyses

Pooling methods
The common variables and data values in all data files were recoded into identical
variables and files were merged.
We used random-effect meta-analytical methods to pool test accuracy measures from
the different study sites for each category of CIN [Sharp, 1997; Sutton, 2000]. Such
methods allow for inter-study heterogeneity, which is very common in diagnostic
research. Two types of meta-analyses are performed: (1) pooling to the accuracy of
separate tests and (2) pooling of the relative sensitivity and specificity of one test
compared to another test.

Regression models
We applied a logistic regression model on the pooled individual patient files to
explore the multi-variate impact of study characteristics on the positive predictive
value, the sensitivity and the specificity [Hosmer, 1989]. From the estimated constant
in the logit-transformed regression equation we could compute the studied accuracy
parameter. For instance, the PPV of the basic or reference case is computed as:
           e b0
PPV0 =            , where b0= is the constant term of the logistic regression equation.
         1 + e b0

Most logistic software packages provide odds ratios (OR) for the respective
categories.
We transformed these odds ratios into relative risks (RR) using the following formula:
                 ORi                           e ( b0 + bi )
RRi =                           .where ORi =                 and bi is the coefficient of the
        (1 − PPV0 + PPV0 .ORi )                   e b0
logistic equation term corresponding with a certain category i [Zhang, 1998; McNut,
2003].
This computed RRi has a straightforward interpretation: the PPVi is RRi times that of
PPV0.


The summary Receiver Operating Characteristic (ROC) Curve allows simultaneous
consideration of sensitivity and specificity of a diagnostic test assessed in a number of
independent studies [Moses, 1993; Irwig, 1994; Irwig, 1995].
A fitted ROC curve is obtained by applying the following steps:

a
  When the prevalence is low, the term c is automatically low as well since it represents only a part of
the subjects with disease. When sensitivity is high, the FNR (and so also c) must be low. When
specificity is high the weight of term d increases.


                                                                                                       27
   1. Fit a linear regression for D as dependent variable and S as explanatory
      variable, where D and S are respectively the difference and the sum of the
      logits of the sensitivity and the FPR (=1-Specificity).

              D = a + b* S
                     ⎛ Sensitivity ⎞            ⎛ (1 − Specificity ) ⎞
               D = Ln⎜
                     ⎜ (1 − Sensitivity ) ⎟ − Ln⎜ Specificity ⎟
                                          ⎟     ⎜                    ⎟
                     ⎝                    ⎠     ⎝                    ⎠

                     ⎛ Sensitivity ⎞            ⎛ (1 − Specificity ) ⎞
               S = Ln⎜
                     ⎜ (1 − Sensitivity ) ⎟ + Ln⎜ Specificity ⎟
                                          ⎟     ⎜                    ⎟
                     ⎝                    ⎠     ⎝                    ⎠

       The parameter D is equivalent to the log of the diagnostic odds-ratio (odds of a
       positive result among women with, for instance, CIN2+ to the odds of a
       positive test among women without CIN2+).
       S is a proxy for the test threshold; b1 is the slope and b0 the intercept of the
       linear regression equation. If b1 does not differ significantly from zero, then
       D=b0.
       In this case, a single constant odds ratio defines a single symmetric SROC.
       When the slope b1 is not different form zero, the odds ratio depends on the
       threshold yielding an asymmetric summary ROC curve [Glasziou, 2001].
       Covariate variables can be included in the linear model allowing explanation
       of the variation of sensitivity and specificity by study characteristics.

   2. Back transform the results into the ROC space where sensitivity is plotted
                                                                                     ^
       against FPR (=1-specificity). The relation between the fitted sensitivity ( Se )
       and the false positive rate can be obtained as follows, from the estimated linear
       regression parameters b0 and b1:

                   ⎡ (b + logit(FPR)(1 + b ) ⎤
               exp ⎢ 1                     0 ⎥
                   ⎢         (1 − b )        ⎥
        Se =
         ˆ         ⎣               0         ⎦
                     ⎡ (b + logit(FPR)(1 + b ) ⎤
             1 + exp ⎢ 1                    0 ⎥
                     ⎢        (1 − b )         ⎥
                     ⎣               0         ⎦
The regression equation can be extended by inclusion of covariates:
D= b0 + b1S + BaX+ BpY + BlZ, where b0 is the intercept, b1 is the slope of the
relation between D and S, S is the sum of logit of the TPR and the FPR; Ba, Bp and Bl
are the column vectors containing the coefficients corresponding to the age, period
and location categories.

Statistical software
Statistical analyses were performed with software package STATA, version 7 and 8
(Stata Corp., College Station, Texas, US).




                                                                                     28
5. Results of the separate studies

5.1. Cross-sectional multi-center study on the test accuracy of
     VIA, VIAM, VILI, cytology and the HC2 assay


5.1.1. Test accuracy of VIA and VILI for CIN2+
The forest plots in Figure 3 display the variation of the sensitivity and specificity of
VIA or VILI, considering CIN2 or worse disease as outcome. The sensitivity of VIA
varied between 61.5% (CI= 53.5% to 69.0%), in Calcutta 1, and 91.1% (CI: 85.7% to
94.9%) in Conakry. The pooled sensitivity was 79.2% (CI= 73.3% to 85.0%). The
minimal specificity of VIA (74.2%; CI= 72.2 to 76.1) was observed in Ouagadougou,
and the highest specificity (93.8%; CI= 93.2% to 94.3%) was found again in Conakry.
The pooled specificity of VIA was 84.7% (CI= 80.7% to 88.8%). In general, the
sensitivity of VILI was higher than VIA with the exception of Jaipur (87.5%; CI=
76.8% to 83.2%) and Trivandrum-2 (80.2%; CI= 70.9% to 88.3%) where sensitivities
were equal to those of VIA. The specificities of VILI varied over a similar range as
VIA, between 73.0 % and 91.6%. The overall pooled sensitivity for VILI (91.2%;
CI= 87.8% to 94.6%) was statistically significantly higher than for VIA. On the other
hand, the pooled specificity of VILI 84.5% (CI= 81.3% to 87.8%) was not
significantly different from that of VIA.

Table 3 shows, besides sensitivity and specificity, also the predictive values, the
prevalence of CIN2+ and the detection rates of CIN2+ in all settings where VIA and
VILI were evaluated. The pooled prevalence of CIN2+ was 2.3% (CI= 1.6% to
3.0%) with a lowest value of 0.8%, noted in Niamey, and a highest value of 3.3% in
Trivandrum 1. This yielded pooled positive predictive values (PPV) with wide
overlapping confidence intervals, for VIA (11.6%; CI: 8.1% to 15.1%) and VILI
(12.9%; CI: 8.0% to 17.9%). The negative predictive values (NPV) of both inspection
methods were less heterogeneous and in general higher than 99%. Moreover the
pooled negative predictive value of VILI (99.8%; CI: 99.7% to 99.9%) was
significantly higher than that of VIA (99.4%; CI: 99.2-99.6%). The test positivity
rates varied widely, but were highly correlated (Spearman’s correlation
coefficient=0.93), ranging from 6.0% and 9.0%, observed in Niamey, to 24.2% and
21.3%, observed in Trivandrum 1, for respectively VIA and VILI.


Summary of test accuracy of all screening tests for all categories of CIN
The sensitivity and specificity for all tests and outcomes are summarized in Table 4.
The sensitivity rose substantially with increasing severity of the outcome (>22%
difference in sensitivity for CIN1+ and cancer), whereas the specificity decreased (≤3
% difference in specificity for CIN1+ and cancer). All accuracy measures showed
statistically significant inter-study heterogeneity (p<0.01 for Cochrane’s Q test) with
the exception of the sensitivity of the HC2 test for outcomes of CIN2+, CIN3+ and
cancer, which were statistically homogeneous (p>0.2 for Cochrane’s Q test).




                                                                                     29
Table 3. Number of true and false positive and negative results, test accuracy of VIA and VILI to
detect CIN2 or more severe cervical neoplasia; test positivity rate, prevalence of CIN2+ and detection
rate of CIN2+; values from 11 centers in Africa and India and meta-analytically pooled values.

            VIA
Study location    TP       FN      FP     TN        Se      Sp     PPV      NPV T+ rate       Prev Det rate
Bamako           130        34    494    4894    0.793   0.908    0.208    0.993 0.112       0.030  0.023
Brazzaville      313        76   1532    5014    0.805   0.766    0.170    0.985 0.266       0.056  0.045
Conakry          153        15    527    7932    0.911   0.938    0.225    0.998 0.079       0.019  0.018
Niamey            13         7    139    2375    0.650   0.945    0.086    0.997 0.060       0.008  0.005
Ouagadougou       45         5    516    1485    0.900   0.742    0.080    0.997 0.274       0.024  0.022
Calcutta 1        99        62   1023    4710    0.615   0.822    0.088    0.987 0.190       0.027  0.017
Calcutta 2        52        19    858    7151    0.732   0.893    0.057    0.997 0.113       0.009  0.006
Jaipur            56         8   1426    4296    0.875   0.751    0.038    0.998 0.256       0.011  0.010
Mumbai            50        31    467    3456    0.617   0.881    0.097    0.991 0.129       0.020  0.012
Trivandrum 1     132        17    945    3363    0.886   0.781    0.123    0.995 0.242       0.033  0.030
Trivandrum 2      65        16    514    4164    0.802   0.890    0.112    0.996 0.122       0.017  0.014
TOTAL/Pooled 1108          290   8441   48840    0.792   0.847    0.116    0.994 0.167       0.023  0.018
            VILI
Study location    TP       FN    FP   TN            Se      Sp     PPV      NPV T+ rate Det rate
Bamako           159         5 568 4820          0.970   0.895    0.219    0.999 0.131   0.029
Brazzaville      371        17 723 5823          0.956   0.890    0.339    0.997 0.158   0.054
Conakry          163         5 811 7648          0.970   0.904    0.167    0.999 0.113   0.019
Niamey            18         2 210 2304          0.900   0.916    0.079    0.999 0.090   0.007
Ouagadougou       49         1 539 1462          0.980   0.731    0.083    0.999 0.287   0.024
Calcutta 2        57        13 1081 6925         0.814   0.865    0.050    0.998 0.141   0.007
Jaipur            56         8 1543 4179         0.875   0.730    0.035    0.998 0.276   0.010
Mumbai            60        21 626 3296          0.741   0.840    0.087    0.994 0.171   0.015
Trivandrum 1     136        13 813 3495          0.913   0.811    0.143    0.996 0.213   0.031
Trivandrum 2      65        16 615 4063          0.802   0.869    0.096    0.996 0.143   0.014
TOTAL/Pooled 1134          101 7529 44015        0.912   0.845    0.129    0.998 0.172   0.021



Table 4. Sensitivity and specificity of 5 screening tests for CIN1 or more severe disease (CIN1+),
CIN2+, CIN3+ and cancer; minimum, maximum and meta-analytically pooled measures.
Test   Outcome Test cutoff              Sensitivity                               Specificity
                               Min       Max        Pooled (95% CI)        Min     Max       Pooled (95% CI)
VIA  CIN 1+      AW lesions   0.425     0.900 0.618 (0.523 to 0.713)      0.752   0.951 0.865 (0.828 to 0.901)
     CIN2+       or growth    0.650     0.911 0.792 (0.733 to 0.850)      0.742   0.945 0.847 (0.807 to 0.888)
     CIN3+                    0.583     0.946 0.829 (0.771 to 0.887)      0.738   0.943 0.842 (0.800 to 0.883)
     Cancer                   0.667     1.000 0.887 (0.831 to 0.943)      0.731   0.941 0.836 (0.793 to 0.880)
VILI CIN 1+      Non iodine 0.503       0.941 0.737 (0.630 to 0.845)      0.741   0.928 0.866 (0.834 to 0.898)
     CIN2+       uptake       0.741     0.980 0.912 (0.878 to 0.946)      0.730   0.916 0.845 (0.813 to 0.878)
     CIN3+       yellow areas 0.729     1.000 0.938 (0.906 to 0.971)      0.726   0.914 0.838 (0.805 to 0.871)
     Cancer      or growth    0.667     1.000 0.957 (0.918 to 0.997)      0.719   0.911 0.832 (0.798 to 0.865)
VIAM CIN1+       AW lesions 0.425       0.684 0.585 (0.432 to 0.739)      0.864   0.901 0.881 (0.858 to 0.904)
     CIN2+       or growth    0.646     0.732 0.670 (0.618 to 0.722)      0.833   0.893 0.862 (0.824 to 0.900)
     CIN3+                    0.657     0.744 0.682 (0.618 to 0.747)      0.828   0.891 0.859 (0.820 to 0.898)
     Cancer                   0.763     1.000 0.826 (0.677 to 0.976)      0.824   0.889 0.855 (0.815 to 0.896)




                                                                                                     30
                Test      Outcome Test cutoff                            Sensitivity                                           Specificity
                                                                Min       Max        Pooled (95% CI)                    Min     Max       Pooled (95% CI)
                Pap CIN1+               ASCUS+                 0.230     0.655 0.343 (0.153 to 0. 532)                 0.866   0.987 0.946 (0.915 to 0. 977)
                smear CIN2+                                    0.333     0.819 0.570 (0.376 to 0. 763)                 0.865   0.985 0.928 (0.887 to 0. 968)
                      CIN3+                                    0.356     0.964 0.630 (0.379 to 0. 882)                 0.863   0.982 0.923 (0.881 to 0. 966)
                      Cancer                                   0.400     1.000 0.725 (0.549 to 0. 900)                 0.857   0.977 0.918 (0.875 to 0. 962)
                      CIN1+             LSIL+                  0.172     0.633 0.306 (0.112 to 0. 499)                 0.929   0.993 0.967 (0.948 to 0. 985)
                      CIN2+                                    0.238     0.779 0.512 (0.300 to 0. 724)                 0.886   0.991 0.949 (0.921 to 0. 977)
                      CIN3+                                    0.267     0.893 0.561 (0.327 to 0. 796)                 0.873   0.988 0.945 (0.916 to 0. 975)
                      Cancer                                   0.200     1.000 0.651 (0.432 to 0. 871)                 0.865   0.983 0.941 (0.910 to 0. 971)
                Pap CIN2+               HSIL+                  0.175     0.617 0.426 (0.265 to 0. 586)                 0.977   0.997 0.993 (0.988 to 0. 997)
                Smear CIN3+                                    0.222     0.768 0.516 (0.320 to 0. 711)                 0.975   0.997 0.990 (0.984 to 0. 995)
                      Cancer                                   0.200     1.000 0.651 (0.432 to 0. 871)                 0.973   0.995 0.985 (0.978 to 0. 993)
                HC2 CIN1+               RLU>1                  0.215     0.337 0.266 (0.215 to 0.316)                  0.922   0.951 0.940 (0.929 to 0.951)
                      CIN2+                                    0.484     0.677 0.619 (0.562 to 0.677)                  0.916   0.946 0.936 (0.924 to 0.948)
                      CIN3+                                    0.623     0.735 0.684 (0.615 to 0.754)                  0.914   0.944 0.934 (0.922 to 0.946)
                      Cancer                                   0.615     0.857 0.721 (0.603 to 0.838)                  0.911   0.940 0.930 (0.918 to 0.942)


                 VIA, Outcome=CIN2+                                                                      VIA, Outcome=CIN2+


    Bamako                                                                                   Bamako
  Brazzavile                                                                               Brazzavile
    Conakry                                                                                  Conakry
     Niamey                                                                                   Niamey
Ouagadougou                                                                              Ouagadougou
  Ca1cutta 1                                                                               Ca1cutta 1
   Calcutta 2                                                                               Calcutta 2
      Jaipur                                                                                   Jaipur
    Mumbai                                                                                   Mumbai
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2


  Combined                                                                                 Combined
                  0       .1      .2   .3   .4      .5         .6   .7     .8   .9   1                    0       .1      .2   .3   .4      .5         .6   .7   .8   .9   1
                                                 Sensitivity                                                                             Specificity

                 VILI, Outcome=CIN2+                                                                     VILI, Outcome=CIN2+


    Bamako                                                                                   Bamako
  Brazzavile                                                                               Brazzavile
    Conakry                                                                                  Conakry
     Niamey                                                                                   Niamey
Ouagadougou                                                                              Ouagadougou
   Calcutta 2                                                                               Calcutta 2
      Jaipur                                                                                   Jaipur
    Mumbai                                                                                   Mumbai
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2


  Combined                                                                                 Combined
                  0       .1      .2   .3   .4      .5         .6   .7     .8   .9   1                    0       .1      .2   .3   .4      .5         .6   .7   .8   .9   1
                                                 Sensitivity                                                                             Specificity




                Figure 3. Forest plot of the sensitivity and specificity of visual inspection of the cervix after
                application of acetic acid (VIA) or Lugol’s iodine (VILI) to detect CIN2 or more serious cervical
                disease. The forest plot at the bottom represents the 95% confidence interval of the pooled measure
                computed from a random effect model.




                                                                                                                                                            31
5.1.2. Pooled relative accuracy of the screening tests
The forest plots in Figure 4 display the relative sensitivity and specificity of VILI
compared to VIA with respect to the prediction of CIN2+ or CIN3+. The relative
accuracy of the other screening tests is documented in Table 5. Overall, the
sensitivity of VILI for CIN2+ and CIN3+ was respectively 10.5% (CI= 4.8% to
16.5%) and 7.4% (CI= 4.3% to 10.6%) higher than the sensitivity of VIA. The
relative sensitivity of VILI was considerably higher in the African studies.
Specificities of both tests were not statistically significantly different. The accuracy
of VIAM was similar to that of VIA. The Pap smear had a significantly lower
sensitivity for CIN2+, even at the lowest cytological cutoff of ASCUS+ (relative
sensitivity= 0.742; CI= 0.576 to 0.958), but also showed a significantly higher
specificity, and this difference rose with the test threshold. The sensitivity of HC2 was
lower than that of VIA but this difference did not reach the level of statistical
significance. On the other hand, the specificity of HC2 was 7% to 8% higher than
that of VIA, and this difference was significant. For all histological outcomes and
cytological cutoffs, the Pap smear was significantly less sensitive but more specific
than VILI. The HC2 assay also had lower sensitivity than VILI, but this finding was
only significant for CIN2+. On the other hand, the specificity of the HC2 test was
significantly higher than VILI. The Pap smear showed a lower sensitivity and a
higher specificity than the HC2 test. The difference in sensitivity was never
significant but was significant for specificity when LSIL+ and HSIL+ were
considered as cutoff.

                Outcome CIN2+                                                                      Outcome CIN3+


         Mali                                                                               Mali
       Congo                                                                              Congo
      Guinea                                                                             Guinea
        Niger                                                                              Niger
Burkina-Fasso                                                                      Burkina-Fasso
    Kolkata 2                                                                          Kolkata 2
       Jaipur                                                                             Jaipur
     Mumbai                                                                             Mumbai
Trivandrum 1                                                                       Trivandrum 1
Trivandrum 2                                                                       Trivandrum 2


   Combined                                                                           Combined

                .5              .67                  1                   1.5   2                   .5              .67                  1                   1.5        2
                                      Ratio of sensitivity of VILI/VIA                                                   Ratio of sensitivity of VILI/VIA

                Outcome CIN2+                                                                      Outcome CIN3+


         Mali                                                                               Mali
       Congo                                                                              Congo
      Guinea                                                                             Guinea
        Niger                                                                              Niger
Burkina-Fasso                                                                      Burkina-Fasso
    Kolkata 2                                                                          Kolkata 2
       Jaipur                                                                             Jaipur
     Mumbai                                                                             Mumbai
Trivandrum 1                                                                       Trivandrum 1
Trivandrum 2                                                                       Trivandrum 2


   Combined                                                                           Combined
                .5              .67                  1                   1.5   2                   .5              .67                  1                   1.5        2
                                      Ratio of specificity of VILI/VIA                                                   Ratio of specificity of VILI/VIA




Figure 4. Forest plot of the relative sensitivity and specificity of VILI compared to VIA for the
prediction of cervical intraepithelial neoplasia, grade 2 or more severe neoplasia (CIN2+) and for
CIN3+.



                                                                                                                                                                  32
Table 5. Relative sensitivity and specificity of VIA, VILI, VIAM, cytology (at cutoffs ASCUS, LSIL
and HSIL) and the HC2 assay versus another screening test to detect CIN2 or CIN3 or more serious
cervical disease.
Test combinations            Outcome      Relative sensitivity       Relative specificity
                                            Pooled (95%)               Pooled (95%)
VILI/VIA                     CIN2+     1.105 (1.048 to 1.165)*    0.996 (0.962 to 1.031)
                             CIN3+     1.074 (1.043 to 1.106)*    0.994 (0.962 to 1.027)
VIAM/VIA                     CIN2+     1.036 (0.926 to 1.159)     0.997 (0.978 to 1.016)
                             CIN3+     1.028 ( 0.897 to 1.180)    0.997 (0.978 to 1.016)
Pap smear (ASCUS+)/VIA       CIN2+     0.742 (0.576 to 0.958)*    1.125 (1.072 to 1.181)*
                             CIN3+     0.795 (0.613 to 1.032)*    1.127 (1.073 to 1.183)*
Pap smear (LSIL+)/VIA        CIN2+     0.659 (0.491 to 0.884)*    1.152 (1.099 to 1.208)*
                             CIN3+     0.708 (0.535 to 0.937)*    1.154 (1.099 to 1.211)*
Pap smear (HSIL+)/VIA        CIN2+     0.552 (0.400 to 0.763)*    1.205 (1.132 to 1.284)*
                             CIN3+     0.660 (0.499 to 0.872)*    1.209 (1.133 to 1.291)*
HC2/VIA                      CIN2+     0.883 (0.775 to 1.007)     1.074 (1.051 to 1.097)*
                             CIN3+     0.956 (0.781 to 1.169)     1.075 (1.051 to 1.099)*
Pap smear (ASCUS+)/VILI      CIN2+     0.735 (0.570 to 0.948)*    1.162 (1.092 to 1.236)*
                             CIN3+     0.796 (0.618 to 1.024)     1.164 (1.094 to 1.239)*
Pap smear (LSIL+)/VILI       CIN2+     0.668 (0.500 to 0.892)*    1.176 (1.096 to 1.261)*
                             CIN3+     0.721 (0.550 to 0.945)*    1.178 (1.097 to 1.265)*
Pap smear (HSIL+)/VILI       CIN2+     0.552 (0.392 to 0.777)*    1.228 (1.144 to 1.318)*
                             CIN3+     0.676 (0.518 to 0.882)*    1.233 (1.145 to 1.327)*
HC2/VILI                     CIN2+     0.834 (0.740 to 0.939)*    1.097 (1.085 to 1.110)*
                             CIN3+     0.857 (0.714 to 1.028)     1.098 (1.084 to 1.112)*
Pap smear (ASCUS+)/HC2       CIN2+     0.957 (0.825 to 1.109)     1.008 (0.956 to 1.063)
                             CIN3+     0.915 (0.742 to 1.130)     1.008 (0.956 to 1.064)
Pap smear (LSIL+)/HC2        CIN2+     0.870   (0.723 to 1.047)   1.037   (1.013 to 1.061)*
                             CIN3+     0.816   (0.609 to 1.093)   1.037   (1.014 to 1.060)*
Pap smear (HSIL+)/HC2        CIN2+     0.786   (0.562 to 1.099)   1.061   (1.052 to 1.070)*
                             CIN3+     0.974   (0.756 to 1.256)   1.061   (1.052 to 1.071)*




5.2. Cross-sectional study on the test accuracy of VIA,
     cytology and the HC2 assay in Zimbabwe

As with the previous multi-center study, the Zimbabwe study also allows computation
of test accuracy without verification bias for 3 screening tests: VIA, HPV DNA
detection using the Hybrid Capture II assay and the conventional Pap smear. Three
different outcomes were considered: histologically confirmed CIN1+, CIN2+ and
cervical cancer. No distinction between CIN2 and CIN3 was made. The absolute
values and accuracy parameters derived from them are shown in Table 6.




                                                                                                33
Table 6. Number women with true- and false positives and negatives for 3 screening tests considering
histologically confirmed CIN1+, CIN2+ or cancer as outcome (part A); derived accuracy parameters
(part B); from a cross-sectional cervical cancer screening study conducted by the University of Harare
and JHPIEGO, where all tested women were submitted to gold standard verification [University
Zimbabwe, 1999; Womack, 2000a; Womack, 2000b, Blumenthal, 2001].
Test       Outcome     test cutoff        tp       fn       fp        tn
VIA        CIN1+       VIA+              347      217      502      1064
           CIN2+       VIA+              158       48      691      1233
           Cancer      VIA+                3        0      846      1281
Cytology   CIN1+       ASCUS+            257      295      324      1216
                       LSIL+             158      394      109      1431
           CIN2+       ASCUS+            130       71      451      1440
                       LSIL+              89      112      178      1713
                       HSIL+              33      168       40      1851
           Cancer      ASCUS+              3        0      578      1511
                       LSIL+               3        0      264      1825
                       HSIL+               3        0       70      2019
HC2        CIN1+       HC2+              361      205      556      1023
           CIN2+       HC2+              166       41      751      1187
           Cancer      HC2+                2        1      915      1227

Test       Outcome     test cutoff        Se       Sp     PPV      NPV     T+ rate    Prev   Det rate
VIA        CIN1+       VIA+            61.5%    67.9%    40.9%    83.1%    39.9%     26.5%    16.3%
           CIN2+       VIA+            76.7%    64.1%    18.6%    96.3%    39.9%     9.7%      7.4%
           Cancer      VIA+           100.0%    60.2%     0.4%   100.0%    39.9%     0.1%      0.1%
Cytology   CIN1+       ASCUS+          46.6%    79.0%    44.2%    80.5%    27.8%     26.4%    12.3%
                       LSIL+           28.6%    92.9%    59.2%    78.4%    12.8%     26.4%     7.6%
           CIN2+       ASCUS+          64.7%    76.2%    22.4%    95.3%    27.8%     9.6%      6.2%
                       LSIL+           44.3%    90.6%    33.3%    93.9%    12.8%     9.6%      4.3%
                       HSIL+           16.4%    97.9%    45.2%    91.7%     3.5%     9.6%      1.6%
           Cancer      ASCUS+         100.0%    72.3%     0.5%   100.0%    27.8%     0.1%      0.1%
                       LSIL+          100.0%    87.4%     1.1%   100.0%    12.8%     0.1%      0.1%
                       HSIL+          100.0%    96.6%     4.1%   100.0%     3.5%     0.1%      0.1%
HC2        CIN1+       HC2+            63.8%    64.8%    39.4%    83.3%    42.8%     26.4%    16.8%
           CIN2+       HC2+            80.2%    61.2%    18.1%    96.7%    42.8%     9.7%      7.7%
           Cancer      HC2+            66.7%    57.3%     0.2%    99.9%    42.8%     0.1%      0.1%


The ratios of the sensitivities and specificities of one test relative to another test for all
considered outcomes are presented in Table 7.

The prevalence of CIN was particularly high: more than one quarter had histologically
confirmed CIN1 or worse and one in ten showed high-grade CIN. The sensitivity of
VIA and HC2 for CIN1+ and CIN2+ was always higher than that of the Pap smear,
even at the lowest cytological cutoff. On the other hand, the specificity of cytology
always was higher than the other two tests. The sensitivity of HC2 and VIA was
similar, but the specificity of VIA was marginally significantly higher than the
specificity ofHC2.




                                                                                                        34
Table 7. Relative sensitivity and specificity of the Pap smear, VIA and HPV DNA detection to detect
different degrees of cervical dysplasia and cancer, derived from the cross-sectional study conducted in
Zimbabwe.

A                     Cytology,ASCUS+                                       VIA+                                         Ratio (VIA/Cyto)
Outcome     Se     lcib      ucib    Sp     lcib    ucib     Se     lcib   ucib     Sp     lcib    ucib    Se     lcib     ucib    Sp    lcib   ucib
CIN1+      0.466   0.424    0.507   0.790   0.769   0.809   0.615   0.574 0.654    0.679   0.656   0.702   1.32   1.18     1.48   0.86   0.82   0.90
CIN2+      0.647   0.578    0.710   0.762   0.742   0.780   0.767   0.705 0.820    0.641   0.619   0.662   1.19   1.04     1.35   0.84   0.81   0.88

Ca         1.000   0.438    1.000   0.723   0.704   0.742   1.000   0.438 1.000    0.602   0.581   0.623   1.00   1.00     1.00   0.83   0.80   0.87

B                         Cytology,LSIL+                                    VIA+                                         Ratio (VIA/Cyto)
Outcome     Se     lcib      ucib    Sp     lcib    ucib     Se     lcib   ucib     Sp     lcib    ucib    Se     lcib     ucib    Sp    lcib   ucib
CIN1+      0.286   0.250    0.325   0.929   0.915   0.941   0.615   0.574 0.654    0.679   0.656   0.702   2.15   1.86     2.49   0.73   0.70   0.76
CIN2+      0.443   0.376    0.512   0.906   0.892   0.918   0.767   0.705 0.820    0.641   0.619   0.662   1.73   1.46     2.06   0.71   0.68   0.73

Ca         1.000   0.438    1.000   0.874   0.859   0.887   1.000   0.438 1.000    0.602   0.581   0.623   1.00   1.00     1.00   0.69   0.66   0.72

C                         Cytology,HSIL+                                    VIA+                                         Ratio (VIA/Cyto)
Outcome     Se     lcib      ucib    Sp     lcib    ucib     Se     lcib   ucib     Sp     lcib    ucib    Se     lcib     ucib    Sp    lcib   ucib
CIN2+      0.164   0.119    0.222   0.979   0.971   0.984   0.767   0.705 0.820    0.641   0.619   0.662   4.67   3.39     6.44   0.65   0.63   0.68

Ca         1.000   0.438    1.000   0.966   0.958   0.973   1.000   0.438 1.000    0.602   0.581   0.623   1.00   1.00     1.00   0.62   0.60   0.65

D                      Cytology,ASCUS+                                      HC2+                                         Ratio (HC2/Cyto)
Outcome     Se     lcib    ucib    Sp       lcib    ucib     Se     lcib   ucib  Sp        lcib    ucib    Se     lcib     ucib Sp      lcib    Ucib
CIN1+      0.466   0.424    0.507   0.790   0.769   0.809   0.638   0.597 0.676    0.648   0.624   0.671   1.37   1.23     1.53   0.82   0.78   0.86
CIN2+      0.647   0.578    0.710   0.762   0.742   0.780   0.802   0.742 0.851    0.612   0.591   0.634   1.24   1.10     1.40   0.80   0.77   0.84

Ca         1.000   0.438    1.000   0.723   0.704   0.742   0.667   0.208 0.939    0.573   0.552   0.594   0.67   0.30     1.48   0.79   0.76   0.83

E                         Cytology,LSIL+                                    HC2+                                         Ratio (HC2/Cyto)
Outcome     Se     lcib      ucib    Sp     lcib    ucib     Se     lcib   ucib  Sp        lcib    ucib    Se     lcib     ucib Sp      lcib    Ucib
CIN1+      0.286   0.250    0.325   0.929   0.915   0.941   0.638   0.597 0.676    0.648   0.624   0.671   2.23   1.93     2.58   0.70   0.67   0.72
CIN2+      0.443   0.376    0.512   0.906   0.892   0.918   0.802   0.742 0.851    0.612   0.591   0.634   1.81   1.53     2.15   0.68   0.65   0.70

Ca         1.000   0.438    1.000   0.874   0.859   0.887   0.667   0.208 0.939    0.573   0.552   0.594   0.67   0.30     1.48   0.66   0.63   0.68

F                         Cytology,HSIL+                                    HC2+                                         Ratio (HC2/Cyto)
Outcome     Se     lcib      ucib    Sp     lcib    ucib     Se     lcib   ucib  Sp        lcib    ucib    Se     lcib     ucib Sp      lcib    Ucib
CIN2+      0.164   0.119    0.222   0.979   0.971   0.984   0.638   0.597 0.676    0.648   0.624   0.671   3.88   2.83     5.34   0.66   0.64   0.69

Ca         1.000   0.438    1.000   0.966   0.958   0.973   0.802   0.742 0.851    0.612   0.591   0.634   0.80   0.75     0.86   0.63   0.61   0.66


E                              HC2                                           VIA                                         Ratio (VIA/HC2)
Outcome     Se     lcib      ucib  Sp       lcib    ucib     Se     lcib   ucib  Sp        lcib    ucib    Se     lcib     ucib Sp      lcib    Ucib
CIN1+      0.638   0.597    0.676   0.648   0.624   0.671   0.615   0.574 0.654    0.679   0.656   0.702   0.96   0.88     1.06   1.05   1.00   1.10
CIN2+      0.802   0.742    0.851   0.612   0.591   0.634   0.767   0.705 0.820    0.641   0.619   0.662   0.96   0.86     1.06   1.05   1.00   1.10

Ca         0.667   0.208    0.939   0.573   0.552   0.594   1.000   0.438 1.000    0.602   0.581   0.623   1.50   0.67     3.34   1.05   1.00   1.11




5.3. Randomized trial of VIA screening in rural South India

In a series of tables, we summarize the main short-term results of the randomized trial
conducted in the Ambilikai are in the Dindigul district, which were reported in the
International Journal of Cancer [Sankaranarayanan, 2004b] (see Table 8 to Table 11).




                                                                                                                                  35
More than 30,000 women or 63.4% of the total eligible population participated in arm
A.
In the Indian trial only a limited number of test accuracy outcomes are available: the
test positivity rate for VIA was 9.6% (CI: 9.3% to 9.9%); the PPV of a positive VIA
test result for an outcome of CIN2 or CIN3 was 9.5% (CI: 8.3% to 10.8%) and the
detection rate of CIN2+ was 0.73% (CI: 0.63% to 0.83%).
Among the 97 invasive cervical cancers found in group A, 69 (71.1%; CI: 61.0% to
79.9%) were found at screening. The observed incidence was 78.1 (CI: 63.4 to 95.3)
per 100,000 women-years in group A, whereas only 37.7 (CI: 26.1 to 52.7) per
100,000 women-years in group B. But in group A, a much more favorable stage
distribution was observed (see Table 10).

Table 8. Attendance at screening and test performance indicators in group A. [from
Sankaranarayanan, 2004b].
Process indicators              number    % Definition of the Indicator
Eligible population              48,225
Screened with VIA                30,577 63.4% Participation rate, among eligible population
Non-responders                   17,648

VIA+                               2,939 9.6% Test+ rate among women who received VIA
Number colposcoped                 2,939 100.0% Compliance with colposcopy
Number biopsied                    2,777 94.5% % with colposcopy who were biopsied
Number of VIA+ with CIN+
 CIN 1                             1,778   5.8% Detection rate, among screened women
 CIN2/3                              222   0.7%
 Cancer                               69   0.2%
 Total with lesions                2,069   6.8%
PPV of VIA for
 CIN 1+                            2,069 70.4% PPV, among VIA+ women
 CIN2+                               291 9.9% PPV, among VIA+ women
 Cancer                               69 2.3% PPV, among VIA+ women


Table 9. Occasion of cancer detection in group A [from Sankaranarayanan, 2004b].
Cancers detected in the FU period, by occasion
Screen detected ca                                           69    71.1% program sensitivity
Interval ca (VIA-, detected within 2yr after screen)          7
Ca among non responders to screening                         13
Ca after randomization but before screening                   8
                                            TOTAL            97


Table 10. Comparison of short term longitudinal outcomes, number of included women, number of
women-years in the follow-up period, number of cervical cancers per stage and cancer incidence rate,
in the two arms A (VIA-screened population) and B (control population) [from Sankaranarayanan,
2004b].
Comparison between arms                             A                              B
Number of women                                     30 577                    30 167
Number of women-years in FU period                 124 144                    90 172
Number of cancers in FU period, per stage (%)
   I                                                   34 (35.1%)                    0   (0.0%)



                                                                                                   36
     II                                                 18 (18.6%)                 6 (17.6%)
     III                                                45 (46.4%)                26 (76.5%)
     IV                                                  0 (0.0%)                  2 (5.9%)
     Total                                              97 (100.0%)               34 (100.0%)
Cancer incidence rate over FU period
(per 100 000 women-years)                             78.1                      37.7

More than 70% of CIN1 and 80% of CIN2/3 cases were treated (see Table 11). Most
of CIN1 cases were treated with cryotherapy the same day (93% of treated cases),
whereas almost 4 in 10 cases with high-grade CIN were treated with LEEP or cold
knife conization. Fifty-two of the 69 women with screen detected cancer received
appropriate cancer treatment.
Fifteen percent of women treated for CIN came back for a follow-up visit after one
year.

Table 11. Treatment compliance in group A [from Sankaranarayanan, 2004b].

             To be                T with % of     Cryo    % of     LEEP/     % of FU after % of
CIN         treated Treated % T    cryo treated same day treated conization treated 1 yr treated
CIN1         1778    1263 71.0%     1179 93.3%                           84    6.7%
CIN2/3        222     178   80.2%    109 61.2%                           69 38.8%
Total        2000    1441 72.1%     1288 89.4% 983       68.2%          153 10.6%      222 15.4%




5.4. Western Kenya Cervical Cancer Prevention Project
     (WKCCPP)

Since the results of the WKCCPP study are not yet published, we produced a report,
from which we extract the main tables below. About 19% of the examined women
had a positive result for VIA, 2% showed an indeterminate result and in 0.7% cancer
was suspected. In total 489 among 2295 tested women, or 21.3%, had an abnormal
VIA result.
Table 12. Distribution of VIA test results in the WKCCPP study.
VIA results                   Number         %
Negative                         1806        78.7%
Indeterminate                      45         2.0%
Positive                          427        18.6%
Suspect for cancer                 17         0.7%
Total                            2295       100.0%



5.4.1. Positive predictive value and approximated specificity of VIA
Three hundred and twelve women among 489 women with abnormal VIA result
(63.8%) presented at the district hospital for colposcopic exploration. For 168
women biopsy results are available. We constructed a pseudo-gold standard variable
based on the biopsy results, accepting expert colposcopya if no biopsy was taken and
finally accepting the nurse colposcopy result when no biopsy or expert colposcopy

a
    Expert colposcopy: Dr. E. Kauffmann, expert colposcopist, did colposcopy for 133 women.


                                                                                                37
results were available. This yielded a pseudo-gold standard diagnosis for 327
VIAindeter+ cases.
The positive predictive value of respectively VIA+ or VIAindeter+ can be computed
from the verified test positives. Assuming the PPV among the not verified cases is
equal to the PPV among verified cases, allows us to compute the extrapolated number
of tp' and fp' for all VIA+ (#tp'= PPV*T+rate).
The detection rate of disease is computed as the number of true-positives over the
number of screened subjects. This parameter reflects sensitivity (but is also
dependent on prevalence of the disease and the verification). Finally we computed
the approximated specificity, which is an acceptable proxy for the real specificity
when the prevalence of disease is low (<10%).
All these parameters are shown in Table 13.
The PPV for CIN2+ was respectively 11.0% (CI: 7.6% to 15.1%) (when manifest
VIA+ is considered as cutoff) or 10.4% (CI: 7.3% to 14.2%) (when indeterminate
cases are considered also as VIA+). The approximate specificity to exclude CIN2+
was respectively 82.4% (CI: 80.8% to 84.4%) and 80.5% (CI: 78.8% to 82.1%).

Table 13. Number of true- and false positives, number of verified test-positives, PPV, number of
expected true- & false-positives assuming PPV is equal for non verified cases, detection rate of disease
and approximate specificity of VIA for different degrees of CIN (WKCCPP study).
                                                    TP/                                         TP/
                                                  (TP+FP)                                     (T+v+T-)     T-/(N-tp')
       test       outcome
Test   cutoff     threshold      TP FP T+verif PPV            T+     tp'    fp'  T-    N         Det rate App Spec
VIA    Indeter-   CIN1+         124 203 327 37.30%           489    182    307 1806 2295           5.8%     85.5%
       minate+    CIN2+          34 293     327 10.00%       489     49    440 1806 2295           1.6%        80.4%
                  CIN3+          17 310     327     5.30%    489     26    463 1806 2295           0.8%        79.6%
                  Ca              6 321     327     1.90%    489       9   480 1806 2295           0.3%        79.0%
       VIA+       CIN1+         109 183     292 36.80%       444    163    281 1851 2295           5.1%        86.8%
                  CIN2+          32 260     292 10.50%       444     47    397 1851 2295           1.5%        82.3%
                  CIN3+          15 277     292     5.30%    444     24    420 1851 2295           0.7%        81.5%
                  Ca              6 286     292     2.10%    444      9    435 1851 2295           0.3%        81.0%




5.4.2. Performance of triage methods

Respectively 271, 280, and 76 women with an abnormal VIA screen test result were
submitted to triage testing with VIAM, cytology and VILI and have a pseudo-gold
standard result. The number of TP, FN, FP, TN and derived accuracy parameters are
shown the following tables (see Table 14).




                                                                                                     38
Table 14. Number of true- and false-positive cases and derived accuracy for different degrees of CIN
of three triage methods (Pap smear, VIAM and VILI) applied to women referred for an abnormal VIA
screen test.
Test       Test cutoffOutcome threshold              TP             FN              FP               TN
Pap        ASCUS+     CIN1+                               60              43               86              87
                      CIN2+                               18               7              128             123
                      CIN3+                                9               2              137             128
                      Ca                                   1               0              145             130
           AGUS/LSIL+ CIN1+                               52              51               57             116
                      CIN2+                               17               8               92             159
                      CIN3+                                9               2              100             165
                      Ca                                   1               0              108             167
           AGUS/HSIL+ CIN2+                                8              17               10             241
                      CIN3+                                6               5               12             253
                      Ca                                   1               0               17             258
                      Outcome
Test       Test cutoffthreshold          Sens        Spec            T+              PPV             NPV           Prev
Pap        ASCUS+     CIN1+               58.3%       50.3%           52.9%           41.1%           66.9%         37.3%
                      CIN2+               72.0%       49.0%           52.9%           12.3%           94.6%           9.1%
                      CIN3+               81.8%       48.3%           52.9%            6.2%           98.5%           4.0%
                      Ca                 100.0%       47.3%           52.9%            0.7%          100.0%           0.4%
           LSIL       CIN1+               50.5%       67.1%           39.5%           47.7%           69.5%         37.3%
                      CIN2+               68.0%       63.3%           39.5%           15.6%           95.2%           9.1%
                      CIN3+               81.8%       62.3%           39.5%            8.3%           98.8%           4.0%
                      Ca                 100.0%       60.7%           39.5%            0.9%          100.0%           0.4%
           AGUS/HSIL+ CIN2+               32.0%       96.0%            6.5%           44.4%           93.4%           9.1%
                      CIN3+               54.5%       95.5%            6.5%           33.3%           98.1%           4.0%
                      Ca                 100.0%       93.8%            6.5%            5.6%          100.0%           0.4%


Test       Test cutoff Outcome threshold        TP             FN              FP               TN          Tot
VIAM       VIAM indet+ CIN1+                         86              14              91              80           271
                       CIN2+                         26               2             151              92           271
                       CIN3+                         14               1             163              93           271
                       Ca                             5               0             172              94           271
           VIAM+       CIN1+                         86              14              90              81           271
                       CIN2+                         26               2             150              93           271
                       CIN3+                         14               1             162              94           271
                       Ca                             5               0             171              95           271
                       Outcome
Test       Test cutoff threshold       Sens       Spec              T+          PPV              NPV            Prev
VIAM       VIAM indet+ CIN1+            86.0%      46.8%             65.3%       48.6%            85.1%          36.9%
                       CIN2+            92.9%      37.9%             65.3%       14.7%            97.9%          10.3%
                       CIN3+            93.3%      36.3%             65.3%        7.9%            98.9%            5.5%
                       Ca              100.0%      35.3%             65.3%        2.8%           100.0%            1.8%
           VIAM+       CIN1+            86.0%      47.4%             64.9%       48.9%            85.3%          36.9%
                       CIN2+            92.9%      38.3%             64.9%       14.8%            97.9%          10.3%
                       CIN3+            93.3%      36.7%             64.9%        8.0%            98.9%            5.5%
                       Ca              100.0%      35.7%             64.9%        2.8%           100.0%            1.8%




                                                                                                                  39
                        Outcome
Test        Test cutoff threshold                   TP          FN               FP               TN
VILI        ASCUS+ CIN1+                                 19            5                 4              48
                        CIN2+                             6            0                17              53
                        CIN3+                             2            0                21              53
                        Ca                                1            0                22              53
                        Outcome
Test        Test cutoff threshold               Sens           Spec              T+              PPV             NPV             Prev
VILI        VILI+       CIN1+                    79.2%          92.3%             30.3%           82.6%           90.6%           31.6%
                        CIN2+                   100.0%          75.7%             30.3%           26.1%          100.0%             7.9%
                        CIN3+                   100.0%          71.6%             30.3%            8.7%          100.0%             2.6%
                        Ca                      100.0%          70.7%             30.3%            4.3%          100.0%             1.3%


The relative performance of the triage tests is evaluated by computing the relative
sensitivity and specificity (see Table 15).
Table 15. Ratio of sensitivities and specificities of the 3 applied triage tests (cytology, VIAM and
VILI).
A                      Cytology,ASCUS+                                VIAM, Indeterminate+                                Ratio (VIAM/Cyto)
Outcome      Se      lcib   ucib     Sp      lcib    ucib       Se    lcib     ucib      Sp      lcib   ucib     Se    lcib   ucib    Sp    lcib   ucib
CIN1+       0.583   0.486   0.673   0.503   0.429    0.577    0.860    0.779   0.915    0.468   0.395   0.543   1.48   1.23   1.77   0.93   0.75   1.16
CIN2+       0.720   0.524   0.857   0.490   0.429    0.552    0.929    0.774   0.980    0.379   0.320   0.441   1.29   0.99   1.68   0.77   0.63   0.95
CIN3+       0.818   0.523   0.949   0.483   0.424    0.543    0.933    0.702   0.988    0.363   0.307   0.424   1.14   0.84   1.55   0.75   0.61   0.92
Ca          1.000   0.207   1.000   0.473   0.415    0.532    1.000    0.566   1.000    0.353   0.298   0.413   1.00   1.00   1.00   0.75   0.61   0.92

B                     Cytology,LSIL+/AGUS                              VIAM, Indeterminate+                               Ratio (VIAM/Cyto)
Outcome      Se      lcib   ucib    Sp    lcib       ucib       Se    lcib   ucib   Sp      lcib        ucib     Se    lcib ucib Sp       lcib     ucib
CIN1+       0.505   0.410 0.599 0.671 0.597          0.736    0.860    0.779 0.915 0.468 0.395          0.543   1.70   1.38 2.10 0.70 0.58         0.84
CIN2+       0.680   0.484 0.828 0.633 0.572          0.691    0.929    0.774 0.980 0.379 0.320          0.441   1.37   1.02 1.82 0.60 0.50         0.72
CIN3+       0.818   0.523 0.949 0.623 0.563          0.679    0.933    0.702 0.988 0.363 0.307          0.424   1.14   0.84 1.55 0.58 0.48         0.70
Ca          1.000   0.207 1.000 0.607 0.548          0.663    1.000    0.566 1.000 0.353 0.298          0.413   1.00   1.00 1.00 0.58 0.48         0.70

C                    Cytology,HSIL+/AGUS                              VIAM, Indeterminate+                                Ratio (VIAM/Cyto)
Outcome      Se      lcib   ucib     Sp      lcib    ucib       Se    lcib   ucib        Sp      lcib   ucib     Se    lcib   ucib    Sp    lcib   ucib
CIN2+       0.320   0.172   0.516   0.960   0.928    0.978    0.929    0.774 0.980      0.379   0.320   0.441   2.90   1.62   5.19   0.39   0.33   0.46
CIN3+       0.545   0.280   0.787   0.955   0.923    0.974    0.933    0.702 0.988      0.363   0.307   0.424   1.71   0.98   2.98   0.38   0.32   0.45
Ca          1.000   0.207   1.000   0.938   0.903    0.961    1.000   0.566 1.000       0.353   0.298   0.413   1.00   1.00   1.00   0.38   0.32   0.44

D                      Cytology,ASCUS+                                           VILI                                     Ratio (VILI/Cyto)
Outcome      Se      lcib   ucib     Sp      lcib    ucib       Se    lcib     ucib      Sp      lcib   ucib     Se    lcib   ucib    Sp    lcib   ucib
CIN1+       0.583   0.486   0.673   0.503   0.429    0.577    0.792    0.595   0.908    0.923   0.818   0.970   1.36   1.05   1.77   1.84   1.55   2.17
CIN2+       0.720   0.524   0.857   0.490   0.429    0.552    1.000    0.610   1.000    0.757   0.645   0.842   1.39   1.09   1.77   1.55   1.29   1.86
CIN3+       0.818   0.523   0.949   0.483   0.424    0.543    1.000    0.342   1.000    0.716   0.605   0.806   1.22   0.93   1.61   1.48   1.23   1.79
Ca          1.000   0.207   1.000   0.473   0.415    0.532    1.000   0.207 1.000       0.707   0.596   0.798   1.00   1.00   1.00   1.49   1.23   1.81

E                     Cytology,LSIL+/AGUS                                         VILI                                     Ratio (VILI/Cyto)
Outcome      Se      lcib   ucib    Sp    lcib       ucib       Se    lcib     ucib    Sp        lcib   ucib     Se    lcib ucib Sp         lcib   ucib
CIN1+       0.505   0.410 0.599 0.671 0.597          0.736    0.792    0.595   0.908 0.923      0.818   0.970   1.57   1.18 2.08 1.38 1.21         1.57
CIN2+       0.680   0.484 0.828 0.633 0.572          0.691    1.000    0.610   1.000 0.757      0.645   0.842   1.47   1.12 1.92 1.20 1.02         1.41
CIN3+       0.818   0.523 0.949 0.623 0.563          0.679    1.000    0.342   1.000 0.716      0.605   0.806   1.22   0.93 1.61 1.15 0.97         1.37
Ca          1.000   0.207 1.000 0.607 0.548          0.663    1.000    0.207   1.000 0.707      0.596   0.798   1.00   1.00 1.00 1.16 0.98         1.38

F                    Cytology,HSIL+/AGUS                                         VILI                                     Ratio (VILI/Cyto)
Outcome      Se      lcib   ucib     Sp      lcib    ucib       Se    lcib   ucib        Sp      lcib   ucib     Se    lcib   ucib    Sp    lcib   ucib
CIN2+       0.320   0.172   0.516   0.960   0.928    0.978    1.000    0.610 1.000      0.757   0.645   0.842   3.13   1.76   5.53   0.79   0.69   0.90
CIN3+       0.545   0.280   0.787   0.955   0.923    0.974    1.000    0.342 1.000      0.716   0.605   0.806   1.83   1.07   3.14   0.75   0.65   0.87
Ca          1.000   0.207   1.000   0.938   0.903    0.961    1.000   0.207 1.000       0.707   0.596   0.798   1.00   1.00   1.00   0.75   0.65   0.87




                                                                                                                                     40
E                                VIAM                                              VILI                                  Ratio (VILI/VIA)
Outcome          Se     lcib   ucib   Sp        lcib   ucib      Se    lcib     ucib    Sp     lcib   ucib     Se    lcib ucib Sp       lcib      ucib
CIN1+          0.860   0.779   0.915 0.468     0.395   0.543   0.792    0.595   0.908 0.923   0.818   0.970   0.92   0.74 1.15 1.97 1.65          2.36
CIN2+          0.929   0.774   0.980 0.379     0.320   0.441   1.000    0.610   1.000 0.757   0.645   0.842   1.08   0.97 1.19 2.00 1.62          2.46
CIN3+          0.933   0.702   0.988 0.363     0.307   0.424   1.000    0.342   1.000 0.716   0.605   0.806   1.07   0.94 1.23 1.97 1.59          2.45
Ca             1.000   0.566   1.000   0.353   0.298   0.413   1.000   0.207 1.000    0.707   0.596   0.798   1.00   1.00   1.00    2.00   1.61   2.49


VIAM is more sensitive, but less specific than cytology at all cytological cutoffs for
detection of CIN1+, CIN2+ and CIN3+. The sensitivity of detecting cancer is the
same.

Differences in sensitivity were significant (using independent comparisonsa) when:
    • the outcome is CIN1+ for all cytological cutoffs;
    • the outcome is CIN2+ for the cytological cutoffs LSIL/AGUS+ and
       HSIL/AGUS+.

Differences in specificity are significant (using independent comparisons) when:
    • the outcome is CIN1+ for the cytological cutoffs LSIL/AGUS+ and
       HSIL/AGUS+
    • the outcome is CIN2+ for all cytological cutoffs.

The difference in sensitivity was marginally not significant for the outcome CIN2+
when the cytological cutoff was ASCUS+ (relative sensitivity of 1.29 (CI: 0.99-1.68).

Although VILI triage was applied to a limited number of screen positives, some
statistically significant results were obtained.
VILI is more sensitive than cytology even at the lowest cytological cutoff and this
difference is significant for the outcome CIN1+ and CIN2+. The sensitivity of VILI
triage is similar to that of VIAM but the specificity of VILI was higher. This
difference in specificity was statistically significant for all outcomes. To conclude:
VILI looks the most accurate triage method, but this finding is based on a limited
number of observations. Moreover, VILI does not require technical equipment and
allows a diagnosis on the spot.


5.4.3. Combination of VIA screening with subsequent triage

The advantage of adding a triage method is an increase in PPV and a decrease in the
proportion of treated women who did not require treatment.
The PPV of the combination screen test followed by triage can be computed as
following: 1-(1-PPVscreen test)*(1-Spec triage test). The PPV of VIA for CIN2+ and
CIN3+ was respectively 10.0% and 5.3%. The specificity of VILI triage of VIA+
cases considering the same outcomes was respectively 75.7% and 71.6%. This
means that the PPV of the combination becomes, for CIN2+: 1-(1-0.10)*(1-0.757)
=78.1% and for CIN3+: 1-(1-0.053)*(1-0.716) =73.1%. This means that "see and
treat" VIA+ cases includes treatment of women where 90% (1-PPVVIA) do not have
CIN2+. With VILI triage (see-triage-treat strategy), only 22% of treated women will
not have a CIN2+ lesion.

a
    The statistical significance of differences did not change using paired comparisons (McNemar test).


                                                                                                                                   41
A see and treat strategy based on VIA-positivity, applied to the WKCCPP situation
would require treatment of 18.6% of the eligible screening population (or even 20.6%
if indeterminate cases are included). Adding VILI triage should decrease this
proportion. This proportion to be treated when combining screening and triage can
be computed as following: T+ ratescreen test * T+ ratetriage test. For the combination of
VIA screening followed by VILI triage, the proportion of eligible screened population
that is treated would be: 18.6%*33.3%=5.6%.
In absolute figures: in a population of 10,000 eligible screened women: 1860 women
should require treatment in a see and treat strategy based on VIA screening alone;
whereas only 560 women should need to be treated in a see-triage-treat strategy.
Triage increases the specificity and the PPV of the screening strategy, but includes a
risk of drop out when triage is organized at another occasion at a distant place.
Another risk is to miss cases when the triage method has a sensitivity lower than
100%. In the WKCCPP project 36.2% of VIA+ women did not present at the district
hospital for diagnostic follow-up. The prevalence of disease among VIA+ cases was:
7.9% of CIN2+, 2.6% of CIN3+, and 1.3% of cancer. This dropout rate means that in
a population of 10,000 women eligible for screening, 147 of CIN2+ would not receive
treatment, as well as 49 with CIN3+ and 24 with cancer (10000*test positivity
rate*drop out rate*prevalence of disease among VIA-positives).

The see-triage-treatment procedure can reduce the number of women to be treated but
is only acceptable when a high follow-up rate can be assured or triage is done at the
time of screening. It also reduces the number of true cases of disease picked up due to
sensitivity problems resulting in decreased effectiveness.



5.4.4. Experience of women in the 1-3 month period after
       cryotherapy
The quality of the information concerning safety and acceptability of cryotherapy is
limited given the low attendance of treated women at the foreseen follow-up visits.
Further the post -treatment follow-up procedures and the definition of follow-up
variables changed over time. In a first phase a contact was foreseen at 1 and 3
months; in the second period there was only one visit between 1 to 3 months after
treatment.
Among the 116 women having received cryotherapy, 31 had a follow-up in the first
pilot phase or in the expansion phase.

Below, we present a few mono-variate frequency distributions for the main follow-up
questions:




                                                                                      42
Lower back or abdominal pain
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          9       29.03       29.03
        Yes |         19       61.29       90.32
    missing |          3        9.68      100.00
------------+-----------------------------------
      Total |         31      100.00

Severe back pain or abdominal pain after cryotherapy
            |      Freq.     Percent        Cum.
------------+-----------------------------------
       mild |          4       12.90       12.90
   moderate |          3        9.68       22.58
     severe |          2        6.45       29.03
    missing |         22       70.97      100.00
------------+-----------------------------------
      Total |         31      100.00

Vaginal bleeding 1-3M post-cryotherapy
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |         23       74.19       74.19
        Yes |          8       25.81      100.00
------------+-----------------------------------
      Total |         31      100.00

Severity of vaginal bleeding 1-3 months post-cryo
            |      Freq.     Percent        Cum.
------------+-----------------------------------
       mild |          5       16.13       16.13
   moderate |          3        9.68       25.81
    missing |         23       74.19      100.00
------------+-----------------------------------
      Total |         31      100.00

Cervical abnormality noted (in expansion phase only, 1-3 months post-cryotherapy).
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          9      100.00      100.00
------------+-----------------------------------
      Total |          9      100.00

Colposcopy results at 3 months follow-up (exam-pilot phase only).
            |      Freq.     Percent        Cum.
------------+-----------------------------------
   negative |         13       81.25       81.25
      CIN 1 |          2       12.50       93.75
      CIN 2 |          1        6.25      100.00
------------+-----------------------------------
      Total |         16      100.00

Biopsy results at 3 month follow-up (exam-pilot phase only)
            |      Freq.     Percent        Cum.
------------+-----------------------------------
      CIN 1 |          1        5.88        5.88
    missing |         16       94.12      100.00
------------+-----------------------------------
      Total |         17      100.00




                                                                                     43
Pap smear results at 3 month follow-up exam-pilot phase only
            |      Freq.     Percent        Cum.
------------+-----------------------------------
   negative |          3       60.00       60.00
      ASCUS |          1       20.00       80.00
       LSIL |          1       20.00      100.00
------------+-----------------------------------
      Total |          5      100.00


Final diagnosis at 3 month follow-up exam-pilot phase only
            |       Freq.     Percent        Cum.
------------+-----------------------------------
   negative |          1        5.88        5.88
     CIN 1+ |          1        5.88       11.76
    missing |         15       88.24      100.00
------------+-----------------------------------
      Total |         17      100.00

Sex since cryotherapy?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          6       19.35       19.35
        Yes |         21       67.74       87.10
    missing |          4       12.90      100.00
------------+-----------------------------------
      Total |         31      100.00

Bleeding with sex post-cryotherapy?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          8       25.81       25.81
        Yes |          1        3.23       29.03
    missing |         22       70.97      100.00
------------+-----------------------------------
      Total |         31      100.00

Pain with sex post-cryotherapy?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          6       19.35       19.35
        Yes |          4       12.90       32.26
    missing |         21       67.74      100.00
------------+-----------------------------------
      Total |         31      100.00

Other problems with sex post-cryotherapy?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          8       25.81       25.81
        Yes |          1        3.23       29.03
    missing |         22       70.97      100.00
------------+-----------------------------------
      Total |         31      100.00

Other problems with sex post-cryotherapy
                 |      Freq.     Percent        Cum.
-----------------+-----------------------------------
post-coital pain |          1      100.00      100.00
-----------------+-----------------------------------
           Total |          1      100.00




                                                               44
Days between treatment and sex
            |      Freq.     Percent        Cum.
------------+-----------------------------------
          7 |          1        3.23        3.23
         10 |          2        6.45        9.68
         14 |          1        3.23       12.90
         21 |          1        3.23       16.13
         25 |          1        3.23       19.35
         28 |          3        9.68       29.03
         30 |          3        9.68       38.71
         35 |          1        3.23       41.94
         42 |          1        3.23       45.16
         45 |          1        3.23       48.39
         60 |          1        3.23       51.61
         99 |          1        3.23       54.84
    missing |         14       45.16      100.00
------------+-----------------------------------
      Total |         31      100.00

Did client wait 1 month post-cryotherapy before having sex?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
        Yes |          9       29.03       29.03
         No |         14       45.16       74.19
    missing |          8       25.81      100.00
------------+-----------------------------------
      Total |         31      100.00

Were condoms used during sex? Expansion phase only.
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          4       44.44       44.44
    missing |          5       55.56      100.00
------------+-----------------------------------
      Total |          9      100.00

Vaginal discharge post-cryotherapy?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |          2        6.45        6.45
        Yes |         29       93.55      100.00
------------+-----------------------------------
      Total |         31      100.00

Severity of the post-cryo vaginal discharge.
            |      Freq.     Percent        Cum.
------------+-----------------------------------
       mild |          8       25.81       25.81
   moderate |         20       64.52       90.32
     severe |          1        3.23       93.55
    missing |          2        6.45      100.00
------------+-----------------------------------
      Total |         31      100.00

Has the discharge stopped?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
        Yes |         28       90.32       90.32
    missing |          3        9.68      100.00
------------+-----------------------------------
      Total |         31      100.00




                                                              45
Number of days until discharge stopped
            |      Freq.     Percent        Cum.
------------+-----------------------------------
          0 |          1        3.23        3.23
          2 |          1        3.23        6.45
          3 |          1        3.23        9.68
          4 |          1        3.23       12.90
          5 |          1        3.23       16.13
         10 |          2        6.45       22.58
         14 |         10       32.26       54.84
         18 |          1        3.23       58.06
         21 |          6       19.35       77.42
         30 |          1        3.23       80.65
        999 |          6       19.35      100.00
------------+-----------------------------------
      Total |         31      100.00

Type of post-cryotherapy vaginal discharge- 1month pilot phase & 1-3 month expansion
phase only.
              |      Freq.     Percent        Cum.
--------------+-----------------------------------
       watery |         23       74.19       74.19
foul-smelling |          3        9.68       83.87
      missing |          5       16.13      100.00
--------------+-----------------------------------
        Total |         31      100.00

Other treatment sought for post-cryotherapy problems thought to be associated with
treatment?
            |      Freq.     Percent        Cum.
------------+-----------------------------------
         No |         19       61.29       61.29
        Yes |          8       25.81       87.10
    missing |          4       12.90      100.00
------------+-----------------------------------
      Total |         31      100.00




5.4.5. Follow-up 1 year after cryotherapy
Of the 116 treated women, 34 presented at the final visit 1 year after treatment at the
moment that the data file was prepared.
We will focus at the VILI, colposcopy and biopsy results. Based on biopsy and
colposcopy we constructed a final gold standard outcome as defined before at the
initial diagnostic assessment (using the biopsy result if available and considering a
negative colposcopy result as a truly negative result). For 28 women a VILI result
was available and 26 colposcopy and/or biopsy results were provided.
            VILI at 1Yr |      Freq.     Percent        Cum.
------------------------+-----------------------------------
               negative |         20       71.43       71.43
               positive |          7       25.00       96.43
        suspect for ca |           1        3.57      100.00
------------------------+-----------------------------------
                  Total |         28      100.00




                                                                                       46
                 |                  gold standard outcome
     VILI at 1Yr | negative       CIN 1      CIN 2       CIN3 |     Total
-----------------+--------------------------------------------+----------
        negative |        17          1          0          0 |        18
        positive |         1          3          2          1 |         7
  suspect for ca |         0          0          0          1 |         1
-----------------+--------------------------------------------+----------
           Total |        18          4          2          2 |        26


There were still 4/26 cases with CIN2+ (2 CIN2 and 2 CIN3). Three of them were
retreated. They were all detected by VILI. 18/26 did not show any sign of CIN and 4
cases only showed low grade CIN.

The high frequency of missing values in the follow-up files and the low attendance at
triage and post-treatment follow-up seriously compromises the quality of information
on the safety, acceptability and effectiveness of cryotherapy in this study. Safety and
acceptability of cryotherapy will be addressed in extenso in the next two studies,
conducted in Thailand and Ghana.




                                                                                    47
5.5. Safety, acceptability, and feasibility of a single-visit
     approach to cervical-cancer prevention in rural Thailand

Among the 5999 women tested by VIA in the Thai demonstration project, 5146 were negative, 51
had an indeterminate result, 798 had a positive result and 4 showed clinical signs compatible with
suspicion of cervical cancer (see flowchart in
Figure 5).



Figure 5. Flow of participants through the different steps of the Thai demonstration project.


                                                          5999
                                                       women tested




                                  51                                                                           4
       5146                                                                      798
                            indeterminate                                                                 suspect for
 negative VIA test                                                        positive VIA test
                               VIA test                                                                     cancer
     (85.8%)                                                                  (13.3%)
                               (0.9%)                                                                      (0.067%)



                                              33                                              60                               4
                                        no cryo-therapy                                 no cryo-therapy                 no cryo-therapy




                                  18                                            738
                            received cryo                                  received cryo
                               (35.3%)                                        (92.5%)




                       8                    10                       607                   131
                 immediate cryo       postponed cryo            immediate cryo        postponed cryo
                    (44.4%)              (55.6%)                   (82.3%)               (17,7%)




                                                          629
                                                    folow-up at 3-4M
                                                     (83.2% of 756)



                                                                       707
                                                                  folow-up at 1Y
                                                                  (93.5% of 756)




The VIA test positivity rate did not differ significantly between fixed services (district
hospitals) or mobile services set up at the health centers (p for χ2=0.13), but differed
significantly by district (p for χ2=0.00). Nevertheless, the variation by district was not
so large (between 9.4% in Pathumrat and 14.3% in Kasetwisai).




                                                                                                                                     48
Table 16. Frequency distribution of the different VIA categories for all districts combined and for the
districts Katsetwisai, Pathumrat, Chaturapakpiman and Phanomphrai.
                All districts             95% CI
VIA                         N   %     lower upper
Negative                 5146   85.8% 84.9% 86.7%
Indeterminate              51     0.9% 0.6% 1.1%
Positive                  798   13.3% 12.4% 14.2%
Suspect Ca                  4     0.1% 0.0% 0.1%
Total                    5999    100%

                Kasetwisai               95% CI  Pathumrat                            95% CI
VIA                         N   %    lower upper          N              %     lower      Upper
Negative                 1051 85.7% 83.7% 87.6%       1130               85.6%     83.7%      87.5%
Indeterminate               1   0.1% 0.0% 0.2%           43               3.3%       0.0%       4.2%
Positive                  175 14.3% 12.3% 16.2%        147               11.1%       9.4%     12.8%
Suspect Ca                  0   0.0% 0.0% 0.0%             0              0.0%       0.0%       0.0%
Total                    1227 100.0%                  1320              100.0%

              Chaturapakpiman          95% CI  Phanomphrai                            95% CI
VIA                      N    %    lower upper         N                %      lower      Upper
Negative              1675 85.8% 84.2% 87.3%        1290                85.8%      84.0%      87.6%
Indeterminate            6     0.9% 0.4% 1.3%          1                  0.9%       0.4%       1.3%
Positive               307 13.3% 11.8% 14.8%         169                13.3%      11.6%      15.0%
Suspect Ca               2     0.0% 0.0% 0.1%          2                  0.0%       0.0%       0.1%
Total                 1990    100%                  1462                 100%

The VIA positivity rate did not differ significantly by age group. The rate differed by
VIA provider, but when controlling for district it differed by provider only in the
district of Chaturapakpiman. The inter-provider range was 9.4%-17.8%.

In total 756 women received cryotherapy (18/51 = 35.3% of women with an
intermediate result; 738/798=92.5% of women being VIA+). Of 756 treated women,
615 (81.3%) received cryotherapy the same day.

Of 756 treated women, 629 (83.2%) presented for the planned follow-up at 3 months
after treatment and 707 (93.5%) of treated women presented for the final follow-up
visit at one year. The main experiences of tested and treated women are presented in
Table 17 below.

The data in the tables clearly show that the level of acceptance among tested and
treated women is high, the number of secondary effects is low, and if present they are
mild and of short duration. The rate of residual disease 1 year after treatment is low
as well.




                                                                                                     49
Table 17. Selection of answers to questionnaires, observations of health providers and experiences of women after testing, cryotherapy and post-therapy follow-up
Question (Thailand).                                            Definition of denominator                         Denominator Percent
Experience about testing
Satisfaction about being tested                                 Tested woman                                               5742   98.5%
Experience of being tested was better than expected             Tested woman                                               5729   89.6%
Declared having received enough information                     Tested woman                                               5709   99.8%

Compliance with treatment decision
Management decision to treat immediately                        Women being VIA+                                            780   77.7%
Management decision to treat immediately                        Women being VIA indeterminate                                22   36.4%
Management decision to treat immediately                        Women being VIA+ or indeterminate                           802   76.6%
Received cryotherapy                                            Women VIA+,indet,ca                                         802   92.0%
Received cryotherapy                                            Women being VIA+                                            798   92.5%
Received cryotherapy                                            Women being VIA indeterminate                                51   35.3%
Received cryotherapy                                            Women being VIA+ or indeterminate                           853   88.6%
Received cryotherapy on same day                                Women being VIA+ and treated                                738   82.2%
Received cryotherapy on same day                                Women being VIA indeterminate and treated                    18   44.4%
Received cryotherapy on same day                                Women being VIA+ or indeterminate and treated               756   81.3%
Reason to postpone: menstruation                                Management decision to postpone treatment                   125   80.8%
Reason to postpone: lacking material                            Management decision to postpone treatment                   125    8.0%
Treatment of postponed women                                    Management decision to postpone treatment                   126   91.3%
Treatment of referred women                                     Management decision to refer                                 65   16.9%
Referred women                                                  All                                                        5999    1.2%
Reason of reference: suspicion of cancer                        Referred women                                               74    5.4%
Reason of reference: lesion occupying >75% of TZ                Referred women                                               74   31.1%
Reason of reference: lesion extending to vagina                 Referred women                                               74   28.4%
Reason of reference: large fibroma                              Referred women                                               74    8.1%
Reason of reference: adnexal mass                               Referred women                                               74    2.7%
Reason of reference: other                                      Referred women                                               74   23.0%
Reason of reference: bleeding                                   Referred women                                               74    0.0%




                                                                                                                                                                    50
Question (Thailand).                                          Definition of denominator                        Denominator Percent
Experience at the moment of treatment
Pain reported by provider                                     Treated women                                            756 39.6%
Pain was mild                                                 Treated women reporting pain                             290 79.0%
Pain was moderate                                             Treated women reporting pain                             290 18.3%
Pain was severe                                               Treated women reporting pain                             290   2.8%
An analgesic drug was given                                   Treated women reporting pain                             746   6.2%
Pain reported by women immediately after cryo                 Treated women                                            753 40.8%
Bleeding after cryotherapy                                    Treated women                                            748   1.7%
Bleeding was mild                                             Treated women reporting bleeding                          11 100.0%
Bleeding could be treated by pressure                         Treated women reporting bleeding                          10 100.0%
Satisfaction about being treated                              Treated women                                            752 99.1%
Experience of treatment was better than expected              Treated women                                            752 93.0%
Declared having received enough information about treatment   Treated women                                            744 99.5%
Woman will recommend VIA testing to others                    Women with negative VIA result                          5122 99.8%
Woman will recommend VIA testing to others                    Women with positive VIA result                           751 97.5%

Problem visit of a health structure
Women contacted health service after cryotherapy              Treated women                                            756    4.4%
The visit: related to the cryotherapy                         Women having contacted a health service                   33   21.2%
Reason of problem visit: bleeding related to menses           Women having contacted a health service                   33    9.1%
Reason of problem visit: bleeding unrelated to menses         Women having contacted a health service                   33   12.1%
Reason of problem visit: pain/cramping unrelated to menses    Women having contacted a health service                   33   27.3%
Reason of problem visit was: abnormal vaginal discharge       Women having contacted a health service                   34   44.1%
Reason of problem visit: chills/hot sweats/fever              Women having contacted a health service                   35    2.9%
Reason of problem visit: another problem                      Women having contacted a health service                   36    2.8%

Planned follow-up visit at 3 months
Attended at the visit                                         Treated women                                            756   83.2%
Had bleeding not associated with menses                       Treated women presenting at 3M follow-up visit           627    2.9%




                                                                                                                                     51
Question (Thailand).                                       Definition of denominator                      Denominator Percent
Observed presence of blood clots                           Treated women presenting at 3M follow-up visit         627    0.5%
Had pain or cramping not associated with menses            Treated women presenting at 3M follow-up visit         626 13.6%
Observed changes in menstruation                           Treated women presenting at 3M follow-up visit         552 10.0%
Less menstrual blood loss since cryotherapy                Treated women presenting at 3M follow-up visit         552    5.6%
More menstrual blood loss since cryotherapy                Treated women presenting at 3M follow-up visit         552    4.3%
Changed duration of menstruation                           Treated women presenting at 3M follow-up visit         552    7.4%
Shorter menses                                             Treated women presenting at 3M follow-up visit         552    4.3%
Longer menses                                              Treated women presenting at 3M follow-up visit         552    3.1%
Change in menstrual cramping                               Treated women presenting at 3M follow-up visit         552 11.4%
More cramping                                              Treated women presenting at 3M follow-up visit         552 10.0%
Less cramping                                              Treated women presenting at 3M follow-up visit         552    1.4%
Abnormal vaginal discharge                                 Treated women presenting at 3M follow-up visit         628    0.5%
Woman will recommend VIA testing to others                 Treated women presenting at 3M follow-up visit         627 97.9%

Compliance with recommendation concerning sexual hygiene
Woman had sex after treatment                             Treated women presenting at 3M follow-up visit         628   72.3%
Woman had sex only after 4W post-treatment                Treated women presenting at 3M follow-up visit         459   69.1%
Woman had sex within 4W post-treatment                    Treated women presenting at 3M follow-up visit         459   30.9%
Condom use if sex within 4W post-treatment                Having had sex <4W post-treatment                      142   89.4%
Condom use all the time if sex within 4W post-treatment   Having had sex <4W post-treatment                      142   79.6%
No condom use if sex within 4W post-treatment             Having had sex <4W post-treatment                      142   10.6%
Declared that abstinence from sex should not be a problem Treated women                                          756   92.2%
Had problem convincing partner to abstain                 Treated women presenting at 3M follow-up visit         628    7.2%
Had problem convincing partner to use condoms             Treated women presenting at 3M follow-up visit         454    2.9%
Husband was satisfied about decision for treatment        Treated women presenting at 3M follow-up visit         628   94.9%




                                                                                                                                52
Question (Thailand).                             Definition of denominator                    Denominator Percent
Planned follow-up at 12 months after treatment
Attended at follow-up                            Treated women                                        756     93.5%
Suspect for cancer at VIA examination            Treated women, attending at 12 month visit           704      0.1%
VIA positive                                     Treated women, attending at 12 month visit           704      5.7%
Indeterminate VIA result                         Treated women, attending at 12 month visit           704      0.3%




                                                                                                                      53
5.6. Safety, acceptability, and feasibility of a single-visit
     approach to cervical cancer prevention in Ghana

Of the 3665 women who participated in the Ghanaian demonstration project,3177 had
a negative VIA test result, 484 were positive and 4 were suspect for cancer (see
flowchart in Figure 6).

Figure 6. Flow of participants through the different steps of the Ghanaian demonstration project.



                                                           3665
                                                        women tested




                                                                                   4
       3177                       484
                                                                               suspect for
 negative VIA test         positive VIA test
                                                                                 cancer
     (86.7%)                   (13.2%)
                                                                                (0.11%)



                                               47                                                   2
                                         no cryo-therapy                                     no cryo-therapy




                                 437                                                2
                            received cryo                                     received cryo
                               (90.3%)                                           (50%%)




                      308                   129                         0                       2
                 immediate cryo        postponed cryo             received cryo          postponed cryo
                    (70.5%)               (29.5%)                     (0%)                   (100%)




                                                           339
                                                     folow-up at 3-4M
                                                      (77.2% of 439)



                                                                             241
                                                                        folow-up at 1Y
                                                                        (54.9% of 439)




                                                                                                               54
The VIA test positivity rate varied significantly by age group: it was highest in the
youngest age group (16.0% in the 25-29 age group) and decreased until 10.6% in the
age group 35-39 (see Table 18). After the age of 40 the positivity rate rose about 2%.

Table 18. Frequency distribution of the different VIA categories by 5-year age group.
Age group          Negative     VIA+     Suspect Ca      Total
25-29                    852        163            1        1016
                      83.9%       16.0%        0.1%      100.0%
30-34                    820        132            1         953
                      86.0%       13.9%        0.1%      100.0%
35-39                    830          98           0         928
                      89.4%       10.6%        0.0%      100.0%
40-49                    563          71           1         635
                      88.7%       11.2%        0.2%      100.0%
45-49                    107          16           1         124
                      86.3%       12.9%        0.8%      100.0%
Total                  3175         481            4        3660

Pearson chi2(8) = 22.2016 Pr = 0.005

The test positivity rate also varied significantly by provider (range: 10.1%-17%).

In total, 437 of the 484 (90.3%) VIA-positive women received cryotherapy, among
whom 308 were treated the same day (70.5%). Also 2 cases, suspect for cancer at VIA
but confirmed free of cancer at the reference hospital, received cryotherapy.

Of 439 treated women, 339 (77.2%) presented for the planned follow-up at 3 months
after treatment and 241 (54.9%) of treated women were present at the final follow-up
visit at one year. The main experiences of tested and treated women are presented in
Table 17 below. No major complications were noted. The reported side effects were
rare or mild. Twenty-three percent mentioned pain after treatment, which was mild in
86% of the cases reporting pain. In two percent of women mild blood loss was
observed, which was easily treated with simple pressure. The reported side effects
were rare. Only 1% of treated women contacted the health service after treatment and
more than 98% of treated women declared themselves to be satisfied with the received
procedure.

As in the Thai study, we can conclude that cryotherapy offered to VIA-positive
women is an acceptable and safe strategy.

In the Amasaman Health Center, 3206 women participated and were tested with VIA.
The test positivity rate was 5.9%. The Amasaman data will be analyzed when a
completely documented data file will be obtained.




                                                                                        55
Table 19. Selection of answers to questionnaires, observations of health providers and experiences of women after testing, cryotherapy and post-therapy follow-up
Question (Ghana, Accra)                                         Definition of denominator                         Denominator Percent
Experience about testing
Satisfaction about being tested                                 Tested woman                                               3621      79.8%
Experience of being tested was better than expected             Tested woman                                               3598      83.6%
Declared having received enough information                     Tested woman                                               3582      99.7%

Compliance with treatment decision
Management decision to treat immediately                        Women being VIA+                                            480      74.4%
Management decision to treat immediately                        Women being VIA+ or indeterminate                           480      74.4%
Received cryotherapy                                            Women VIA+,indet,ca                                         488      90.0%
Received cryotherapy                                            Women being VIA+                                            484      90.3%
Received cryotherapy                                            Women being VIA+ or indeterminate                           488      90.0%
Received cryotherapy on same day                                Women being VIA+ and treated                                437      70.5%
Received cryotherapy on same day                                Women being VIA+ or indeterminate and treated               437      70.5%
Reason to postpone: menstruation                                Management decision to postpone treatment                   141       1.4%
Reason to postpone: lacking material                            Management decision to postpone treatment                   141       5.7%
Treatment of postponed women                                    Management decision to postpone treatment                   113      69.9%
Treatment of referred women                                     Management decision to refer                                 13      61.5%
Reason of reference: suspicion of cancer                        Referred women                                               25      16.0%
Reason of reference: lesion occupying >75% of TZ                Referred women                                               25       0.0%
Reason of reference: lesion extending to vagina                 Referred women                                               25       0.0%
Reason of reference is fibroma (size ~>20W pregnant uterus)     Referred women                                               25      28.0%
Reason of reference: adnexal mass                               Referred women                                               25       0.0%
Reason of reference: other                                      Referred women                                               25      48.0%
Reason of reference: bleeding                                   Referred women                                               25      20.0%

Experience at the moment of treatment
Pain reported by provider                                       Treated women                                               412      22.6%
Pain was mild                                                   Treated women reporting pain                                 90      85.6%
Pain was moderate                                               Treated women reporting pain                                 90      12.2%
Pain was severe                                                 Treated women reporting pain                                 90       2.2%

                                                                                                                                                                    56
Question (Ghana, Accra)                                             Definition of denominator                          Denominator Percent
An analgesic drug was given                                         Treated women reporting pain                               422     1.7%
Pain reported by women immediately after cryotherapy                Treated women                                              413    34.9%
Bleeding after cryotherapy                                          Treated women                                              400     2.0%
Bleeding was mild                                                   Treated women reporting bleeding                             5   100.0%
Bleeding could be treated by pressure                               Treated women reporting bleeding                             8    12.5%
Satisfaction about being treated                                    Treated women                                              421    98.6%
Experience of treatment was better than expected                    Treated women                                              428    82.5%
Declared having received enough information about treatment         Treated women                                              412    98.8%
Woman will recommend VIA testing to others                          Women with negative VIA result                            3115    99.2%
Woman will recommend VIA testing to others                          Women with positive VIA result                             417    99.8%

Problem visit of a health structurea
Women contacted health service after cryotherapy                    Treated women                                             439       1.1%
The visit: related to the cryotherapy                               Women having contacted a health service            -            -
Reason of problem visit: bleeding related to menses                 Women having contacted a health service            -            -
Reason of problem visit: bleeding unrelated to menses               Women having contacted a health service            -            -
Reason of problem visit: pain/cramping unrelated to menses          Women having contacted a health service            -            -
Reason of problem visit was: abnorm vaginal discharge               Women having contacted a health service            -            -
Reason of problem visit: chills/hot sweats/fever                    Women having contacted a health service            -            -
Reason of problem visit: another problem                            Women having contacted a health service            -            -

Planned follow-up visit at 3 months
Attended at the visit                                               Treated women                                             439       77.2%
Had bleeding not associated with menses                             Treated women presenting at 3M follow-up visit            324        6.2%
Observed presence of blood clots                                    Treated women presenting at 3M follow-up visit            337        2.4%
Had pain or cramping not associated with menses                     Treated women presenting at 3M follow-up visit            316       10.1%
Observed changes in menstruation                                    Treated women presenting at 3M follow-up visit            337       20.5%
Less menstrual blood loss since cryotherapy                         Treated women presenting at 3M follow-up visit            337        5.9%
More menstrual blood loss since cryotherapy                         Treated women presenting at 3M follow-up visit            337       14.5%


a
    The problem visit variables in the Accra file could not be analysed because of lack of codebook and data labels.

                                                                                                                                                57
Question (Ghana, Accra)                                    Definition of denominator                      Denominator Percent
Changed duration of menstruation                           Treated women presenting at 3M follow-up visit         337    16.0%
Shorter menses                                             Treated women presenting at 3M follow-up visit         337     5.0%
Longer menses                                              Treated women presenting at 3M follow-up visit         337    11.0%
Change in menstrual cramping                               Treated women presenting at 3M follow-up visit         337    17.5%
More cramping                                              Treated women presenting at 3M follow-up visit         337     8.0%
Less cramping                                              Treated women presenting at 3M follow-up visit         337     9.5%
Abnormal vaginal discharge                                 Treated women presenting at 3M follow-up visit         310     5.5%
Woman will recommend VIA testing to others                 Treated women presenting at 3M follow-up visit         335    98.5%

Compliance with recommendation concerning sexual hygiene
Woman had sex after treatment                             Treated women presenting at 3M follow-up visit        337     68.0%
Woman had sex only after 4W post-treatment                Treated women presenting at 3M follow-up visit        229     85.6%
Woman had sex within 4W post-treatment                    Treated women presenting at 3M follow-up visit        229     14.4%
Condom use if sex within 4W post-treatment                Having had sex <4W post-treatment                      32     96.9%
Condom use all the time if sex within 4W post-treatment   Having had sex <4W post-treatment                      30     86.7%
No condom use if sex within 4W post-treatment             Having had sex <4W post-treatment                      32      3.1%
Declared that abstinence from sex should not be a problem Treated women                                         422     85.1%
Had problem convincing partner to abstinate               Treated women presenting at 3M follow-up visit        337      7.7%
Had problem convincing partner to use condoms             Treated women presenting at 3M follow-up visit        337      8.3%
Husband was satisfied about decision for treatment        Treated women presenting at 3M follow-up visit        337     78.9%

Planned follow-up at 12 months after treatment
Attended at follow-up                                      Treated women                                        439     54.9%
Suspect for cancer at VIA examination                      Treated women, attending at 12 month visit           232      0.0%
VIA positive                                               Treated women, attending at 12 month visit           232      2.6%
Indeterminate VIA result                                   Treated women, attending at 12 month visit           232      0.0%
VIA technically impossible                                 Treated women, attending at 12 month visit           232      2.2%




                                                                                                                                 58
6. Pooled analyses
In the next subchapter we will pool the available test characteristics of the five screening
methods applied in the respective ACCP studies. Test positivity rates of VIA are
documented in all studies. The positive predictive value of VIA can be evaluated from four
studies, where screen positive women are submitted to gold standard verification: the cross
sectional multi-center study, the Zimbabwe cross-sectional study, the Ambilikai RCT and
the Kenyan WKCCPP study. In these four studies also the detection rate of disease and the
approximated specificity can be derived. Finally, the sensitivity, specificity and negative
predictive value can only be assessed in the multi-center cross-sectional study and in the
Zimbabwean study, where all screened women are verified with a gold-standard.
In the next five subchapters we describe subsequently the test characteristics of VIA, VILI,
VIAM, high-risk HPV type detection by Hybrid Capture II and the conventional Pap smear,
considered at 3 cytological cutoffs (ASCUS+, LSIL+ and HSIL+) for each outcome
(CIN1+, CIN2+, CIN3+ and cancer). We present for each parameter of a given test the
forest plot and the meta-analytically pooled measure. Subsequently, we pool the ratio of
the sensitivity and specificity from the multi-center and Zimbabwe cross-sectional studies.



6.1. Meta-analysis of test characteristics of applied screening
     methods

6.1.1. Test characteristics of VIA
The accuracy of VIA is assessed for the outcomes CIN1+, CIN2+, CIN3+ and cancer (see
Table 20).

Table 20. Test characteristics of VIA assessed in 14 locations.
A: Outcome=CIN1+
Setting      Country       TP      FN       FP      TN        T+        N      Se      Sp    PPV    NPV T+ rate    Prev Det rate
Bamako       Mali          253     278     371    4,650      624    5,552   0.476   0.926   0.405   0.944 0.112   0.096   0.046
Brazzaville  Congo         452     179   1,393    4,911    1,845    6,935   0.716   0.779   0.245   0.965 0.266   0.091   0.065
Conakry      Guinea        205     252     475    7,695      680    8,627   0.449   0.942   0.301   0.968 0.079   0.053   0.024
Jaipur       India         207      23   1,275    4,281    1,482    5,786   0.900   0.771   0.140   0.995 0.256   0.040   0.036
Kolkata 1    India         316     194     806    4,578    1,122    5,894   0.620   0.850   0.282   0.959 0.190   0.087   0.054
Kolkata 2    India         135     183     775    6,987      910    8,080   0.425   0.900   0.148   0.974 0.113   0.039   0.017
Mumbai       India         129      77     388    3,410      517    4,004   0.626   0.898   0.250   0.978 0.129   0.051   0.032
Niamey       India          31      20     121    2,362      152    2,534   0.608   0.951   0.204   0.992 0.060   0.020   0.012
Ouagadougou B-Fasso         73      11     488    1,479      561    2,051   0.869   0.752   0.130   0.993 0.274   0.041   0.036
Trivandrum 1 India         397     316     680    3,064    1,077    4,457   0.557   0.818   0.369   0.907 0.242   0.160   0.089
Trivandrum 2 India         231     187     348    3,993      579    4,759   0.553   0.920   0.399   0.955 0.122   0.088   0.049
Harare       Zimbabwe      347     217     502    1,064      849    2,130   0.615   0.679   0.409   0.831 0.399   0.265   0.163
Total 1a                 2,776   1,937   7,622   48,474   10,398   60,809   0.589   0.864   0.267   0.962 0.171   0.078   0.046
Ambilikai    India       1,871           1,110             2,981   31,282                   0.628         0.095           0.060
Busia        Kenya         163             281               444    2,295                   0.367         0.193           0.071
Total 2b                 4,810           9,013            13,823   94,386                   0.348         0.146           0.051



a
  Total 1: total of all studies with complete verification using colposcopy and biopsy from colposcopically
suspect areas.
b
  Total 2: total of all studies with complete and incomplete verification; where incomplete verification
involved only test positive cases. Total 2 includes Total 1 & Ambilikai RCT and the Busia study.


                                                                                                                  59
B: Outcome=CIN2+
Setting     Country         TP    FN       FP      TN        T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Bamako         Mali         130    34      494    4,894      624    5,552   0.793   0.908   0.208   0.993   0.112   0.030   0.023
Brazzaville    Congo        313    76    1,532    5,014    1,845    6,935   0.805   0.766   0.170   0.985   0.266   0.056   0.045
Conakry        Guinea       153    15      527    7,932      680    8,627   0.911   0.938   0.225   0.998   0.079   0.019   0.018
Jaipur         India         56     8    1,426    4,296    1,482    5,786   0.875   0.751   0.038   0.998   0.256   0.011   0.010
Kolkata 1      India         99    62    1,023    4,710    1,122    5,894   0.615   0.822   0.088   0.987   0.190   0.027   0.017
Kolkata 2      India         52    19      858    7,151      910    8,080   0.732   0.893   0.057   0.997   0.113   0.009   0.006
Mumbai         India         50    31      467    3,456      517    4,004   0.617   0.881   0.097   0.991   0.129   0.020   0.012
Niamey         India         13     7      139    2,375      152    2,534   0.650   0.945   0.086   0.997   0.060   0.008   0.005
Ouagadougou    B-Fasso       45     5      516    1,485      561    2,051   0.900   0.742   0.080   0.997   0.274   0.024   0.022
Trivandrum 1   India        132    17      945    3,363    1,077    4,457   0.886   0.781   0.123   0.995   0.242   0.033   0.030
Trivandrum 2   India         65    16      514    4,164      579    4,759   0.802   0.890   0.112   0.996   0.122   0.017   0.014
Harare         Zimbabwe     158    48      691    1,233      849    2,130   0.767   0.641   0.186   0.963   0.399   0.097   0.074
Total 1                   1,266   338    9,132   50,073   10,398   60,809   0.789   0.846   0.122   0.993   0.171   0.026   0.021
Ambilikai      India        272          2,709             2,981   31,282                   0.091           0.095           0.009
Busia          Kenya         47            397               444    2,295                   0.106           0.193           0.020
Total 2                   1,585         12,238            13,823   94,386                   0.115           0.146           0.017



C: Outcome=CIN3+
Setting     Country         TP    FN       FP      TN        T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Bamako         Mali         75      8      549    4,920      624    5,552   0.904   0.900   0.120   0.998   0.112   0.015   0.014
Brazzaville    Congo       176     24    1,669    5,066    1,845    6,935   0.880   0.752   0.095   0.995   0.266   0.029   0.025
Conakry        Guinea      113     10      567    7,937      680    8,627   0.919   0.933   0.166   0.999   0.079   0.014   0.013
Jaipur         India        40      6    1,442    4,298    1,482    5,786   0.870   0.749   0.027   0.999   0.256   0.008   0.007
Kolkata 1      India        64     35    1,058    4,737    1,122    5,894   0.646   0.817   0.057   0.993   0.190   0.017   0.011
Kolkata 2      India        29     10      881    7,160      910    8,080   0.744   0.890   0.032   0.999   0.113   0.005   0.004
Mumbai         India        37     22      480    3,465      517    4,004   0.627   0.878   0.072   0.994   0.129   0.015   0.009
Niamey         India         7      5      145    2,377      152    2,534   0.583   0.943   0.046   0.998   0.060   0.005   0.003
Ouagadougou    B-Fasso      33      4      528    1,486      561    2,051   0.892   0.738   0.059   0.997   0.274   0.018   0.016
Trivandrum 1   India        53      3    1,024    3,377    1,077    4,457   0.946   0.767   0.049   0.999   0.242   0.013   0.012
Trivandrum 2   India        51     10      528    4,170      579    4,759   0.836   0.888   0.088   0.998   0.122   0.013   0.011
Total 1                    678    137    8,871   48,993    9,549   58,679   0.832   0.847   0.071   0.997   0.163   0.014   0.012
Ambilikai      India       131           2,850             2,981   31,282                   0.044           0.095           0.004
Busia          Kenya        24             420               444    2,295                   0.054           0.193           0.010
Total 2                    833          12,141            12,974   92,256                   0.064           0.141           0.009



D: Outcome=Cancer
Setting     Country         TP    FN       FP      TN        T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Ouagadougou    B-Fasso      14     3    547       1,487      561    2,051   0.824   0.731   0.025   0.998   0.274   0.008   0.007
Kolkata 1      India        30     8 1,092        4,764    1,122    5,894   0.789   0.814   0.027   0.998   0.190   0.006   0.005
Kolkata 2      India         8     0    902       7,170      910    8,080   1.000   0.888   0.009   1.000   0.113   0.001   0.001
Brazzaville    Congo        22     4 1,823        5,086    1,845    6,935   0.846   0.736   0.012   0.999   0.266   0.004   0.003
Conakry        Guinea       84     5    596       7,942      680    8,627   0.944   0.930   0.124   0.999   0.079   0.010   0.010
Jaipur         India         4     2 1,478        4,302    1,482    5,786   0.667   0.744   0.003   1.000   0.256   0.001   0.001
Bamako         Mali         52     2    572       4,926      624    5,552   0.963   0.896   0.083   1.000   0.112   0.010   0.009
Mumbai         India        20     7    497       3,480      517    4,004   0.741   0.875   0.039   0.998   0.129   0.007   0.005
Niamey         India         3     2    149       2,380      152    2,534   0.600   0.941   0.020   0.999   0.060   0.002   0.001
Trivandrum 1   India         6     0 1,071        3,380    1,077    4,457   1.000   0.759   0.006   1.000   0.242   0.001   0.001
Trivandrum 2   India        13     2    566       4,178      579    4,759   0.867   0.881   0.022   1.000   0.122   0.003   0.003
Harare         Zimbabwe      3     0    846       1,281      849    2,130   1.000   0.602   0.004   1.000   0.399   0.001   0.001
Total 1                    259    35 10,139      50,376   10,398   60,809   0.881   0.832   0.025   0.999   0.171   0.005   0.004
Ambilikai      India        66        2,915                2,981   31,282                   0.022           0.095           0.002
Busia          Kenya         9          435                  444    2,295                   0.020           0.193           0.004
Total 2                    334       13,489               13,823   94,386                   0.024           0.146           0.004




                                                                                                                    60
E: Test positivity rate
Setting           Country                          T+        N             T+ rate
Bamako          Mali                              624     5,552              0.112
Brazzaville     Congo                            1,845    6,935              0.266
Conakry         Guinea                            680     8,627              0.079
Jaipur          India                            1,482    5,786              0.256
Kolkata 1       India                            1,122    5,894              0.190
Kolkata 2       India                             910     8,080              0.113
Mumbai          India                             517     4,004              0.129
Niamey          India                             152     2,534              0.060
Ouagadougou     B-Fasso                           561     2,051              0.274
Trivandrum 1    India                            1,077    4,457              0.242
Trivandrum 2    India                             579     4,759              0.122
Harare          Zimbabwe                          849     2,130              0.399
Ambilikai       India                            2,981   31,282              0.095
Busia           Kenya                             444     2,295              0.193
Chaturapakpiman Thailand                          309     1,990              0.155
Kasetwisai      Thailand                          175     1,227              0.143
Pathumrat       Thailand                          147     1,320              0.111
Phanomphrai     Thailand                          171     1,462              0.117
Accra           Ghana                             488     3,665              0.133
Amasaman        Ghana                              194   3,206               0.061
Total                                           15,307 107,256               0.143




                            VIA; all studies

         Bamako
      Brazzaville
        Conakry
           Jaipur
       Kolkata 1
       Kolkata 2
        Mumbai
         Niamey
   Ouagadougou
   Trivandrum 1
   Trivandrum 2
          Harare
       Ambilikai
           Busia
Chaturapakpiman
      Kasetwisai
       Pathumrat
    Phanomphrai
           Accra
      Amasaman
            Combined
                             0          .1       .2           .3      .4             .5
                                               Test positivity rate

Meta-analysis of the test-positivity rate of VIA (including all studies)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.121   0.119   0.122 123.289     0.000     20
Random |   0.162   0.134   0.191   11.164    0.000
Test for heterogeneity: Q= 3708.324 on 19 degrees of freedom (p= 0.000)




                                                                                     61
                VIA, Outcome=CIN1+                                                       VIA, Outcome=CIN1+

     Bamako                                                                   Bamako
  Brazzaville                                                              Brazzaville
     Conakry                                                                  Conakry
       Jaipur                                                                   Jaipur
    Kolkata 1                                                                Kolkata 1
    Kolkata 2                                                                Kolkata 2
     Mumbai                                                                   Mumbai
     Niamey                                                                   Niamey
Ouagadougou                                                              Ouagadougou
Trivandrum 1                                                             Trivandrum 1
Trivandrum 2                                                             Trivandrum 2
      Harare                                                                   Harare
   Combined                                                                 Combined
                0   .1   .2   .3     .4    .5    .6   .7   .8   .9   1                   0    .1   .2        .3   .4    .5    .6   .7        .8   .9   1
                                       Sensitivity                                                                  Specificity
                VIA, Outcome=CIN1+                                                       VIA, Outcome=CIN1+

     Bamako                                                                   Bamako
  Brazzaville                                                              Brazzaville
     Conakry                                                                  Conakry
       Jaipur                                                                   Jaipur
    Kolkata 1
    Kolkata 2                                                                Kolkata 1
     Mumbai                                                                  Kolkata 2
     Niamey                                                                   Mumbai
Ouagadougou                                                                   Niamey
Trivandrum 1                                                             Ouagadougou
Trivandrum 2                                                             Trivandrum 1
      Harare
   Ambilikai                                                             Trivandrum 2
        Busia                                                                  Harare
   Combined                                                                 Combined
                0   .1   .2   .3     .4    .5    .6   .7   .8   .9   1                   .6             .7             .8               .9             1
                                          PPV                                                                         NPV


Meta-analysis of the sensitivity of VIA+ (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.621   0.608   0.634   91.859    0.000     12
Random |   0.618   0.532   0.703   14.170    0.000
Test for heterogeneity: Q= 441.564 on 11 degrees of freedom (p= 0.000)

Meta-analysis of specificity of VIA+ (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.894   0.891   0.896 701.545     0.000     12
Random |   0.849   0.812   0.887   44.271    0.000
Test for heterogeneity: Q= 2368.152 on 11 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIA+ (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.310   0.303   0.317   84.731    0.000     14
Random |   0.306   0.211   0.400    6.346    0.000
Test for heterogeneity: Q= 2162.335 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VIA+ (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.979   0.978   0.980 1554.227    0.000     12
Random |   0.957   0.945   0.969 152.887     0.000
Test for heterogeneity: Q= 975.985 on 11 degrees of freedom (p= 0.000)




                                                                                                                                                           62
                 VIA, Outcome=CIN1+                                                       VIA, Outcome=CIN1+

 Ouagadougou                                                              Ouagadougou
     Kolkata 1                                                                Kolkata 1
     Kolkata 2                                                                Kolkata 2
   Brazzaville                                                              Brazzaville
                                                                               Conakry
      Conakry                                                                    Jaipur
        Jaipur                                                                 Bamako
      Bamako                                                                   Mumbai
      Mumbai                                                                   Niamey
      Niamey                                                              Trivandrum 1
 Trivandrum 1                                                             Trivandrum 2
 Trivandrum 2                                                                   Harare
                                                                             Ambilikai
       Harare                                                                     Busia
    Combined                                                                 Combined
                 0        .1         .2         .3         .4        .5                   0        .1        .2           .3        .4   .5
                                 Prevalence of disease                                                  Detection rate of disease
                 VIA, Outcome=CIN1+

 Ouagadougou
     Kolkata 1
     Kolkata 2
   Brazzaville
      Conakry
        Jaipur
      Bamako
      Mumbai
      Niamey
 Trivandrum 1
 Trivandrum 2
       Harare
    Ambilikai
         Busia
    Combined
                 0   .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                               Approximative specificity



Meta-analysis of the prevalence of disease (CIN1+) in VIA studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.059   0.057   0.061   62.319    0.000     12
Random |   0.085   0.063   0.107    7.721    0.000
Test for heterogeneity: Q= 1440.016 on 11 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN1+) using VIA
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.039   0.038   0.040   62.587    0.000     14
Random |   0.053   0.040   0.066    8.277    0.000
Test for heterogeneity: Q= 1260.909 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIA (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.932   0.931   0.934 1135.602    0.000     14
Random |   0.865   0.832   0.897   51.610    0.000
Test for heterogeneity: Q= 3926.540 on 13 degrees of freedom (p= 0.000)




                                                                                                                                         63
                VIA, Outcome=CIN2+                                                                      VIA, Outcome=CIN2+

     Bamako                                                                                  Bamako
  Brazzaville                                                                             Brazzaville
     Conakry                                                                                 Conakry
       Jaipur                                                                                  Jaipur
    Kolkata 1                                                                               Kolkata 1
    Kolkata 2                                                                               Kolkata 2
     Mumbai                                                                                  Mumbai
     Niamey                                                                                  Niamey
Ouagadougou                                                                             Ouagadougou
Trivandrum 1                                                                            Trivandrum 1
Trivandrum 2                                                                            Trivandrum 2
      Harare                                                                                  Harare
   Combined                                                                                Combined
                0   .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    0    .1   .2         .3   .4    .5    .6   .7         .8   .9   1
                                           Sensitivity                                                                              Specificity
                VIA, Outcome=CIN2+                                                                      VIA, Outcome=CIN2+

     Bamako                                                                                  Bamako
  Brazzaville                                                                             Brazzaville
     Conakry                                                                                 Conakry
       Jaipur                                                                                  Jaipur
    Kolkata 1
    Kolkata 2                                                                               Kolkata 1
     Mumbai                                                                                 Kolkata 2
     Niamey                                                                                  Mumbai
Ouagadougou                                                                                  Niamey
Trivandrum 1                                                                            Ouagadougou
Trivandrum 2                                                                            Trivandrum 1
      Harare
   Ambilikai                                                                            Trivandrum 2
        Busia                                                                                 Harare
   Combined                                                                                Combined
                0        .1         .2        .3          .4             .5        .6                   .8             .85             .9               .95             1
                                             PPV                                                                                      NPV


Meta-analysis of the sensitivity of VIA+ (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.817   0.799   0.836   86.848    0.000     12
Random |   0.790   0.736   0.843   28.927    0.000
Test for heterogeneity: Q= 81.387 on 11 degrees of freedom (p= 0.000)

Meta-analysis of specificity of VIA+ (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.877   0.875   0.880 666.421     0.000     12
Random |   0.830   0.788   0.872   38.513    0.000
Test for heterogeneity: Q= 2794.893 on 11 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIA+ (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.092   0.087   0.097   38.023    0.000     14
Random |   0.118   0.091   0.146    8.347    0.000
Test for heterogeneity: Q= 403.079 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VIA+ (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.996   0.996   0.997 3748.138    0.000     12
Random |   0.993   0.991   0.996 889.063     0.000
Test for heterogeneity: Q= 160.584 on 11 degrees of freedom (p= 0.000)




                                                                                                                                                                            64
                VIA, Outcome=CIN2+                                                             VIA, Outcome=CIN2+

Ouagadougou                                                                    Ouagadougou
    Kolkata 1                                                                      Kolkata 1
    Kolkata 2                                                                      Kolkata 2
  Brazzaville                                                                    Brazzaville
                                                                                    Conakry
     Conakry                                                                          Jaipur
       Jaipur                                                                       Bamako
     Bamako                                                                         Mumbai
     Mumbai                                                                         Niamey
     Niamey                                                                    Trivandrum 1
Trivandrum 1                                                                   Trivandrum 2
Trivandrum 2                                                                         Harare
                                                                                  Ambilikai
      Harare                                                                           Busia
   Combined                                                                       Combined
                0             .05            .1           .15             .2                   0          .05              .1             .15   .2
                                    Prevalence of disease                                                       Detection rate of disease
                VIA, Outcome=CIN2+

Ouagadougou
    Kolkata 1
    Kolkata 2
  Brazzaville
     Conakry
       Jaipur
     Bamako
     Mumbai
     Niamey
Trivandrum 1
Trivandrum 2
      Harare
   Ambilikai
        Busia
   Combined
                0   .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                Approximative specificity



Meta-analysis of the prevalence of disease (CIN2+) in VIA studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.059   0.057   0.061   62.319    0.000     12
Random |   0.085   0.063   0.107    7.721    0.000
Test for heterogeneity: Q= 1440.016 on 11 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using VIA
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.012   0.011   0.012   33.537    0.000     14
Random |   0.021   0.016   0.025    8.351    0.000
Test for heterogeneity: Q= 522.856 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIA (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.891   0.889   0.893 884.553     0.000     14
Random |   0.837   0.804   0.870   49.710    0.000
Test for heterogeneity: Q= 3114.155 on 13 degrees of freedom (p= 0.000)




                                                                                                                                                     65
                VIA, Outcome=CIN3+                                                                      VIA, Outcome=CIN3+

     Bamako                                                                                  Bamako
  Brazzaville                                                                             Brazzaville
     Conakry                                                                                 Conakry
       Jaipur                                                                                  Jaipur
    Kolkata 1                                                                               Kolkata 1
    Kolkata 2                                                                               Kolkata 2
     Mumbai                                                                                  Mumbai
     Niamey                                                                                  Niamey
Ouagadougou                                                                             Ouagadougou
Trivandrum 1                                                                            Trivandrum 1
Trivandrum 2                                                                            Trivandrum 2

   Combined                                                                                Combined
                0   .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    .6         .7            .8        .9    1
                                           Sensitivity                                                                       Specificity
                VIA, Outcome=CIN3+                                                                      VIA, Outcome=CIN3+

     Bamako                                                                                  Bamako
  Brazzaville                                                                             Brazzaville
     Conakry                                                                                 Conakry
       Jaipur
    Kolkata 1                                                                                  Jaipur
    Kolkata 2                                                                               Kolkata 1
     Mumbai                                                                                 Kolkata 2
     Niamey                                                                                  Mumbai
Ouagadougou                                                                                  Niamey
Trivandrum 1                                                                            Ouagadougou
Trivandrum 2                                                                            Trivandrum 1
   Ambilikai
        Busia                                                                           Trivandrum 2

   Combined                                                                                Combined
                0        .1         .2        .3          .4             .5        .6                   .8         .85          .9         .95   1
                                             PPV                                                                               NPV


Meta-analysis of the sensitivity of VIA+ (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.871   0.849   0.894   76.818    0.000     11
Random |   0.829   0.771   0.887   28.126    0.000
Test for heterogeneity: Q= 56.160 on 10 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of VIA+ (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.875   0.872   0.878 649.327     0.000     11
Random |   0.842   0.800   0.883   39.554    0.000
Test for heterogeneity: Q= 2382.681 on 10 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIA+ (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.051   0.048   0.055   26.703    0.000     13
Random |   0.068   0.052   0.085    8.228    0.000
Test for heterogeneity: Q= 195.937 on 12 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VIA+ (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.998   0.999 5201.754    0.000     11
Random |   0.997   0.997   0.998 2178.608    0.000
Test for heterogeneity: Q= 48.227 on 10 degrees of freedom (p= 0.000)




                                                                                                                                                     66
                VIA, Outcome=CIN3+                                                             VIA, Outcome=CIN3+

Ouagadougou                                                                    Ouagadougou
    Kolkata 1                                                                      Kolkata 1
    Kolkata 2                                                                      Kolkata 2
                                                                                 Brazzaville
  Brazzaville                                                                       Conakry
     Conakry                                                                          Jaipur
       Jaipur                                                                       Bamako
     Bamako                                                                         Mumbai
     Mumbai                                                                         Niamey
     Niamey                                                                    Trivandrum 1
Trivandrum 1                                                                   Trivandrum 2
                                                                                  Ambilikai
Trivandrum 2                                                                           Busia
   Combined                                                                       Combined
                0             .05            .1           .15             .2                   0          .05              .1             .15   .2
                                    Prevalence of disease                                                       Detection rate of disease
                VIA, Outcome=CIN3+

Ouagadougou
    Kolkata 1
    Kolkata 2
  Brazzaville
     Conakry
       Jaipur
     Bamako
     Mumbai
     Niamey
Trivandrum 1
Trivandrum 2
   Ambilikai
        Busia
   Combined
                0   .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                Approximative specificity



Meta-analysis of the prevalence of disease (CIN3+) in VIA studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.010   0.010   0.011   24.979    0.000     11
Random |   0.014   0.010   0.017    6.819    0.000
Test for heterogeneity: Q= 205.416 on 10 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using VIA
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.006   0.006   0.007   23.963    0.000     13
Random |   0.010   0.008   0.013    7.388    0.000
Test for heterogeneity: Q= 267.316 on 12 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIA (CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.887   0.885   0.890 861.713     0.000     13
Random |   0.845   0.813   0.878   50.692    0.000
Test for heterogeneity: Q= 2705.057 on 12 degrees of freedom (p= 0.000)




                                                                                                                                                     67
                VIA, Outcome=Cancer                                                                      VIA, Outcome=Cancer

     Bamako                                                                                   Bamako
  Brazzaville                                                                              Brazzaville
     Conakry                                                                                  Conakry
       Jaipur                                                                                   Jaipur
    Kolkata 1                                                                                Kolkata 1
    Kolkata 2                                                                                Kolkata 2
     Mumbai                                                                                   Mumbai
     Niamey                                                                                   Niamey
Ouagadougou                                                                              Ouagadougou
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2
      Harare                                                                                   Harare
   Combined                                                                                 Combined
                0    .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    .6          .7            .8        .9    1
                                            Sensitivity                                                                        Specificity
                VIA, Outcome=Cancer                                                                      VIA, Outcome=Cancer

     Bamako                                                                                   Bamako
  Brazzaville                                                                              Brazzaville
     Conakry                                                                                  Conakry
       Jaipur                                                                                   Jaipur
    Kolkata 1
    Kolkata 2                                                                                Kolkata 1
     Mumbai                                                                                  Kolkata 2
     Niamey                                                                                   Mumbai
Ouagadougou                                                                                   Niamey
Trivandrum 1                                                                             Ouagadougou
Trivandrum 2                                                                             Trivandrum 1
      Harare
   Ambilikai                                                                             Trivandrum 2
        Busia                                                                                  Harare
   Combined                                                                                 Combined
                0         .1         .2        .3          .4             .5        .6                   .8         .85           .9         .95   1
                                              PPV                                                                                NPV


Meta-analysis of the sensitivity of VIA+ (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.925   0.895   0.955   60.452    0.000     12
Random |   0.891   0.837   0.945   32.455    0.000
Test for heterogeneity: Q= 19.855 on 11 degrees of freedom (p= 0.047)

Meta-analysis of the specificity of VIA+ (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.866   0.863   0.868 640.193     0.000     12
Random |   0.817   0.771   0.863   34.889    0.000
Test for heterogeneity: Q= 3143.746 on 11 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIA+ (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.008   0.011   11.744    0.000     14
Random |   0.025   0.017   0.032    6.429    0.000
Test for heterogeneity: Q= 220.219 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VIA+ (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   1.000   1.00011411.930    0.000     12
Random |   0.999   0.999   1.000 5265.901    0.000
Test for heterogeneity: Q= 35.123 on 11 degrees of freedom (p= 0.000)




                                                                                                                                                       68
                VIA, Outcome=Cancer                                                             VIA, Outcome=Cancer

Ouagadougou                                                                     Ouagadougou
    Kolkata 1                                                                       Kolkata 1
    Kolkata 2                                                                       Kolkata 2
  Brazzaville                                                                     Brazzaville
                                                                                     Conakry
     Conakry                                                                           Jaipur
       Jaipur                                                                        Bamako
     Bamako                                                                          Mumbai
     Mumbai                                                                          Niamey
     Niamey                                                                     Trivandrum 1
Trivandrum 1                                                                    Trivandrum 2
Trivandrum 2                                                                          Harare
                                                                                   Ambilikai
      Harare                                                                            Busia
   Combined                                                                        Combined
                0              .05            .1           .15             .2                   0          .05              .1             .15   .2
                                     Prevalence of disease                                                       Detection rate of disease
                VIA, Outcome=Cancer

Ouagadougou
    Kolkata 1
    Kolkata 2
  Brazzaville
     Conakry
       Jaipur
     Bamako
     Mumbai
     Niamey
Trivandrum 1
Trivandrum 2
      Harare
   Ambilikai
        Busia
   Combined
                0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                 Approximative specificity



Meta-analysis of the prevalence of disease (cancer) in VIA studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.002   0.003   11.886    0.000     12
Random |   0.004   0.003   0.006    5.439    0.000
Test for heterogeneity: Q= 154.944 on 11 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (cancer) using VIA
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.002   0.002   13.716    0.000     14
Random |   0.003   0.002   0.004    6.318    0.000
Test for heterogeneity: Q= 141.677 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIA (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.881   0.879   0.883 850.124     0.000     14
Random |   0.823   0.787   0.859   44.269    0.000
Test for heterogeneity: Q= 3590.107 on 13 degrees of freedom (p= 0.000)




                                                                                                                                                      69
6.1.2. Test characteristics of VILI
The accuracy of VILI is assessed for the outcomes CIN1+, CIN2+, CIN3+ and cancer (see
Table 21).

Table 21. Test characteristics of VILI assessed in 10 locations (included in the multi-center cross-sectional
study [Tables A-D]) and the test positivity rate of VILI observed at 11 locations (multi-center and Kenyan
study [Table E]).


A: Outcome=CIN1+
Setting      Country       TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Bamako         Mali       336    195    391     4,630    727     5,552   0.633   0.922   0.462   0.960   0.131   0.096        0.061
Brazzaville    Congo      556    74     538     5,766   1,094    6,934   0.883   0.915   0.508   0.987   0.158   0.091        0.080
Conakry        Guinea     301    156    673     7,497    974     8,627   0.659   0.918   0.309   0.980   0.113   0.053        0.035
Jaipur         India      212    18    1,387    4,169   1,599    5,786   0.922   0.750   0.133   0.996   0.276   0.040        0.037
Kolkata 2      India      159    157    979     6,781   1,138    8,076   0.503   0.874   0.140   0.977   0.141   0.039        0.020
Mumbai         India      159    47     527     3,270    686     4,003   0.772   0.861   0.232   0.986   0.171   0.051        0.040
Niamey         Niger       48     3     180     2,303    228     2,534   0.941   0.928   0.211   0.999   0.090   0.020        0.019
Ouagadougou    B-Fasso     78      6    510     1,457    588     2,051   0.929   0.741   0.133   0.996   0.287   0.041        0.038
Trivandrum 1   India      365    348    584     3,160    949     4,457   0.512   0.844   0.385   0.901   0.213   0.160        0.082
Trivandrum 2   India       261   157     419    3,922     680    4,759   0.624   0.903   0.384   0.962   0.143   0.088        0.055
Overall                  2,475 1,161   6,188   42,955   8,663   52,779   0.681   0.874   0.286   0.974   0.164   0.069        0.047


B: Outcome=CIN2+
Setting      Country       TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Bamako         Mali       159      5    568     4,820    727     5,552   0.970   0.895   0.219   0.999   0.131   0.030        0.029
Brazzaville    Congo      371    17     723     5,823   1,094    6,934   0.956   0.890   0.339   0.997   0.158   0.056        0.054
Conakry        Guinea     163      5    811     7,648    974     8,627   0.970   0.904   0.167   0.999   0.113   0.019        0.019
Jaipur         India       56      8   1,543    4,179   1,599    5,786   0.875   0.730   0.035   0.998   0.276   0.011        0.010
Kolkata 2      India       57     13   1,081    6,925   1,138    8,076   0.814   0.865   0.050   0.998   0.141   0.009        0.007
Mumbai         India       60    21     626     3,296    686     4,003   0.741   0.840   0.087   0.994   0.171   0.020        0.015
Niamey         Niger       18     2     210     2,304    228     2,534   0.900   0.916   0.079   0.999   0.090   0.008        0.007
Ouagadougou    B-Fasso     49      1    539     1,462    588     2,051   0.980   0.731   0.083   0.999   0.287   0.024        0.024
Trivandrum 1   India      136    13     813     3,495    949     4,457   0.913   0.811   0.143   0.996   0.213   0.033        0.031
Trivandrum 2   India        65    16     615    4,063     680    4,759   0.802   0.869   0.096   0.996   0.143   0.017        0.014
Overall                  1,134   101   7,529   44,015   8,663   52,779   0.918   0.854   0.131   0.998   0.164   0.023        0.021


C: Outcome=CIN3+
Setting      Country       TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Bamako         Mali        81      2    646     4,823    727     5,552   0.976   0.882   0.111   1.000   0.131   0.015        0.015
Brazzaville    Congo      192      7    902     5,833   1,094    6,934   0.965   0.866   0.176   0.999   0.158   0.029        0.028
Conakry        Guinea     121      2    853     7,651    974     8,627   0.984   0.900   0.124   1.000   0.113   0.014        0.014
Jaipur         India       38      8   1,561    4,179   1,599    5,786   0.826   0.728   0.024   0.998   0.276   0.008        0.007
Kolkata 2      India       33      6   1,105    6,932   1,138    8,076   0.846   0.863   0.029   0.999   0.141   0.005        0.004
Mumbai         India       43    16     643     3,301    686     4,003   0.729   0.837   0.063   0.995   0.171   0.015        0.011
Niamey         Niger       11     1     217     2,305    228     2,534   0.917   0.914   0.048   1.000   0.090   0.005        0.004
Ouagadougou    B-Fasso     37      0    551     1,463    588     2,051   1.000   0.726   0.063   1.000   0.287   0.018        0.018
Trivandrum 1   India       55      1    894     3,507    949     4,457   0.982   0.797   0.058   1.000   0.213   0.013        0.012
Trivandrum 2   India       52     9      628    4,070     680    4,759   0.852   0.866   0.076   0.998   0.143   0.013        0.011
Setting                   663    52    8,000   44,064   8,663   52,779   0.927   0.846   0.077   0.999   0.164   0.014        0.013




                                                                                                                         70
D: Outcome=Cancer
Setting        Country    TP FN          FP         TN     T+         N      Se      Sp    PPV     NPV     T+ rate   Prev    Det rate
Bamako         Mali        52      2    675     4,823     727      5,552   0.963   0.877   0.072   1.000     0.131   0.010        0.009
Brazzaville    Congo       25      1   1,069    5,839    1,094     6,934   0.962   0.845   0.023   1.000     0.158   0.004        0.004
Conakry        Guinea      88     1     886     7,652     974      8,627   0.989   0.896   0.090   1.000     0.113   0.010        0.010
Jaipur         India          4   2    1,595    4,185    1,599     5,786   0.667   0.724   0.003   1.000     0.276   0.001        0.001
Kolkata 2      India          8    0   1,130    6,938    1,138     8,076   1.000   0.860   0.007   1.000     0.141   0.001        0.001
Mumbai         India       20      7    666     3,310     686      4,003   0.741   0.832   0.029   0.998     0.171   0.007        0.005
Niamey         Niger          4   1     224     2,305     228      2,534   0.800   0.911   0.018   1.000     0.090   0.002        0.002
Ouagadougou    B-Fasso     17     0     571     1,463     588      2,051   1.000   0.719   0.029   1.000     0.287   0.008        0.008
Trivandrum 1   India          6    0    943     3,508     949      4,457   1.000   0.788   0.006   1.000     0.213   0.001        0.001
Trivandrum 2   India       13      2     667    4,077      680     4,759   0.867   0.859   0.019   1.000     0.143   0.003        0.003
Overall                   237     16   8,426   44,100    8,663    52,779   0.937   0.840   0.027   1.000     0.164   0.005        0.004

E.
PS: the test positivity rate of VILI is also documented in a small subpopulation of the WKCCPP (Busia):
19/137=13.9%

                         VILI

Ouagadougou
    Kolkata 2
  Brazzaville
     Conakry
       Jaipur
     Bamako
     Mumbai
     Niamey
Trivandrum 1
Trivandrum 2
       Busia

         Combined
                          0                    .1                  .2           .3                         .4                .5
                                                                 Test positivity rate

Meta-analysis of the test-positivity rate of VILI

       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.152   0.149   0.155   98.351    0.000     11
Random |   0.170   0.138   0.201   10.525    0.000

Test for heterogeneity: Q= 1021.571 on 10 degrees of freedom (p= 0.000)




                                                                                                                             71
                VILI, Outcome=CIN1+                                                                      VILI, Outcome=CIN1+

Ouagadougou                                                                              Ouagadougou
    Kolkata 2                                                                                Kolkata 2
  Brazzaville                                                                              Brazzaville
     Conakry                                                                                  Conakry
       Jaipur                                                                                   Jaipur
     Bamako                                                                                   Bamako
     Mumbai                                                                                   Mumbai
     Niamey                                                                                   Niamey
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0    .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    .6          .7            .8        .9    1
                                            Sensitivity                                                                        Specificity
                VILI, Outcome=CIN1+                                                                      VILI, Outcome=CIN1+

Ouagadougou                                                                              Ouagadougou
    Kolkata 2                                                                                Kolkata 2
  Brazzaville                                                                              Brazzaville
     Conakry                                                                                  Conakry
       Jaipur                                                                                   Jaipur
     Bamako                                                                                   Bamako
     Mumbai                                                                                   Mumbai
     Niamey                                                                                   Niamey
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0         .1         .2        .3          .4             .5        .6                   .8         .85           .9         .95   1
                                              PPV                                                                                NPV


Meta-analysis of the sensitivity of VILI (CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.755   0.742   0.768 114.091     0.000     10
Random |   0.737   0.630   0.845   13.425    0.000
Test for heterogeneity: Q= 590.110 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of VILI (CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.890   0.888   0.893 639.643     0.000     10
Random |   0.866   0.834   0.898   53.400    0.000
Test for heterogeneity: Q= 1176.071 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VILI (CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.241   0.233   0.250   55.266    0.000     10
Random |   0.289   0.199   0.379    6.308    0.000
Test for heterogeneity: Q= 940.246 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VILI (CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.991   0.990   0.991 2167.038    0.000     10
Random |   0.975   0.966   0.984 211.414     0.000
Test for heterogeneity: Q= 792.965 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                       72
                VILI, Outcome=CIN1+                                                             VILI, Outcome=CIN1+

Ouagadougou                                                                     Ouagadougou
    Kolkata 2                                                                       Kolkata 2
  Brazzaville                                                                     Brazzaville
     Conakry                                                                         Conakry
       Jaipur                                                                          Jaipur
     Bamako                                                                          Bamako
     Mumbai                                                                          Mumbai
     Niamey                                                                          Niamey
Trivandrum 1                                                                    Trivandrum 1
Trivandrum 2                                                                    Trivandrum 2

   Combined                                                                        Combined
                0              .05            .1           .15             .2                   0          .05              .1             .15   .2
                                     Prevalence of disease                                                       Detection rate of disease
                VILI, Outcome=CIN1+

Ouagadougou
    Kolkata 2
  Brazzaville
     Conakry
       Jaipur
     Bamako
     Mumbai
     Niamey
Trivandrum 1
Trivandrum 2

   Combined
                0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                 Approximative specificity



Meta-analysis of the prevalence of disease (CIN1+) in VILI studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.054   0.053   0.056   55.624    0.000     10
Random |   0.068   0.048   0.087    6.776    0.000
Test for heterogeneity: Q= 900.857 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN1+) using VILI
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.037   0.036   0.039   45.563    0.000     10
Random |   0.046   0.033   0.059    6.993    0.000
Test for heterogeneity: Q= 549.588 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VILI (CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.893   0.890   0.896 655.823     0.000     10
Random |   0.869   0.838   0.900   54.706    0.000
Test for heterogeneity: Q= 1179.316 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                      73
                VILI, Outcome=CIN2+                                                                      VILI, Outcome=CIN2+

Burkina-Fasso                                                                            Burkina-Fasso
    Kolkata 2                                                                                Kolkata 2
       Congo                                                                                    Congo
      Guinea                                                                                   Guinea
       Jaipur                                                                                   Jaipur
         Mali                                                                                     Mali
     Mumbai                                                                                   Mumbai
        Niger                                                                                    Niger
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0    .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    .6          .7            .8        .9    1
                                            Sensitivity                                                                        Specificity
                VILI, Outcome=CIN2+                                                                      VILI, Outcome=CIN2+

Burkina-Fasso                                                                            Burkina-Fasso
    Kolkata 2                                                                                Kolkata 2
       Congo                                                                                    Congo
      Guinea                                                                                   Guinea
       Jaipur                                                                                   Jaipur
         Mali                                                                                     Mali
     Mumbai                                                                                   Mumbai
        Niger                                                                                    Niger
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0         .1         .2        .3          .4             .5        .6                   .8         .85           .9         .95   1
                                              PPV                                                                                NPV


Meta-analysis of the sensitivity of VILI (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.950   0.938   0.962 156.881     0.000     10
Random |   0.912   0.878   0.946   52.760    0.000
Test for heterogeneity: Q= 51.760 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of VILI (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.868   0.865   0.871 589.058     0.000     10
Random |   0.845   0.812   0.879   50.177    0.000
Test for heterogeneity: Q= 1135.139 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VILI (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.083   0.077   0.088   28.873    0.000     10
Random |   0.129   0.080   0.179    5.111    0.000
Test for heterogeneity: Q= 612.294 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VILI (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.999   0.998   0.999 5615.658    0.000     10
Random |   0.998   0.997   0.999 2408.406    0.000
Test for heterogeneity: Q= 39.520 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                       74
                VILI, Outcome=CIN2+                                                             VILI, Outcome=CIN2+

Burkina-Fasso                                                                   Burkina-Fasso
    Kolkata 2                                                                       Kolkata 2
       Congo                                                                           Congo
      Guinea                                                                          Guinea
       Jaipur                                                                          Jaipur
         Mali                                                                            Mali
     Mumbai                                                                          Mumbai
        Niger                                                                           Niger
Trivandrum 1                                                                    Trivandrum 1
Trivandrum 2                                                                    Trivandrum 2

   Combined                                                                        Combined
                0              .05            .1           .15             .2                   0          .05              .1             .15   .2
                                     Prevalence of disease                                                       Detection rate of disease
                VILI, Outcome=CIN2+

Burkina-Fasso
    Kolkata 2
       Congo
      Guinea
       Jaipur
         Mali
     Mumbai
        Niger
Trivandrum 1
Trivandrum 2

   Combined
                0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                 Approximative specificity



Meta-analysis of the prevalence of disease (CIN2+) in VILI studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.016   0.015   0.018   29.877    0.000     10
Random |   0.023   0.015   0.030    6.043    0.000
Test for heterogeneity: Q= 380.122 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using VILI
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.014   0.013   0.015   27.998    0.000     10
Random |   0.021   0.014   0.028    5.736    0.000
Test for heterogeneity: Q= 411.348 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VILI (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.868   0.866   0.871 590.181     0.000     10
Random |   0.846   0.813   0.879   50.412    0.000
Test for heterogeneity: Q= 1129.326 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                      75
                VILI, Outcome=CIN3+                                                                      VILI, Outcome=CIN3+

Burkina-Fasso                                                                            Burkina-Fasso
    Kolkata 2                                                                                Kolkata 2
       Congo                                                                                    Congo
      Guinea                                                                                   Guinea
       Jaipur                                                                                   Jaipur
         Mali                                                                                     Mali
     Mumbai                                                                                   Mumbai
        Niger                                                                                    Niger
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0    .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    .6          .7            .8        .9    1
                                            Sensitivity                                                                        Specificity
                VILI, Outcome=CIN3+                                                                      VILI, Outcome=CIN3+

Burkina-Fasso                                                                            Burkina-Fasso
    Kolkata 2                                                                                Kolkata 2
       Congo                                                                                    Congo
      Guinea                                                                                   Guinea
       Jaipur                                                                                   Jaipur
         Mali                                                                                     Mali
     Mumbai                                                                                   Mumbai
        Niger                                                                                    Niger
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0         .1         .2        .3          .4             .5        .6                   .8         .85           .9         .95   1
                                              PPV                                                                                NPV


Meta-analysis of the sensitivity of VILI (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.969   0.956   0.981 148.626     0.000     10
Random |   0.938   0.906   0.971   56.176    0.000
Test for heterogeneity: Q= 39.512 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of VILI (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.860   0.857   0.863 570.570     0.000     10
Random |   0.838   0.805   0.871   49.823    0.000
Test for heterogeneity: Q= 1084.136 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VILI (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.050   0.046   0.055   21.804    0.000     10
Random |   0.077   0.050   0.103    5.598    0.000
Test for heterogeneity: Q= 272.054 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VILI (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   0.999   1.000 8864.979    0.000     10
Random |   0.999   0.999   1.000 3719.816    0.000
Test for heterogeneity: Q= 38.767 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                       76
                VILI, Outcome=CIN3+                                                             VILI, Outcome=CIN3+

Burkina-Fasso                                                                   Burkina-Fasso
    Kolkata 2                                                                       Kolkata 2
       Congo                                                                           Congo
      Guinea                                                                          Guinea
       Jaipur                                                                          Jaipur
         Mali                                                                            Mali
     Mumbai                                                                          Mumbai
        Niger                                                                           Niger
Trivandrum 1                                                                    Trivandrum 1
Trivandrum 2                                                                    Trivandrum 2

   Combined                                                                        Combined
                0              .05            .1           .15             .2                   0          .05              .1             .15   .2
                                     Prevalence of disease                                                       Detection rate of disease
                VILI, Outcome=CIN3+

Burkina-Fasso
    Kolkata 2
       Congo
      Guinea
       Jaipur
         Mali
     Mumbai
        Niger
Trivandrum 1
Trivandrum 2

   Combined
                0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                 Approximative specificity



Meta-analysis of the prevalence of disease (CIN3+) in VILI studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.010   0.009   0.011   23.503    0.000     10
Random |   0.013   0.009   0.017    6.415    0.000
Test for heterogeneity: Q= 188.156 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using VILI
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.008   0.010   21.875    0.000     10
Random |   0.012   0.008   0.016    5.948    0.000
Test for heterogeneity: Q= 206.184 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VILI (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.860   0.857   0.863 571.052     0.000     10
Random |   0.838   0.806   0.871   50.002    0.000
Test for heterogeneity: Q= 1078.657 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                      77
                VILI, Outcome=Cancer                                                                     VILI, Outcome=Cancer

Burkina-Fasso                                                                            Burkina-Fasso
    Kolkata 2                                                                                Kolkata 2
       Congo                                                                                    Congo
      Guinea                                                                                   Guinea
       Jaipur                                                                                   Jaipur
         Mali                                                                                     Mali
     Mumbai                                                                                   Mumbai
        Niger                                                                                    Niger
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0    .1    .2   .3        .4    .5    .6        .7   .8        .9   1                    .6          .7             .8        .9    1
                                            Sensitivity                                                                         Specificity
                VILI, Outcome=Cancer                                                                     VILI, Outcome=Cancer

Burkina-Fasso                                                                            Burkina-Fasso
    Kolkata 2                                                                                Kolkata 2
       Congo                                                                                    Congo
      Guinea                                                                                   Guinea
       Jaipur                                                                                   Jaipur
         Mali                                                                                     Mali
     Mumbai                                                                                   Mumbai
        Niger                                                                                    Niger
Trivandrum 1                                                                             Trivandrum 1
Trivandrum 2                                                                             Trivandrum 2

   Combined                                                                                 Combined
                0         .1         .2        .3          .4             .5        .6                   .8          .85           .9         .95   1
                                              PPV                                                                                 NPV


Meta-analysis of the sensitivity of VILI (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.978   0.960   0.997 103.304     0.000     10
Random |   0.957   0.918   0.997   47.504    0.000
Test for heterogeneity: Q= 14.870 on 9 degrees of freedom (p= 0.095)

Meta-analysis of the specificity of VILI (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.853   0.850   0.856 557.448     0.000     10
Random |   0.831   0.798   0.865   48.341    0.000
Test for heterogeneity: Q= 1100.040 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VILI (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.008   0.006   0.010    8.677    0.000     10
Random |   0.027   0.017   0.037    5.163    0.000
Test for heterogeneity: Q= 177.929 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VILI (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   1.000   1.00014107.972    0.000     10
Random |   1.000   1.000   1.00014107.972    0.000
Test for heterogeneity: Q= 6.250 on 9 degrees of freedom (p= 0.715)




                                                                                                                                                        78
                VILI, Outcome=Cancer                                                            VILI, Outcome=Cancer

Burkina-Fasso                                                                   Burkina-Fasso
    Kolkata 2                                                                       Kolkata 2
       Congo                                                                           Congo
      Guinea                                                                          Guinea
       Jaipur                                                                          Jaipur
         Mali                                                                            Mali
     Mumbai                                                                          Mumbai
        Niger                                                                           Niger
Trivandrum 1                                                                    Trivandrum 1
Trivandrum 2                                                                    Trivandrum 2

   Combined                                                                        Combined
                0              .05            .1           .15             .2                   0           .05              .1             .15   .2
                                     Prevalence of disease                                                        Detection rate of disease
                VILI, Outcome=Cancer

Burkina-Fasso
    Kolkata 2
       Congo
      Guinea
       Jaipur
         Mali
     Mumbai
        Niger
Trivandrum 1
Trivandrum 2

   Combined
                0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                 Approximative specificity



Meta-analysis of the prevalence of disease (cancer) in VILI studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.002   0.003   10.616    0.000     10
Random |   0.004   0.003   0.006    4.948    0.000
Test for heterogeneity: Q= 140.216 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (cancer) using VILI
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.002   0.002   10.647    0.000     10
Random |   0.004   0.002   0.006    5.074    0.000
Test for heterogeneity: Q= 129.537 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VILI (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.853   0.850   0.856 557.768     0.000     10
Random |   0.832   0.798   0.865   48.340    0.000
Test for heterogeneity: Q= 1101.527 on 9 degrees of freedom (p= 0.000)




                                                                                                                                                       79
6.1.3. Test characteristics of VIAM
The accuracy of VIAM is assessed for the outcomes CIN1+, CIN2+, CIN3+ and cancer
(see Table 22).

Table 22. Test characteristics of VIAM, assessed at 3 locations included in the multi-center cross-sectional
study [tables A-D]
A: Outcome=CIN1+
Setting    Country        TP    FN      FP      TN       T+       N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1   India        330    180    732     4,651   1,062   1,242   0.647   0.864   0.311   0.963   0.180   0.411        0.266
Kolkata 2   India        135    183    772     6,990    907    1,090   0.425   0.901   0.149   0.974   0.112   0.292        0.124
Mumbai      India        141     65     463    3,334     604     669   0.684   0.878   0.233   0.981   0.151   0.308        0.211
Overall                  606    428   1,967   14,975   2,573   3,001   0.586   0.884   0.236   0.972   0.143   0.345        0.202


B: Outcome=CIN2+
Setting    Country        TP    FN      FP      TN       T+       N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1   India        104     57    958     4,774   1,062   1,119   0.646   0.833   0.098   0.988   0.180   0.144        0.093
Kolkata 2   India         52     19    855     7,154    907     926    0.732   0.893   0.057   0.997   0.112   0.077        0.056
Mumbai      India         53     28     551    3,371     604     632   0.654   0.860   0.088   0.992   0.151   0.128        0.084
Overall                  209    104   2,364   15,299   2,573   2,677   0.668   0.866   0.081   0.993   0.143   0.117        0.078


C: Outcome=CIN3+
Setting    Country        TP    FN      FP      TN       T+       N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1   India         65     34    997     4,797   1,062   1,096   0.657   0.828   0.061   0.993   0.180   0.090        0.059
Kolkata 2   India         29     10    878     7,163    907     917    0.744   0.891   0.032   0.999   0.112   0.043        0.032
Mumbai      India         40     19     564    3,380     604     623   0.678   0.857   0.066   0.994   0.151   0.095        0.064
Overall                  134     63   2,439   15,340   2,573   2,636   0.680   0.863   0.052   0.996   0.143   0.075        0.051


C: Outcome=Cancer
Setting    Country        TP    FN      FP      TN       T+       N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1   India         29      9   1,033    4,822   1,062   1,071   0.763   0.824   0.027   0.998   0.180   0.035        0.027
Kolkata 2   India          8      0    899     7,173    907     907    1.000   0.889   0.009   1.000   0.112   0.009        0.009
Mumbai      India         20      7     584    3,392     604     611   0.741   0.853   0.033   0.998   0.151   0.044        0.033
Overall                   57     16   2,516   15,387   2,573   2,589   0.781   0.859   0.022   0.999   0.143   0.028        0.022




                                                                                                                       80
                VIAM



 Kolkata 1

 Kolkata 2

  Mumbai



Combined
                 0    .1    .2   .3     .4    .5     .6    .7   .8   .9   1
                                      Test positivity rate


Meta-analysis of the test-positivity rate of VIAM

       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.138   0.133   0.143   53.772    0.000      3
Random |   0.148   0.105   0.190    6.790    0.000

Test for heterogeneity: Q= 130.451 on 2 degrees of freedom (p= 0.000)




                                                                          81
            VIAM, Outcome=CIN1+                                                VIAM, Outcome=CIN1+



Kolkata 1                                                          Kolkata 1

Kolkata 2                                                          Kolkata 2

 Mumbai                                                             Mumbai



Combined                                                           Combined
            0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                 Sensitivity                                                        Specificity
            VIAM, Outcome=CIN1+                                                VIAM, Outcome=CIN1+



Kolkata 1                                                          Kolkata 1

Kolkata 2                                                          Kolkata 2

 Mumbai                                                             Mumbai



Combined                                                           Combined
            0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                    PPV                                                                NPV


Meta-analysis of the sensitivity of VIAM (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.590   0.561   0.620   39.561    0.000       3
Random |   0.585   0.432   0.738    7.491    0.000
Test for heterogeneity: Q= 51.120 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of VIAM (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.886   0.881   0.891 363.108     0.000       3
Random |   0.881   0.858   0.905   73.886    0.000
Test for heterogeneity: Q= 43.943 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIAM (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.219   0.203   0.235   27.278    0.000      3
Random |   0.231   0.130   0.331    4.500    0.000
Test for heterogeneity: Q= 77.710 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VIAM (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.974   0.971   0.976 756.946     0.000      3
Random |   0.973   0.964   0.982 207.635     0.000
Test for heterogeneity: Q= 25.100 on 2 degrees of freedom (p= 0.000)




                                                                                                                                      82
            VIAM, Outcome=CIN1+                                                  VIAL, Outcome=CIN1+



Kolkata 1                                                            Kolkata 1

Kolkata 2                                                            Kolkata 2

 Mumbai                                                               Mumbai



Combined                                                             Combined
            0        .1         .2         .3         .4        .5               0        .1        .2           .3        .4   .5
                            Prevalence of disease                                              Detection rate of disease
            VIAM, Outcome=CIN1+



Kolkata 1

Kolkata 2

 Mumbai



Combined
            0   .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                          Approximative specificity



Meta-analysis of the prevalence of disease (CIN1+) in VIAM studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.051   0.048   0.055   31.229    0.000      3
Random |   0.059   0.031   0.087    4.177    0.000
Test for heterogeneity: Q= 127.346 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN1+) using VIAM
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.026   0.024   0.028   22.053    0.000      3
Random |   0.036   0.012   0.059    3.000    0.003
Test for heterogeneity: Q= 149.708 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIAM (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.889   0.884   0.893 372.620     0.000      3
Random |   0.884   0.862   0.906   78.697    0.000
Test for heterogeneity: Q= 40.812 on 2 degrees of freedom (p= 0.000)




                                                                                                                                     83
            VIAM, Outcome=CIN2+                                                VIAM, Outcome=CIN2+



Kolkata 1                                                          Kolkata 1

Kolkata 2                                                          Kolkata 2

 Mumbai                                                             Mumbai



Combined                                                           Combined
            0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1    .2    .3        .4    .5    .6        .7    .8    .9   1
                                 Sensitivity                                                               Specificity
            VIAM, Outcome=CIN2+                                                VIAM, Outcome=CIN2+



Kolkata 1                                                          Kolkata 1

Kolkata 2                                                          Kolkata 2

 Mumbai                                                             Mumbai



Combined                                                           Combined
            0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1   .2    .3    .4      .5 .6         .7    .8    .9   1    1.1
                                    PPV                                                                      NPV


Meta-analysis of the sensitivity of VIAM (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.670   0.618   0.722   25.282    0.000       3
Random |   0.670   0.618   0.722   25.282    0.000
Test for heterogeneity: Q= 1.890 on 2 degrees of freedom (p= 0.389)

Meta-analysis of the specificity of VIAM (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.871   0.866   0.875 345.641     0.000       3
Random |   0.862   0.825   0.899   45.209    0.000
Test for heterogeneity: Q= 104.007 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIAM (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.077   0.067   0.087   14.680    0.000      3
Random |   0.080   0.054   0.107    5.867    0.000
Test for heterogeneity: Q= 12.928 on 2 degrees of freedom (p= 0.002)

Meta-analysis of the NPV of VIAM (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.995   0.994   0.996 1874.234    0.000      3
Random |   0.992   0.987   0.998 341.151     0.000
Test for heterogeneity: Q= 34.444 on 2 degrees of freedom (p= 0.000)




                                                                                                                                                      84
            VIAM, Outcome=CIN2+                                                 VIAL, Outcome=CIN2+



Kolkata 1                                                           Kolkata 1

Kolkata 2                                                           Kolkata 2

 Mumbai                                                              Mumbai



Combined                                                            Combined
            0   .1   .2   .3    .4   .5    .6    .7   .8   .9   1               0        .1        .2           .3        .4   .5
                            Prevalence of disease                                             Detection rate of disease
            VIAM, Outcome=CIN2+



Kolkata 1

Kolkata 2

 Mumbai



Combined
            0   .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                          Approximative specificity




Meta-analysis of the prevalence of disease (CIN2+) in VIAM studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.014   0.012   0.015   15.807    0.000      3
Random |   0.019   0.007   0.030    3.138    0.002
Test for heterogeneity: Q= 67.719 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using VIAM
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.008   0.011   12.795    0.000      3
Random |   0.012   0.005   0.020    3.139    0.002
Test for heterogeneity: Q= 43.681 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIAM (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.871   0.866   0.876 347.574     0.000      3
Random |   0.863   0.826   0.900   45.952    0.000
Test for heterogeneity: Q= 102.125 on 2 degrees of freedom (p= 0.000)




                                                                                                                                    85
            VIAM, Outcome=CIN3+                                                VIAM, Outcome=CIN3+



Kolkata 1                                                          Kolkata 1

Kolkata 2                                                          Kolkata 2

 Mumbai                                                             Mumbai



Combined                                                           Combined
            0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1    .2    .3        .4    .5    .6        .7    .8    .9   1
                                 Sensitivity                                                               Specificity
            VIAM, Outcome=CIN3+                                                VIAM, Outcome=CIN3+



Kolkata 1                                                          Kolkata 1

Kolkata 2                                                          Kolkata 2

 Mumbai                                                             Mumbai



Combined                                                           Combined
            0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1   .2    .3    .4      .5 .6         .7    .8    .9   1    1.1
                                    PPV                                                                      NPV


Meta-analysis of the sensitivity of VIAM (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.683   0.618   0.748   20.637    0.000       3
Random |   0.683   0.618   0.748   20.637    0.000
Test for heterogeneity: Q= 1.065 on 2 degrees of freedom (p= 0.587)

Meta-analysis of the specificity of VIAM (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.867   0.863   0.872 342.104     0.000       3
Random |   0.859   0.820   0.898   43.007    0.000
Test for heterogeneity: Q= 112.657 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIAM (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.047   0.039   0.055   11.295    0.000      3
Random |   0.052   0.030   0.075    4.533    0.000
Test for heterogeneity: Q= 13.742 on 2 degrees of freedom (p= 0.001)

Meta-analysis of the NPV of VIAM (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.997   0.999 2535.322    0.000      3
Random |   0.995   0.991   1.000 449.797     0.000
Test for heterogeneity: Q= 32.132 on 2 degrees of freedom (p= 0.000)




                                                                                                                                                      86
            VIAM, Outcome=CIN3+                                                            VIAL, Outcome=CIN3+



Kolkata 1                                                                      Kolkata 1

Kolkata 2                                                                      Kolkata 2

 Mumbai                                                                         Mumbai



Combined                                                                       Combined
            0             .1              .2               .3             .4               0          .1              .2             .3   .4
                                 Prevalence of disease                                                     Detection rate of disease
            VIAM, Outcome=CIN3+



Kolkata 1

Kolkata 2

 Mumbai



Combined
            0   .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                               Approximative specificity



Meta-analysis of the prevalence of disease (CIN3+) in VIAM studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.008   0.007   0.009   12.233    0.000      3
Random |   0.012   0.004   0.021    2.790    0.005
Test for heterogeneity: Q= 57.541 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using VIAM
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.006   0.005   0.007   10.629    0.000      3
Random |   0.008   0.003   0.013    3.185    0.001
Test for heterogeneity: Q= 29.005 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIAM (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.868   0.863   0.873 343.202     0.000      3
Random |   0.859   0.821   0.898   43.752    0.000
Test for heterogeneity: Q= 109.808 on 2 degrees of freedom (p= 0.000)




                                                                                                                                               87
            VIAM, Outcome=Cancer                                                VIAM, Outcome=Cancer



Kolkata 1                                                           Kolkata 1

Kolkata 2                                                           Kolkata 2

 Mumbai                                                              Mumbai



Combined                                                            Combined
            0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1    .2    .3        .4    .5    .6        .7    .8    .9   1
                                  Sensitivity                                                               Specificity
            VIAM, Outcome=Cancer                                                VIAM, Outcome=Cancer



Kolkata 1                                                           Kolkata 1

Kolkata 2                                                           Kolkata 2

 Mumbai                                                              Mumbai



Combined                                                            Combined
            0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1               0   .1   .2    .3    .4      .5 .6         .7    .8    .9   1    1.1
                                     PPV                                                                      NPV


Meta-analysis of the sensitivity of VIAM (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.814   0.723   0.905   17.521    0.000      3
Random |   0.826   0.677   0.976   10.831    0.000
Test for heterogeneity: Q= 5.191 on 2 degrees of freedom (p= 0.075)

Meta-analysis of the specificity of VIAM (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.865   0.860   0.870 338.802     0.000      3
Random |   0.855   0.815   0.896   41.389    0.000
Test for heterogeneity: Q= 119.248 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of VIAM (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.016   0.011   0.021    6.537    0.000      3
Random |   0.022   0.007   0.038    2.809    0.005
Test for heterogeneity: Q= 15.366 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of VIAM (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   1.000   1.000 7897.081    0.000      3
Random |   0.999   0.997   1.000 1216.134    0.000
Test for heterogeneity: Q= 15.848 on 2 degrees of freedom (p= 0.000)




                                                                                                                                                       88
            VIAM, Outcome=Cancer                                                  VIAL, Outcome=Cancer



Kolkata 1                                                             Kolkata 1

Kolkata 2                                                             Kolkata 2

 Mumbai                                                                Mumbai



Combined                                                              Combined
            0                         .1                         .2               0                        .1               .2
                             Prevalence of disease                                              Detection rate of disease
            VIAM, Outcome=Cancer



Kolkata 1

Kolkata 2

 Mumbai



Combined
            0    .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                           Approximative specificity



Meta-analysis of the prevalence of disease (cancer) in VIAM studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.001   0.002    5.742    0.000      3
Random |   0.005   0.000   0.009    2.088    0.037
Test for heterogeneity: Q= 37.591 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (cancer) using VIAM
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.001   0.002    5.709    0.000      3
Random |   0.004   0.000   0.007    2.225    0.026
Test for heterogeneity: Q= 25.795 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of VIAM (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.864   0.859   0.869 338.959     0.000      3
Random |   0.855   0.815   0.896   41.611    0.000
Test for heterogeneity: Q= 118.211 on 2 degrees of freedom (p= 0.000)




                                                                                                                                 89
6.1.4. Test characteristics of HPV DNA detection by HC2
The accuracy of HPV is assessed for the outcomes CIN1+, CIN2+, CIN3+ and cancer (see
Table 23).

Table 23. Test characteristics of the Hybrid Capture II assay assessed at 5 study locations included in the
multi-center and Zimbabwe cross-sectional studies [Tables A-D].
A: Outcome=CIN1+
Setting     Country      TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1    India       62    151    264     3,126    326     3,603   0.291   0.922   0.190   0.954   0.090   0.059        0.017
Kolkata 2    India       66    207    337     6,066    403     6,676   0.242   0.947   0.164   0.967   0.060   0.041        0.010
Mumbai       India       57    112    211     3,163    268     3,543   0.337   0.937   0.213   0.966   0.076   0.048        0.016
Trivandrum 2 India       90    328    213     4,127    303     4,758   0.215   0.951   0.297   0.926   0.064   0.088        0.019
Harare       Zimbabwe   361    205     556    1,023     917    2,145   0.638   0.648   0.394   0.833   0.428   0.264        0.168
Overall                 275    798   1,025   16,482   1,300   18,580   0.256   0.941   0.212   0.954   0.070   0.058        0.015


B: Outcome=CIN2+
Setting     Country      TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1    India       30     32    296     3,245    326     3,603   0.484   0.916   0.092   0.990   0.090   0.017        0.008
Kolkata 2    India       42     20    361     6,253    403     6,676   0.677   0.945   0.104   0.997   0.060   0.009        0.006
Mumbai       India       43     23    225     3,252    268     3,543   0.652   0.935   0.160   0.993   0.076   0.019        0.012
Trivandrum 2 India       52     29    251     4,426    303     4,758   0.642   0.946   0.172   0.993   0.064   0.017        0.011
Harare       Zimbabwe   166     41     751    1,187     917    2,145   0.802   0.612   0.181   0.967   0.428   0.097        0.077
Overall                 167    104   1,133   17,176   1,300   18,580   0.616   0.938   0.128   0.994   0.070   0.015        0.009


C: Outcome=CIN3+
Setting     Country      TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1    India       19     10    307     3,267    326     3,603   0.655   0.914   0.058   0.997   0.090   0.008        0.005
Setting      India       25      9    378     6,264    403     6,676   0.735   0.943   0.062   0.999   0.060   0.005        0.004
Mumbai       India       35     13    233     3,262    268     3,543   0.729   0.933   0.131   0.996   0.076   0.014        0.010
Trivandrum 2 India       38     23     265    4,432     303    4,758   0.623   0.944   0.125   0.995   0.064   0.013        0.008
Overall                 117     55   1,183   17,225   1,300   18,580   0.680   0.936   0.090   0.997   0.070   0.009        0.006


D: Outcome=Cancer
Setting     Country      TP    FN      FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Kolkata 1    India        8      5    318     3,272    326     3,603   0.615   0.911   0.025   0.998   0.090   0.004        0.002
Kolkata 2    India        6      1    397     6,272    403     6,676   0.857   0.940   0.015   1.000   0.060   0.001        0.001
Mumbai       India       14      5    254     3,270    268     3,543   0.737   0.928   0.052   0.998   0.076   0.005        0.004
Trivandrum 2 India       10      5    293     4,450    303     4,758   0.667   0.938   0.033   0.999   0.064   0.003        0.002
Harare       Zimbabwe     2      1     915    1,227     917    2,145   0.667   0.573   0.002   0.999   0.428   0.001        0.001
Overall                  38     16   1,262   17,264   1,300   18,580   0.704   0.932   0.029   0.999   0.070   0.003        0.002




                                                                                                                       90
                HPV


   Kolkata 1
   Kolkata 2
     Mumbai
Trivandrum 2
      Harare


   Combined
                 0    .1   .2   .3     .4 .5 .6 .7          .8   .9   1
                                     Test positivity rate

Meta-analysis of the test-positivity rate of Hybrid Capture II

       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.079   0.075   0.082   43.240    0.000      5
Random |   0.143   0.079   0.206    4.415    0.000

Test for heterogeneity: Q= 1133.683 on 4 degrees of freedom (p= 0.000)




                                                                          91
               HPV, Outcome=CIN1+                                                    HPV, Outcome=CIN1+


   Kolkata 1                                                             Kolkata 1
   Kolkata 2                                                             Kolkata 2
    Mumbai                                                                Mumbai
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                    Sensitivity                                                           Specificity
               HPV, Outcome=CIN1+                                                    HPV, Outcome=CIN1+


   Kolkata 1                                                             Kolkata 1
   Kolkata 2                                                             Kolkata 2
    Mumbai                                                                Mumbai
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                       PPV                                                                   NPV


Meta-analysis of the sensitivity of HC2 (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.367   0.345   0.389   33.246    0.000      5
Random |   0.345   0.164   0.526    3.731    0.000
Test for heterogeneity: Q= 266.591 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of HC2 (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.937   0.933   0.940 540.691     0.000      5
Random |   0.883   0.839   0.928   38.737    0.000
Test for heterogeneity: Q= 620.852 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of HC2 (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.265   0.247   0.283   28.980    0.000      5
Random |   0.252   0.155   0.348    5.112    0.000
Test for heterogeneity: Q= 111.479 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of HC2 (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.956   0.953   0.959 637.271     0.000      5
Random |   0.932   0.908   0.955   76.938    0.000
Test for heterogeneity: Q= 224.420 on 4 degrees of freedom (p= 0.000)




                                                                                                                                            92
               HPV, Outcome=CIN1+                                                      HPV, Outcome=CIN1+


   Kolkata 1                                                               Kolkata 1
   Kolkata 2                                                               Kolkata 2
    Mumbai                                                                  Mumbai
Trivandrum 2                                                            Trivandrum 2
      Harare                                                                  Harare


  Combined                                                                Combined
               0        .1         .2         .3         .4        .5                  0        .1        .2           .3        .4   .5
                               Prevalence of disease                                                 Detection rate of disease
               HPV, Outcome=CIN1+


   Kolkata 1
   Kolkata 2
    Mumbai
Trivandrum 2
      Harare


  Combined
               0   .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                             Approximative specificity




Meta-analysis of the prevalence of disease (CIN1+) in HC2 studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.059   0.056   0.062   36.564    0.000      5
Random |   0.099   0.058   0.139    4.766    0.000
Test for heterogeneity: Q= 578.683 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN1+) using HC2
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.015   0.014   0.017   18.180    0.000      5
Random |   0.043   0.025   0.061    4.679    0.000
Test for heterogeneity: Q= 382.955 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of HC2 (outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.940   0.936   0.943 567.542     0.000      5
Random |   0.893   0.852   0.934   42.804    0.000
Test for heterogeneity: Q= 570.773 on 4 degrees of freedom (p= 0.000)




                                                                                                                                           93
               HPV, Outcome=CIN2+                                                    HPV, Outcome=CIN2+


   Kolkata 1                                                             Kolkata 1
   Kolkata 2                                                             Kolkata 2
    Mumbai                                                                Mumbai
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                    Sensitivity                                                           Specificity
               HPV, Outcome=CIN2+                                                    HPV, Outcome=CIN2+


   Kolkata 1                                                             Kolkata 1
   Kolkata 2                                                             Kolkata 2
    Mumbai                                                                Mumbai
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                       PPV                                                                   NPV


Meta-analysis of the sensitivity of HC2 (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.715   0.676   0.755   35.616    0.000      5
Random |   0.658   0.545   0.770   11.451    0.000
Test for heterogeneity: Q= 26.562 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of HC2 (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.932   0.928   0.935 536.921     0.000      5
Random |   0.873   0.819   0.926   32.044    0.000
Test for heterogeneity: Q= 887.408 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of HC2 (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.141   0.127   0.155   19.203    0.000      5
Random |   0.141   0.102   0.180    7.060    0.000
Test for heterogeneity: Q= 27.858 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV (of HC2 (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.995   0.994   0.996 1863.343    0.000      5
Random |   0.991   0.986   0.995 446.571     0.000
Test for heterogeneity: Q= 47.978 on 4 degrees of freedom (p= 0.000)




                                                                                                                                            94
               HPV, Outcome=CIN2+                                                      HPV, Outcome=CIN2+


   Kolkata 1                                                               Kolkata 1
   Kolkata 2                                                               Kolkata 2
    Mumbai                                                                  Mumbai
Trivandrum 2                                                            Trivandrum 2
      Harare                                                                  Harare


  Combined                                                                Combined
               0        .1         .2         .3         .4        .5                  0        .1        .2           .3        .4   .5
                               Prevalence of disease                                                 Detection rate of disease
               HPV, Outcome=CIN2+


   Kolkata 1
   Kolkata 2
    Mumbai
Trivandrum 2
      Harare


  Combined
               0   .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                             Approximative specificity



Meta-analysis of the prevalence of disease (CIN2+) in HC2 studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.015   0.013   0.016   17.683    0.000      5
Random |   0.030   0.017   0.042    4.622    0.000
Test for heterogeneity: Q= 191.753 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using HC2
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.008   0.011   13.987    0.000      5
Random |   0.020   0.011   0.029    4.467    0.000
Test for heterogeneity: Q= 152.905 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of HC2 (outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.932   0.929   0.935 540.065     0.000      5
Random |   0.875   0.822   0.927   32.626    0.000
Test for heterogeneity: Q= 870.395 on 4 degrees of freedom (p= 0.000)




                                                                                                                                           95
               HPV, Outcome=CIN3+                                                    HPV, Outcome=CIN3+


   Kolkata 1                                                             Kolkata 1

   Kolkata 2                                                             Kolkata 2

    Mumbai                                                                Mumbai

Trivandrum 2                                                          Trivandrum 2



  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                    Sensitivity                                                           Specificity
               HPV, Outcome=CIN3+                                                    HPV, Outcome=CIN3+


   Kolkata 1                                                             Kolkata 1

   Kolkata 2                                                             Kolkata 2

    Mumbai                                                                Mumbai

Trivandrum 2                                                          Trivandrum 2



  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                       PPV                                                                   NPV


Meta-analysis of the sensitivity of HC2 (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.684   0.615   0.754   19.430    0.000      4
Random |   0.684   0.615   0.754   19.430    0.000
Test for heterogeneity: Q= 2.030 on 3 degrees of freedom (p= 0.566)

Meta-analysis of the specificity of HC2 (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.937   0.934   0.941 524.931     0.000      4
Random |   0.934   0.922   0.946 153.049     0.000
Test for heterogeneity: Q= 33.008 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of HC2 (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.080   0.065   0.094   10.666    0.000      4
Random |   0.091   0.055   0.127    4.952    0.000
Test for heterogeneity: Q= 16.773 on 3 degrees of freedom (p= 0.001)

Meta-analysis of the NPV of HC2 (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.997   0.998 2667.737    0.000      4
Random |   0.997   0.995   0.999 1095.700    0.000
Test for heterogeneity: Q= 13.194 on 3 degrees of freedom (p= 0.004)




                                                                                                                                            96
               HPV, Outcome=CIN3+                                                      HPV, Outcome=CIN3+


   Kolkata 1                                                               Kolkata 1

   Kolkata 2                                                               Kolkata 2

    Mumbai                                                                  Mumbai

Trivandrum 2                                                            Trivandrum 2



  Combined                                                                Combined
               0        .1         .2         .3         .4        .5                  0        .1        .2           .3        .4   .5
                               Prevalence of disease                                                 Detection rate of disease
               HPV, Outcome=CIN3+


   Kolkata 1

   Kolkata 2

    Mumbai

Trivandrum 2



  Combined
               0   .1   .2   .3   .4   .5    .6    .7    .8   .9   1
                             Approximative specificity




Meta-analysis of the prevalence of disease (CIN3+) in HC2 studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.008   0.007   0.009   12.081    0.000      4
Random |   0.010   0.005   0.014    4.479    0.000
Test for heterogeneity: Q= 27.917 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using HC2
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.005   0.004   0.006   10.083    0.000      4
Random |   0.006   0.004   0.009    4.754    0.000
Test for heterogeneity: Q= 16.193 on 3 degrees of freedom (p= 0.001)

Meta-analysis of the approximate specificity of HC2 (outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.937   0.934   0.941 526.551     0.000      4
Random |   0.934   0.922   0.946 153.593     0.000
Test for heterogeneity: Q= 32.993 on 3 degrees of freedom (p= 0.000)




                                                                                                                                           97
               HPV, Outcome=Cancer                                                    HPV, Outcome=Cancer


   Kolkata 1                                                              Kolkata 1
   Kolkata 2                                                              Kolkata 2
    Mumbai                                                                 Mumbai
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                            Specificity
               HPV, Outcome=Cancer                                                    HPV, Outcome=Cancer


   Kolkata 1                                                              Kolkata 1
   Kolkata 2                                                              Kolkata 2
    Mumbai                                                                 Mumbai
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                    NPV


Meta-analysis of the sensitivity of HC2 (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.718   0.603   0.833   12.250    0.000       5
Random |   0.718   0.603   0.833   12.250    0.000
Test for heterogeneity: Q= 1.933 on 4 degrees of freedom (p= 0.748)

Meta-analysis of the specificity of HC2 (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.923   0.919   0.927 511.311     0.000       5
Random |   0.859   0.797   0.922   26.880    0.000
Test for heterogeneity: Q= 1135.945 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of HC2 (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.005   0.002   0.008    3.269    0.001      5
Random |   0.022   0.007   0.038    2.764    0.006
Test for heterogeneity: Q= 30.725 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of HC2 (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   0.999   1.000 7007.301    0.000      5
Random |   0.999   0.998   1.000 2774.918    0.000
Test for heterogeneity: Q= 10.038 on 4 degrees of freedom (p= 0.040)




                                                                                                                                              98
               HPV, Outcome=Cancer                                                            HPV, Outcome=Cancer


   Kolkata 1                                                                      Kolkata 1
   Kolkata 2                                                                      Kolkata 2
    Mumbai                                                                         Mumbai
Trivandrum 2                                                                   Trivandrum 2
      Harare                                                                         Harare


  Combined                                                                       Combined
               0              .05            .1           .15             .2                  0          .05              .1             .15   .2
                                    Prevalence of disease                                                      Detection rate of disease
               HPV, Outcome=Cancer


   Kolkata 1
   Kolkata 2
    Mumbai
Trivandrum 2
      Harare


  Combined
               0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                Approximative specificity



Meta-analysis of the prevalence of disease (cancer) in HC2 studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.001   0.002    6.241    0.000      5
Random |   0.003   0.001   0.004    3.599    0.000
Test for heterogeneity: Q= 18.263 on 4 degrees of freedom (p= 0.001)

Meta-analysis of the detection rate of disease (cancer) using HC2
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.001   0.001   0.002    5.447    0.000      5
Random |   0.002   0.001   0.003    3.740    0.000
Test for heterogeneity: Q= 10.431 on 4 degrees of freedom (p= 0.034)

Meta-analysis of the approximate specificity of HC2 (outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.923   0.920   0.927 511.736     0.000      5
Random |   0.859   0.797   0.922   26.911    0.000
Test for heterogeneity: Q= 1135.545 on 4 degrees of freedom (p= 0.000)




                                                                                                                                                    99
6.1.5. Test characteristics of cervical cytology
The accuracy of cytology is assessed at 3 different cut-offs ASCUS, LSIL and HSIL for the
outcome of respectively CIN1+, CIN2+, CIN3+ and cancer (see Table 24).

Table 24. Test characteristics of the Pap smear assessed at six locations, included in the multi-center and
Zimbabwe cross-sectional studies [Tables A-D].
A: Outcome=CIN1+, threshold>=ASCUS
Setting       Country       TP   FN    FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India       64   162   343     5,187     407    5,756   0.283   0.938   0.157   0.970   0.071   0.039    0.011
Kolkata 1      India      112   375   662     4,263     774    5,412   0.230   0.866   0.145   0.919   0.143   0.090    0.021
Mumbai         India       61   136    49     3,709     110    3,955   0.310   0.987   0.555   0.965   0.028   0.050    0.015
Trivandrum 1   India      467   246   175     3,569     642    4,457   0.655   0.953   0.727   0.936   0.144   0.160    0.105
Trivandrum 2   India       98   320    66     4,275     164    4,759   0.234   0.985   0.598   0.930   0.034   0.088    0.021
Harare         Zimbabwe   257   295   324     1,216     581    2,092   0.466   0.790   0.442   0.805   0.278   0.264    0.123
Overall                   802 1,239 1,295    21,003   2,097   24,339   0.393   0.942   0.382   0.944   0.086   0.084    0.033

B: Outcome=CIN1+, threshold>=LSIL
Setting       Country       TP    FN   FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India       56   170    197    5,333     253    5,756   0.248   0.964   0.221   0.969   0.044   0.039    0.010
Kolkata 1      India       84   403    349    4,576     433    5,412   0.172   0.929   0.194   0.919   0.080   0.090    0.016
Mumbai         India       54   143     28    3,730      82    3,955   0.274   0.993   0.659   0.963   0.021   0.050    0.014
Trivandrum 1   India      451   262    158    3,586     609    4,457   0.633   0.958   0.741   0.932   0.137   0.160    0.101
Trivandrum 2   India       84   334     47    4,294     131    4,759   0.201   0.989   0.641   0.928   0.028   0.088    0.018
Harare         Zimbabwe   158   394    109    1,431     267    2,092   0.286   0.929   0.592   0.784   0.128   0.264    0.076
Overall                   729 1,312    779   21,519   1,508   24,339   0.357   0.965   0.483   0.943   0.062   0.084    0.030

C: Outcome=CIN2+, threshold>= ASCUS
Setting       Country       TP   FN    FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India       21    42   386     5,307     407    5,756   0.333   0.932   0.052   0.992   0.071   0.011    0.004
Kolkata 1      India       62    93   712     4,545     774    5,412   0.400   0.865   0.080   0.980   0.143   0.029    0.011
Mumbai         India       53    26    57     3,819     110    3,955   0.671   0.985   0.482   0.993   0.028   0.020    0.013
Trivandrum 1   India      122    27   520     3,788     642    4,457   0.819   0.879   0.190   0.993   0.144   0.033    0.027
Trivandrum 2   India       50    31   114     4,564     164    4,759   0.617   0.976   0.305   0.993   0.034   0.017    0.011
Harare         Zimbabwe   130    71   451     1,440     581    2,092   0.647   0.762   0.224   0.953   0.278   0.096    0.062
Overall                   308   219 1,789    22,023   2,097   24,339   0.584   0.925   0.147   0.990   0.086   0.022    0.013

D: Outcome=CIN2+, threshold>=LSIL
Setting       Country       TP    FN   FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India       15    48   238     5,455     253    5,756   0.238   0.958   0.059   0.991   0.044   0.011    0.003
Kolkata 1      India       51   104   382     4,875     433    5,412   0.329   0.927   0.118   0.979   0.080   0.029    0.009
Mumbai         India       47    32    35     3,841      82    3,955   0.595   0.991   0.573   0.992   0.021   0.020    0.012
Trivandrum 1   India      116    33   493     3,815     609    4,457   0.779   0.886   0.190   0.991   0.137   0.033    0.026
Trivandrum 2   India       50    31    81     4,597     131    4,759   0.617   0.983   0.382   0.993   0.028   0.017    0.011
Harare         Zimbabwe    89   112   178     1,713     267    2,092   0.443   0.906   0.333   0.939   0.128   0.096    0.043
Overall                   279   248 1,229    22,583   1,508   24,339   0.529   0.948   0.185   0.989   0.062   0.022    0.011

E: Outcome=CIN2+, threshold>=HSIL
Setting       Country       TP    FN   FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India       11    52     17    5,676     28     5,756   0.175   0.997   0.393   0.991   0.005   0.011    0.002
Kolkata 1      India       44   111    121    5,136    165     5,412   0.284   0.977   0.267   0.979   0.030   0.029    0.008
Mumbai         India       43    36     17    3,859     60     3,955   0.544   0.996   0.717   0.991   0.015   0.020    0.011
Trivandrum 1   India       77    72     20    4,288     97     4,457   0.517   0.995   0.794   0.983   0.022   0.033    0.017
Trivandrum 2   India       50    31     18    4,660     68     4,759   0.617   0.996   0.735   0.993   0.014   0.017    0.011
Harare         Zimbabwe    33   168     40    1,851     73     2,092   0.164   0.979   0.452   0.917   0.035   0.096    0.016
Overall                   225   302    193   23,619    418    24,339   0.427   0.992   0.538   0.987   0.017   0.022    0.009




                                                                                                                  100
F: Outcome=CIN3+, threshold>= ASCUS
Setting       Country       TP   FN     FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India        16    29   391     5,320     407    5,756   0.356   0.932   0.039   0.995   0.071   0.008    0.003
Kolkata 1      India        44    52   730     4,586     774    5,412   0.458   0.863   0.057   0.989   0.143   0.018    0.008
Mumbai         India        41    16    69     3,829     110    3,955   0.719   0.982   0.373   0.996   0.028   0.014    0.010
Trivandrum 1   India        54     2   588     3,813     642    4,457   0.964   0.866   0.084   0.999   0.144   0.013    0.012
Trivandrum 2   India        39    22   125     4,573     164    4,759   0.639   0.973   0.238   0.995   0.034   0.013    0.008
Overall                    194   121 1,903    22,121   2,097   24,339   0.616   0.921   0.093   0.995   0.086   0.013    0.008

G: Outcome=CIN3+, threshold>=LSIL
Setting       Country       TP    FN    FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India        12    33   241     5,470     253    5,756   0.267   0.958   0.047   0.994   0.044   0.008    0.002
Kolkata 1      India        37    59   396     4,920     433    5,412   0.385   0.926   0.085   0.988   0.080   0.018    0.007
Mumbai         India        35    22    47     3,851      82    3,955   0.614   0.988   0.427   0.994   0.021   0.014    0.009
Trivandrum 1   India        50     6   559     3,842     609    4,457   0.893   0.873   0.082   0.998   0.137   0.013    0.011
Trivandrum 2   India        39    22    92     4,606     131    4,759   0.639   0.980   0.298   0.995   0.028   0.013    0.008
Overall                    173   142 1,335    22,689   1,508   24,339   0.549   0.944   0.115   0.994   0.062   0.013    0.007

H: Outcome=CIN3+, threshold>=HSIL
Setting       Country       TP   FN     FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India        10    35     18    5,693     28     5,756   0.222   0.997   0.357   0.994   0.005   0.008    0.002
Kolkata 1      India        34    62    131    5,185    165     5,412   0.354   0.975   0.206   0.988   0.030   0.018    0.006
Mumbai         India        34    23     26    3,872     60     3,955   0.596   0.993   0.567   0.994   0.015   0.014    0.009
Trivandrum 1   India        43    13     54    4,347     97     4,457   0.768   0.988   0.443   0.997   0.022   0.013    0.010
Trivandrum 2   India        39    22     29    4,669     68     4,759   0.639   0.994   0.574   0.995   0.014   0.013    0.008
Overall                    160   155    258   23,766    418    24,339   0.508   0.989   0.383   0.994   0.017   0.013    0.007

I: Outcome=Cancer, threshold>= ASCUS
Setting       Country        TP   FN    FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India         2     3   405     5,346     407    5,756   0.400   0.930   0.005   0.999   0.071   0.001    0.000
Kolkata 1      India        20    17   754     4,621     774    5,412   0.541   0.860   0.026   0.996   0.143   0.007    0.004
Setting        India        19     6    91     3,839     110    3,955   0.760   0.977   0.173   0.998   0.028   0.006    0.005
Trivandrum 1   India         6     0   636     3,815     642    4,457   1.000   0.857   0.009   1.000   0.144   0.001    0.001
Trivandrum 2   India        12     3   152     4,592     164    4,759   0.800   0.968   0.073   0.999   0.034   0.003    0.003
Harare         Zimbabwe      3     0   578     1,511     581    2,092   1.000   0.723   0.005   1.000   0.278   0.001    0.001
Overall                     59    29 2,038    22,213   2,097   24,339   0.670   0.916   0.028   0.999   0.086   0.004    0.002

J: Outcome=Cancer, threshold>=LSIL
Setting       Country        TP    FN   FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India         1     4   252     5,499     253    5,756   0.200   0.956   0.004   0.999   0.044   0.001    0.000
Kolkata 1      India        18    19   415     4,960     433    5,412   0.486   0.923   0.042   0.996   0.080   0.007    0.003
Mumbai         India        17     8    65     3,865      82    3,955   0.680   0.983   0.207   0.998   0.021   0.006    0.004
Trivandrum 1   India         6     0   603     3,848     609    4,457   1.000   0.865   0.010   1.000   0.137   0.001    0.001
Trivandrum 2   India        12     3   119     4,625     131    4,759   0.800   0.975   0.092   0.999   0.028   0.003    0.003
Harare         Zimbabwe      3     0   264     1,825     267    2,092   1.000   0.874   0.011   1.000   0.128   0.001    0.001
Overall                     54    34 1,454    22,797   1,508   24,339   0.614   0.940   0.036   0.999   0.062   0.004    0.002

K: Outcome=Cancer, threshold>=HSIL
Setting      Country        TP    FN    FP      TN       T+        N      Se      Sp    PPV     NPV T+ rate     Prev Det rate
Jaipur         India         1     4     27    5,724     28     5,756   0.200   0.995   0.036   0.999   0.005   0.001    0.000
Kolkata 1      India        18    19    147    5,228    165     5,412   0.486   0.973   0.109   0.996   0.030   0.007    0.003
Mumbai         India        17     8     43    3,887     60     3,955   0.680   0.989   0.283   0.998   0.015   0.006    0.004
Trivandrum 1   India         6     0     91    4,360     97     4,457   1.000   0.980   0.062   1.000   0.022   0.001    0.001
Trivandrum 2   India        12     3     56    4,688     68     4,759   0.800   0.988   0.176   0.999   0.014   0.003    0.003
Harare         Zimbabwe      3     0     70    2,019     73     2,092   1.000   0.966   0.041   1.000   0.035   0.001    0.001
Overall                     54    34    364   23,887    418    24,339   0.614   0.985   0.129   0.999   0.017   0.004    0.002




                                                                                                                   101
                ASCUS


   Kolkata 1
       Jaipur
     Mumbai
Trivandrum 1
Trivandrum 2
      Harare


   Combined
                 0   .1    .2   .3     .4 .5 .6 .7          .8   .9   1
                                     Test positivity rate

Meta-analysis of the test-positivity rate at cutoff ASCUS+

       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.063   0.060   0.066   43.281    0.000      6
Random |   0.116   0.067   0.164    4.657    0.000

Test for heterogeneity: Q= 1306.894 on 5 degrees of freedom (p= 0.000)




                                                                          102
               ASCUS, Outcome=CIN1+                                                  ASCUS, Outcome=CIN1+


   Kolkata 1                                                             Kolkata 1
      Jaipur                                                                Jaipur
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                    Sensitivity                                                           Specificity
               ASCUS, Outcome=CIN1+                                                  ASCUS, Outcome=CIN1+


   Kolkata 1                                                             Kolkata 1
      Jaipur                                                                Jaipur
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                       PPV                                                                   NPV


Meta-analysis of the sensitivity of cyto (ASCUS+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.391   0.373   0.408   43.657    0.000      6
Random |   0.363   0.208   0.519    4.583    0.000
Test for heterogeneity: Q= 379.623 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (ASCUS+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.968   0.966   0.971 872.974     0.000      6
Random |   0.921   0.887   0.955   53.379    0.000
Test for heterogeneity: Q= 1029.603 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (ASCUS+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.339   0.324   0.354   42.941    0.000       6
Random |   0.436   0.214   0.658    3.852    0.000
Test for heterogeneity: Q= 917.451 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (ASCUS+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.949   0.946   0.952 671.877     0.000       6
Random |   0.922   0.896   0.948   69.730    0.000
Test for heterogeneity: Q= 397.482 on 5 degrees of freedom (p= 0.000)




                                                                                                                                            103
               ASCUS, Outcome=CIN1+                                                              ASCUS, Outcome=CIN1+


   Kolkata 1                                                                         Kolkata 1
      Jaipur                                                                            Jaipur
    Mumbai                                                                            Mumbai
Trivandrum 1                                                                      Trivandrum 1
Trivandrum 2                                                                      Trivandrum 2
      Harare                                                                            Harare


  Combined                                                                          Combined
               0             .1              .2               .3             .4                  0          .1            .2             .3   .4
                                    Prevalence of disease                                                        Prevalence of disease
               ASCUS, Outcome=CIN1+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0   .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                                  Approximative specificity



Meta-analysis of the prevalence of disease (CIN1+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.073   0.070   0.076   46.268    0.000      6
Random |   0.114   0.071   0.158    5.194    0.000
Test for heterogeneity: Q= 893.924 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN1+) using cytology
(ASCUS+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.020   0.019   0.022   23.709    0.000      6
Random |   0.048   0.028   0.068    4.805    0.000
Test for heterogeneity: Q= 593.645 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (ASCUS+)(outcome
CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.970   0.968   0.972 922.228     0.000      6
Random |   0.929   0.897   0.960   57.768    0.000
Test for heterogeneity: Q= 997.015 on 5 degrees of freedom (p= 0.000)




                                                                                                                                               104
               ASCUS, Outcome=CIN2+                                                  ASCUS, Outcome=CIN2+


   Kolkata 1                                                             Kolkata 1
      Jaipur                                                                Jaipur
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                    Sensitivity                                                           Specificity
               ASCUS, Outcome=CIN2+                                                  ASCUS, Outcome=CIN2+


   Kolkata 1                                                             Kolkata 1
      Jaipur                                                                Jaipur
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                       PPV                                                                   NPV


Meta-analysis of the sensitivity of cyto (ASCUS+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.625   0.592   0.658   37.042    0.000      6
Random |   0.584   0.435   0.732    7.686    0.000
Test for heterogeneity: Q= 95.717 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (ASCUS+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.956   0.954   0.959 771.272     0.000      6
Random |   0.900   0.857   0.944   40.496    0.000
Test for heterogeneity: Q= 1364.330 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (ASCUS+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.118   0.107   0.130   19.639    0.000       6
Random |   0.212   0.131   0.293    5.137    0.000
Test for heterogeneity: Q= 196.150 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (ASCUS+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.991   0.990   0.992 1646.090    0.000       6
Random |   0.986   0.981   0.992 370.110     0.000
Test for heterogeneity: Q= 86.572 on 5 degrees of freedom (p= 0.000)




                                                                                                                                            105
               ASCUS, Outcome=CIN2+                                                              ASCUS, Outcome=CIN2+


   Kolkata 1                                                                         Kolkata 1
      Jaipur                                                                            Jaipur
    Mumbai                                                                            Mumbai
Trivandrum 1                                                                      Trivandrum 1
Trivandrum 2                                                                      Trivandrum 2
      Harare                                                                            Harare


  Combined                                                                          Combined
               0             .1              .2               .3             .4                  0          .1              .2             .3   .4
                                    Prevalence of disease                                                        Detection rate of disease
               ASCUS, Outcome=CIN2+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0   .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                                  Approximative specificity




Meta-analysis of the prevalence of disease (CIN2+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.020   0.018   0.021   23.193    0.000      6
Random |   0.033   0.021   0.045    5.390    0.000
Test for heterogeneity: Q= 224.884 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using cytology
(ASCUS+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.008   0.010   15.465    0.000      6
Random |   0.020   0.012   0.028    4.668    0.000
Test for heterogeneity: Q= 212.913 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (ASCUS+)(outcome
CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.957   0.954   0.959 777.413     0.000      6
Random |   0.903   0.860   0.945   41.160    0.000
Test for heterogeneity: Q= 1349.328 on 5 degrees of freedom (p= 0.000)




                                                                                                                                                 106
               ASCUS, Outcome=CIN3+                                                  ASCUS, Outcome=CIN3+


   Kolkata 1                                                             Kolkata 1
      Jaipur                                                                Jaipur
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                    Sensitivity                                                           Specificity
               ASCUS, Outcome=CIN3+                                                  ASCUS, Outcome=CIN3+


   Kolkata 1                                                             Kolkata 1
      Jaipur                                                                Jaipur
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2


  Combined                                                              Combined
               0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                       PPV                                                                   NPV


Meta-analysis of the sensitivity of cyto (ASCUS+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.794   0.756   0.831   41.664    0.000      5
Random |   0.630   0.379   0.882    4.918    0.000
Test for heterogeneity: Q= 136.376 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (ASCUS+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.955   0.952   0.957 725.854     0.000      5
Random |   0.923   0.881   0.966   42.886    0.000
Test for heterogeneity: Q= 958.654 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (ASCUS+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.067   0.056   0.077   12.499    0.000       5
Random |   0.136   0.081   0.190    4.870    0.000
Test for heterogeneity: Q= 82.562 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (ASCUS+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.997   0.998 3246.354    0.000       5
Random |   0.995   0.992   0.998 585.494     0.000
Test for heterogeneity: Q= 74.665 on 4 degrees of freedom (p= 0.000)




                                                                                                                                            107
               ASCUS, Outcome=CIN3+                                                              ASCUS, Outcome=CIN3+


   Kolkata 1                                                                         Kolkata 1
      Jaipur                                                                            Jaipur
    Mumbai                                                                            Mumbai
Trivandrum 1                                                                      Trivandrum 1
Trivandrum 2                                                                      Trivandrum 2


  Combined                                                                          Combined
               0             .1              .2               .3             .4                  0          .1              .2             .3   .4
                                    Prevalence of disease                                                        Detection rate of disease
               ASCUS, Outcome=CIN3+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2


  Combined
               0   .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                                  Approximative specificity



Meta-analysis of the prevalence of disease (CIN3+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.012   0.011   0.013   17.154    0.000      5
Random |   0.013   0.009   0.016    7.218    0.000
Test for heterogeneity: Q= 25.183 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using cytology
(ASCUS+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.006   0.005   0.007   12.130    0.000      5
Random |   0.008   0.004   0.012    4.325    0.000
Test for heterogeneity: Q= 48.679 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (ASCUS+)(outcome
CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.955   0.952   0.957 729.283     0.000      5
Random |   0.924   0.882   0.966   43.139    0.000
Test for heterogeneity: Q= 957.002 on 4 degrees of freedom (p= 0.000)




                                                                                                                                                 108
               ASCUS, Outcome=Cancer                                                     ASCUS, Outcome=Cancer


   Kolkata 1                                                                 Kolkata 1
      Jaipur                                                                    Jaipur
    Mumbai                                                                    Mumbai
Trivandrum 1                                                              Trivandrum 1
Trivandrum 2                                                              Trivandrum 2
      Harare                                                                    Harare


  Combined                                                                  Combined
                0   .1 .2 .3 .4 .5 .6 .7 .8 .9          1                                0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                  Sensitivity                                                                 Specificity
               ASCUS, Outcome=Cancer                                                     ASCUS, Outcome=Cancer


   Kolkata 1                                                                 Kolkata 1
      Jaipur                                                                    Jaipur
    Mumbai                                                                    Mumbai
Trivandrum 1                                                              Trivandrum 1
Trivandrum 2                                                              Trivandrum 2
      Harare                                                                    Harare


  Combined                                                                  Combined
               0    .1   .2   .3   .4    .5   .6   .7       .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                      NPV


Meta-analysis of the sensitivity of cyto (ASCUS+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.737   0.650   0.824   16.549    0.000      6
Random |   0.758   0.591   0.924    8.928    0.000
Test for heterogeneity: Q= 15.724 on 5 degrees of freedom (p= 0.008)

Meta-analysis of the specificity of cyto (ASCUS+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.942   0.939   0.945 669.879     0.000      6
Random |   0.886   0.838   0.935   35.729    0.000
Test for heterogeneity: Q= 1390.387 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (ASCUS+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.006   0.013    5.016    0.000      6
Random |   0.020   0.007   0.033    3.082    0.002
Test for heterogeneity: Q= 42.368 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (ASCUS+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   0.999   1.000 6270.464    0.000      6
Random |   0.999   0.998   1.000 2748.884    0.000
Test for heterogeneity: Q= 20.421 on 5 degrees of freedom (p= 0.001)




                                                                                                                                                109
               ASCUS, Outcome=Cancer                                                         ASCUS, Outcome=Cancer


   Kolkata 1                                                                     Kolkata 1
      Jaipur                                                                        Jaipur
    Mumbai                                                                        Mumbai
Trivandrum 1                                                                  Trivandrum 1
Trivandrum 2                                                                  Trivandrum 2
      Harare                                                                        Harare


  Combined                                                                      Combined
               0             .05            .1           .15             .2                  0          .05              .1             .15   .2
                                   Prevalence of disease                                                      Detection rate of disease
               ASCUS, Outcome=Cancer


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0   .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                               Approximative specificity




Meta-analysis of the prevalence of disease (cancer) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.001   0.002    7.002    0.000      6
Random |   0.003   0.001   0.005    3.595    0.000
Test for heterogeneity: Q= 42.456 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (cancer) using cytology
(ASCUS+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.001   0.001   0.001    5.243    0.000      6
Random |   0.002   0.001   0.003    3.284    0.001
Test for heterogeneity: Q= 34.724 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (ASCUS+)(outcome
cancer)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.942   0.939   0.945 670.628     0.000      6
Random |   0.887   0.838   0.935   35.772    0.000
Test for heterogeneity: Q= 1390.189 on 5 degrees of freedom (p= 0.000)




                                                                                                                                               110
                LSIL+


   Kolkata 1
       Jaipur
     Mumbai
Trivandrum 1
Trivandrum 2
      Harare


   Combined
                 0   .1    .2   .3     .4 .5 .6 .7          .8   .9   1
                                     Test positivity rate
Meta-analysis of the test positivity rate of cytology at the cutoff LSIL+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.045   0.042   0.047   35.708    0.000      6
Random |   0.073   0.042   0.103    4.680    0.000
Test for heterogeneity: Q= 702.927 on 5 degrees of freedom (p= 0.000)




                                                                          111
               LSIL+, Outcome=CIN1+                                                   LSIL+, Outcome=CIN1+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                            Specificity
               LSIL+, Outcome=CIN1+                                                   LSIL+, Outcome=CIN1+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                    NPV


Meta-analysis of the sensitivity of cyto (LSIL+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.314   0.298   0.331   37.180    0.000      6
Random |   0.303   0.148   0.457    3.831    0.000
Test for heterogeneity: Q= 421.821 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (LSIL+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.980   0.979   0.982 1102.832    0.000      6
Random |   0.961   0.943   0.979 104.176     0.000
Test for heterogeneity: Q= 452.748 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (LSIL+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.473   0.453   0.493   45.979    0.000      6
Random |   0.507   0.279   0.735    4.354    0.000
Test for heterogeneity: Q= 579.698 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (LSIL+)(outcome CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.947   0.944   0.950 669.694     0.000      6
Random |   0.917   0.888   0.946   62.168    0.000
Test for heterogeneity: Q= 495.492 on 5 degrees of freedom (p= 0.000)




                                                                                                                                              112
               LSIL+, Outcome=CIN1+                                                               LSIL+, Outcome=CIN1+


   Kolkata 1                                                                          Kolkata 1
      Jaipur                                                                             Jaipur
    Mumbai                                                                             Mumbai
Trivandrum 1                                                                       Trivandrum 1
Trivandrum 2                                                                       Trivandrum 2
      Harare                                                                             Harare


  Combined                                                                           Combined
               0              .1              .2               .3             .4                  0          .1              .2             .3   .4
                                     Prevalence of disease                                                        Detection rate of disease
               LSIL+, Outcome=CIN1+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0    .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                                   Approximative specificity




Meta-analysis of the prevalence of disease (CIN1+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.073   0.070   0.076   46.268    0.000      6
Random |   0.114   0.071   0.158    5.194    0.000
Test for heterogeneity: Q= 893.924 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN1+) using cytology
(LSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.017   0.016   0.019   21.659    0.000      6
Random |   0.038   0.022   0.054    4.579    0.000
Test for heterogeneity: Q= 485.705 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (LSIL+)(outcome
CIN1+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.981   0.980   0.983 1168.192    0.000      6
Random |   0.965   0.948   0.982 113.109     0.000
Test for heterogeneity: Q= 438.502 on 5 degrees of freedom (p= 0.000)




                                                                                                                                                  113
               LSIL+, Outcome=CIN2+                                                   LSIL+, Outcome=CIN2+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                            Specificity
               LSIL+, Outcome=CIN2+                                                   LSIL+, Outcome=CIN2+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                    NPV


Meta-analysis of the sensitivity of cyto (LSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.516   0.482   0.550   30.083    0.000      6
Random |   0.501   0.332   0.669    5.818    0.000
Test for heterogeneity: Q= 120.847 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (LSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.973   0.971   0.975 969.112     0.000      6
Random |   0.942   0.915   0.969   68.644    0.000
Test for heterogeneity: Q= 784.259 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (LSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.157   0.141   0.173   19.077    0.000      6
Random |   0.266   0.163   0.370    5.047    0.000
Test for heterogeneity: Q= 177.576 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (LSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.990   0.989   0.991 1575.625    0.000      6
Random |   0.983   0.977   0.990 298.052     0.000
Test for heterogeneity: Q= 123.395 on 5 degrees of freedom (p= 0.000)




                                                                                                                                              114
               LSIL+, Outcome=CIN2+                                                               LSIL+, Outcome=CIN2+


   Kolkata 1                                                                          Kolkata 1
      Jaipur                                                                             Jaipur
    Mumbai                                                                             Mumbai
Trivandrum 1                                                                       Trivandrum 1
Trivandrum 2                                                                       Trivandrum 2
      Harare                                                                             Harare


  Combined                                                                           Combined
               0              .1              .2               .3             .4                  0          .1              .2             .3   .4
                                     Prevalence of disease                                                        Detection rate of disease
               LSIL+, Outcome=CIN2+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0    .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                                   Approximative specificity



Meta-analysis of the prevalence of disease (CIN2+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.020   0.018   0.021   23.193    0.000      6
Random |   0.033   0.021   0.045    5.390    0.000
Test for heterogeneity: Q= 224.884 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using cytology
(LSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.007   0.006   0.008   13.723    0.000      6
Random |   0.016   0.009   0.024    4.375    0.000
Test for heterogeneity: Q= 188.353 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (LSIL+)(outcome
CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.973   0.971   0.975 978.653     0.000      6
Random |   0.943   0.917   0.970   69.847    0.000
Test for heterogeneity: Q= 776.718 on 5 degrees of freedom (p= 0.000)




                                                                                                                                                  115
               LSIL+, Outcome=CIN3+                                                   LSIL+, Outcome=CIN3+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                            Specificity
               LSIL+, Outcome=CIN3+                                                   LSIL+, Outcome=CIN3+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                    NPV


Meta-analysis of the sensitivity of cyto (LSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.612   0.565   0.660   25.445    0.000      5
Random |   0.561   0.327   0.796    4.693    0.000
Test for heterogeneity: Q= 94.624 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (LSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.969   0.967   0.971 883.082     0.000      5
Random |   0.945   0.916   0.975   62.518    0.000
Test for heterogeneity: Q= 678.728 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (LSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.086   0.072   0.100   12.192    0.000      5
Random |   0.164   0.096   0.232    4.738    0.000
Test for heterogeneity: Q= 75.473 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (LSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.996   0.995   0.997 2331.996    0.000      5
Random |   0.994   0.991   0.997 637.215     0.000
Test for heterogeneity: Q= 46.902 on 4 degrees of freedom (p= 0.000)




                                                                                                                                              116
               LSIL+, Outcome=CIN3+                                                               LSIL+, Outcome=CIN3+


   Kolkata 1                                                                          Kolkata 1
      Jaipur                                                                             Jaipur
    Mumbai                                                                             Mumbai
Trivandrum 1                                                                       Trivandrum 1
Trivandrum 2                                                                       Trivandrum 2


  Combined                                                                           Combined
               0              .1              .2               .3             .4                  0          .1              .2             .3   .4
                                     Prevalence of disease                                                        Detection rate of disease
               LSIL+, Outcome=CIN3+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2


  Combined
               0    .1   .2        .3   .4   .5    .6    .7         .8   .9   1
                                   Approximative specificity


Meta-analysis of the prevalence of disease (CIN3+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.012   0.011   0.013   17.154    0.000      5
Random |   0.013   0.009   0.016    7.218    0.000
Test for heterogeneity: Q= 25.183 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using cytology
(LSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.005   0.004   0.006   10.961    0.000      5
Random |   0.007   0.004   0.011    3.928    0.000
Test for heterogeneity: Q= 54.348 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (LSIL+)(outcome
CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.969   0.967   0.972 888.178     0.000      5
Random |   0.946   0.916   0.975   62.917    0.000
Test for heterogeneity: Q= 678.215 on 4 degrees of freedom (p= 0.000)




                                                                                                                                                  117
               LSIL+, Outcome=Cancer                                                  LSIL+, Outcome=Cancer


      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                            Specificity
               LSIL+, Outcome=Cancer                                                  LSIL+, Outcome=Cancer


      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                    NPV


Meta-analysis of the sensitivity of cyto (LSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.766   0.660   0.871   14.188    0.000      5
Random |   0.748   0.522   0.975    6.470    0.000
Test for heterogeneity: Q= 16.639 on 4 degrees of freedom (p= 0.002)

Meta-analysis of the specificity of cyto (LSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.964   0.962   0.967 765.223     0.000      5
Random |   0.931   0.898   0.965   54.470    0.000
Test for heterogeneity: Q= 645.168 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (LSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.009   0.004   0.014    3.566    0.000       5
Random |   0.024   0.006   0.043    2.552    0.011
Test for heterogeneity: Q= 32.170 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (LSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   0.999   1.000 6088.234    0.000       5
Random |   0.999   0.999   1.000 3063.869    0.000
Test for heterogeneity: Q= 13.033 on 4 degrees of freedom (p= 0.011))




                                                                                                                                              118
               LSIL+, Outcome=Cancer                                                          LSIL+, Outcome=Cancer


      Jaipur                                                                         Jaipur
    Mumbai                                                                         Mumbai
Trivandrum 1                                                                   Trivandrum 1
Trivandrum 2                                                                   Trivandrum 2
      Harare                                                                         Harare


  Combined                                                                       Combined
               0              .05            .1           .15             .2                  0          .05              .1            .15   .2
                                    Prevalence of disease                                                      Detection rat of disease
               LSIL+, Outcome=Cancer


      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                Approximative specificity



Meta-analysis of the prevalence of disease (cancer) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.001   0.001   0.002    5.359    0.000      5
Random |   0.002   0.001   0.003    3.113    0.002
Test for heterogeneity: Q= 18.984 on 4 degrees of freedom (p= 0.001)

Meta-analysis of the detection rate of disease (cancer) using cytology
(LSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.000   0.000   0.001    2.217    0.027      5
Random |   0.002   0.000   0.003    2.288    0.022
Test for heterogeneity: Q= 31.676 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (LSIL+)(outcome
cancer)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.964   0.962   0.967 766.239     0.000      5
Random |   0.931   0.897   0.965   54.143    0.000
Test for heterogeneity: Q= 654.200 on 4 degrees of freedom (p= 0.000)




                                                                                                                                               119
                HSIL+


   Kolkata 1
       Jaipur
     Mumbai
Trivandrum 1
Trivandrum 2
      Harare


   Combined
                 0           .05           .1             .15       .2
                                   Test positivity rate


Meta-analysis of the test-positivity rate of cytology at cut-off HSIL+

       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.012   0.011   0.013   17.961    0.000      6
Random |   0.020   0.011   0.029    4.453    0.000

Test for heterogeneity: Q= 175.116 on 5 degrees of freedom (p= 0.000)




                                                                         120
               HSIL, Outcome=CIN2+                                                    HSIL, Outcome=CIN2+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                           Specificity
               HSIL, Outcome=CIN2+                                                    HSIL, Outcome=CIN2+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2
      Harare                                                                 Harare


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                   NPV


Meta-analysis of the sensitivity of cyto (HSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.313   0.281   0.344   19.585    0.000      6
Random |   0.381   0.224   0.537    4.766    0.000
Test for heterogeneity: Q= 115.023 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (HSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.995   0.994   0.996 2286.022    0.000      6
Random |   0.991   0.986   0.995 450.614     0.000
Test for heterogeneity: Q= 109.507 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (HSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.539   0.500   0.578   26.905    0.000      6
Random |   0.561   0.354   0.768    5.309    0.000
Test for heterogeneity: Q= 128.581 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (HSIL+)(outcome CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.989   0.987   0.990 1507.454    0.000      6
Random |   0.978   0.970   0.987 228.522     0.000
Test for heterogeneity: Q= 189.425 on 5 degrees of freedom (p= 0.000)




                                                                                                                                             121
               HSIL, Outcome=CIN2+                                                            HSIL, Outcome=CIN2+


   Kolkata 1                                                                      Kolkata 1
      Jaipur                                                                         Jaipur
    Mumbai                                                                         Mumbai
Trivandrum 1                                                                   Trivandrum 1
Trivandrum 2                                                                   Trivandrum 2
      Harare                                                                         Harare


  Combined                                                                       Combined
               0              .05            .1           .15             .2                  0          .05              .1             .15   .2
                                    Prevalence of disease                                                      Detection rate of disease
               HSIL, Outcome=CIN2+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                Approximative specificity




Meta-analysis of the prevalence of disease (CIN2+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.020   0.018   0.021   23.193    0.000      6
Random |   0.033   0.021   0.045    5.390    0.000
Test for heterogeneity: Q= 224.884 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN2+) using cytology
(HSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.005   0.005   0.006   12.044    0.000      6
Random |   0.011   0.005   0.016    4.002    0.000
Test for heterogeneity: Q= 116.210 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (HSIL+)(outcome
CIN2+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.995   0.994   0.996 2313.156    0.000      6
Random |   0.991   0.987   0.995 461.447     0.000
Test for heterogeneity: Q= 107.786 on 5 degrees of freedom (p= 0.000)




                                                                                                                                                122
               HSIL, Outcome=CIN3+                                                    HSIL, Outcome=CIN3+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                     Sensitivity                                                           Specificity
               HSIL, Outcome=CIN3+                                                    HSIL, Outcome=CIN3+


   Kolkata 1                                                              Kolkata 1
      Jaipur                                                                 Jaipur
    Mumbai                                                                 Mumbai
Trivandrum 1                                                           Trivandrum 1
Trivandrum 2                                                           Trivandrum 2


  Combined                                                               Combined
               0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1                  0   .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                        PPV                                                                   NPV


Meta-analysis of the sensitivity of cyto (HSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.507   0.456   0.558   19.604    0.000      5
Random |   0.516   0.320   0.711    5.164    0.000
Test for heterogeneity: Q= 58.826 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (HSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.994   0.993   0.995 1925.546    0.000      5
Random |   0.990   0.984   0.995 343.901     0.000
Test for heterogeneity: Q= 105.361 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (HSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.354   0.310   0.397   15.996    0.000      5
Random |   0.427   0.260   0.594    5.009    0.000
Test for heterogeneity: Q= 49.658 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (HSIL+)(outcome CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.995   0.994   0.996 2116.522    0.000      5
Random |   0.994   0.991   0.996 776.478     0.000
Test for heterogeneity: Q= 28.198 on 4 degrees of freedom (p= 0.000)




                                                                                                                                             123
               HSIL, Outcome=CIN3+                                                            HSIL, Outcome=CIN3+


   Kolkata 1                                                                      Kolkata 1
      Jaipur                                                                         Jaipur
    Mumbai                                                                         Mumbai
Trivandrum 1                                                                   Trivandrum 1
Trivandrum 2                                                                   Trivandrum 2


  Combined                                                                       Combined
               0              .05            .1           .15             .2                  0          .05              .1             .15   .2
                                    Prevalence of disease                                                      Detection rate of disease
               HSIL, Outcome=CIN3+


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2


  Combined
               0    .1   .2     .3   .4   .5    .6    .7        .8   .9   1
                                Approximative specificity




Meta-analysis of the prevalence of disease (CIN3+) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.012   0.011   0.013   17.381    0.000      5
Random |   0.013   0.010   0.017    7.335    0.000
Test for heterogeneity: Q= 24.887 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (CIN3+) using cytology
(HSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.004   0.004   0.005   10.622    0.000      5
Random |   0.007   0.003   0.010    3.895    0.000
Test for heterogeneity: Q= 53.359 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (HSIL+)(outcome
CIN3+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.994   0.993   0.995 1936.774    0.000      5
Random |   0.990   0.984   0.995 346.288     0.000
Test for heterogeneity: Q= 105.136 on 4 degrees of freedom (p= 0.000)




                                                                                                                                                124
               HSIL, Outcome=Cancer                                                          HSIL, Outcome=Cancer


   Kolkata 1                                                                     Kolkata 1
      Jaipur                                                                        Jaipur
    Mumbai                                                                        Mumbai
Trivandrum 1                                                                  Trivandrum 1
Trivandrum 2                                                                  Trivandrum 2
      Harare                                                                        Harare


  Combined                                                                      Combined
               0       .1    .2    .3    .4    .5    .6    .7   .8   .9   1                  0    .1   .2   .3   .4    .5    .6   .7   .8   .9   1
                                           Sensitivity                                                             Specificity
               HSIL, Outcome=Cancer                                                          HSIL, Outcome=Cancer


   Kolkata 1                                                                     Kolkata 1
      Jaipur                                                                        Jaipur
    Mumbai                                                                        Mumbai
Trivandrum 1                                                                  Trivandrum 1
Trivandrum 2                                                                  Trivandrum 2
      Harare                                                                        Harare


  Combined                                                                      Combined
                   0    .1    .2    .3    .4     .5   .6   .7   .8   .9   1                  0    .1   .2   .3   .4    .5 .6      .7   .8   .9   1
                                               PPV                                                                    NPV


Meta-analysis of the sensitivity of cyto (HSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.681   0.593   0.770   15.109    0.000      6
Random |   0.698   0.491   0.904    6.617    0.000
Test for heterogeneity: Q= 24.699 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity of cyto (HSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.989   0.988   0.990 1560.807    0.000      6
Random |   0.982   0.975   0.990 250.472     0.000
Test for heterogeneity: Q= 155.563 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of cyto (HSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.082   0.059   0.106    6.793    0.000       6
Random |   0.104   0.049   0.158    3.745    0.000
Test for heterogeneity: Q= 22.918 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the NPV of cyto (HSIL+)(outcome cancer)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   0.999   1.000 6705.381    0.000       6
Random |   0.999   0.998   1.000 2590.917    0.000
Test for heterogeneity: Q= 25.558 on 5 degrees of freedom (p= 0.000)




                                                                                                                                                     125
               HSIL, Outcome=Cancer                                                         HSIL, Outcome=Cancer


   Kolkata 1                                                                    Kolkata 1
      Jaipur                                                                       Jaipur
    Mumbai                                                                       Mumbai
Trivandrum 1                                                                 Trivandrum 1
Trivandrum 2                                                                 Trivandrum 2
      Harare                                                                       Harare


  Combined                                                                     Combined
                0             .025            .05          .075         .1                   0         .025           .05            .075   .1
                                     Prevalence of disease                                                 Detection rate of disease
               HSIL, Outcome=Cancer


   Kolkata 1
      Jaipur
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               0    .1   .2      .3   .4   .5    .6    .7     .8   .9   1
                                 Approximative specificity




Meta-analysis of the prevalence of disease (cancer) in cytology studies
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.002   0.001   0.002    7.002    0.000      6
Random |   0.003   0.001   0.005    3.595    0.000
Test for heterogeneity: Q= 42.456 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the detection rate of disease (cancer) using cytology
(HSIL+)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.001   0.000   0.001    4.070    0.000      6
Random |   0.002   0.001   0.003    3.024    0.002
Test for heterogeneity: Q= 40.614 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the approximate specificity of cyto (HSIL+)(outcome
cancer)
        | Pooled      95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.989   0.988   0.990 1562.420    0.000      6
Random |   0.982   0.975   0.990 250.901     0.000
Test for heterogeneity: Q= 155.405 on 5 degrees of freedom (p= 0.000)




                                                                                                                                             126
6.1.6. Summary of the meta-analyses of the accuracy for CIN1+
Table 25. Summary of the meta-analyses of screening tests considering CIN1+ as outcome: pooled estimates
and confidence intervals, model of pooling (F=fixed; R=random effect model), range, number of study
locations and identification of studies include (studies reporting lowest and highest parameters are
respectively single and double underlined).

Test          VIA                            Outcome CIN1+
                                                                            Included study
Parameter     Estimate         95% CI        Model        Range      Number locations
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,
Sensitivity          61.8    (53.2 - 70.3)      R      42.5 - 90.0      12  Mu,Ni,Ou,Tr1,Tr2,Ha
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,
Specificity          84.9    (81.2 - 88.7)      R      67.9 - 95.1      12  Mu,Ni,Ou,Tr1,Tr2,Ha
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,
                                                                            Mu,Ni,Ou,Tr1,Tr2,Ha,
PPV                  30.6    (21.1 - 40.0)      R      13.0 - 62.8      14  Am,Bu
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,
NPV                  95.7    (94.5 - 96.9)      R      83.1 - 99.5     12     Mu,Ni,Ou,Tr1,Tr2,Ha
                                                                              Ba,Br,Co,Ja,Ko1,Ko2,
                                                                              Mu,Ni,Ou,Tr1,Tr2,Ha,
                                                                              Am,Bu,Ch,Ka,Pa,Ph,
Test+                16.2    (13.4 - 19.1)      R       6.0 - 39.9     20     Ac,Am

Test          VILI                           Outcome CIN1+
                                                                            Included study
Parameter     Estimate          95% CI       Model       Range       Number locations
                                                                            Ba,Br,Co,Ja,Ko2,Mu,
Sensitivity          73.7    (63.0 - 84.5)      R      50.3 - 94.1      10  Ni,Ou,Tr1,Tr2
                                                                            Ba,Br,Co,Ja,Ko2,Mu,
Specificity          86.6    (83.4 - 89.8)      R      74.1 - 92.8      10  Ni,Ou,Tr1,Tr2
                                                                            Ba,Br,Co,Ja,Ko2,Mu,
PPV                  28.9    (19.9 - 37.9)      R      13.3 - 50.8      10  Ni,Ou,Tr1,Tr2
                                                                            Ba,Br,Co,Ja,Ko2,Mu,
NPV                  97.5    (96.6 - 98.4)      R      90.1 - 99.9      10  Ni,Ou,Tr1,Tr2
                                                                            Ba,Br,Co,Ja,Ko2,Mu,
Test+                17.2    (13.9 - 20.5)      R      13.1 - 28.7      11  Ni,Ou,Tr1,Tr2,Bu

Test          VIAM                           Outcome CIN1+
                                                                              Included study
Parameter   Estimate            95% CI        Model      Range       Number   locations
Sensitivity      58.5        (43.2 - 73.9)      R      42.5 - 68.4      3     Ko1,Ko2,Mu
Specificity      88.1        (85.8 - 90.4)      R      86.4 - 90.1      3     Ko1,Ko2,Mu
PPV              23.1        (13.0 - 33.1)      R      14.9 - 31.1      3     Ko1,Ko2,Mu
NPV              97.3        (96.4 - 98.2)      R      96.3 - 98.1      3     Ko1,Ko2,Mu
Test+            14.8        (10.5 - 19.0)      R      11.2 - 18.0      3     Ko1,Ko2,Mu

Test          HPV                            Outcome CIN1+
                                                                              Included study
Parameter   Estimate            95% CI       Model       Range       Number   locations
Sensitivity      34.5        (16.4 - 52.6)       R     21.5 - 63.8      5     Ko1,Ko2,Mu,Tr2,Ha
Specificity      88.3        (83.9 - 92.8)       R     64.8 - 95.1      5     Ko1,Ko2,Mu,Tr2,Ha
PPV              25.2        (15.5 - 34.8)       R     16.4 - 39.4      5     Ko1,Ko2,Mu,Tr2,Ha
NPV              93.2       (90.87 - 95.5)       R    83.30 - 96.7      5     Ko1,Ko2,Mu,Tr2,Ha
Test+            14.3         (7.9 - 20.6)       R      6.0 - 42.8      5     Ko1,Ko2,Mu,Tr2,Ha

Test          Cytology                       Outcome CIN1+
Threshold     ASCUS+
                                                                              Included study
Parameter   Estimate            95% CI        Model      Range       Number   locations
Sensitivity      36.3        (20.8 - 51.9)      R      23.0 - 65.5      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity      92.1        (88.7 - 95.5)      R      79.0 - 98.7      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV              43.6        (21.4 - 65.8)      R      14.5 - 72.7      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV              92.2        (89.6 - 94.8)      R      80.5 - 97.0      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
Test+            11.6         (6.7 - 16.4)      R       2.8 - 27.8      6     Ja,Ko1,Mu,Tr1,Tr2,Ha




                                                                                                     127
Test          Cytology                   Outcome CIN1+
Threshold     LSIL+
                                                                        Included study
Parameter   Estimate        95% CI       Model       Range       Number locations
Sensitivity      30.3    (14.8 - 45.7)       R   17.2 - 63.3        6   Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity       96.1   (94.3 - 97.9)      R      92.9 - 99.3      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV               50.7   (27.9 - 73.5)      R      19.4 - 74.1      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV               91.7   (88.8 - 94.6)      R      78.4 - 96.9      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
Test+              7.3    (4.2 - 10.3)      R       2.1 - 13.7      6   Ja,Ko1,Mu,Tr1,Tr2,Ha




                                                                                               128
6.1.7. Summary of the meta-analyses of the accuracy for CIN2+
Table 26. Summary of the meta-analyses of screening tests considering CIN2+ as outcome: pooled estimates
and confidence intervals, model of pooling (F=fixed; R=random effect model), range, number of study
locations and identification of studies include (studies reporting lowest and highest parameters are
respectively single and double underlined).
Test          VIA                             Outcome CIN2+
                                                                             Included study
Parameter     Estimate         95% CI         Model       Range       Number locations
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Sensitivity          79.0   (73.6 - 84.3)        R      61.5 - 91.1     12   Ni,Ou,Tr1,Tr2,Ha
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Specificity          83.0   (78.8 - 87.2)        R      64.1 - 94.5     12   Ni,Ou,Tr1,Tr2,Ha
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
PPV                  11.8    (9.1 - 14.6)        R       3.8 - 22.5     14   Ni,Ou,Tr1,Tr2,Ha,Am,Bu
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
NPV                  99.3   (99.1 - 99.6)        R      96.3 - 99.8     12   Ni,Ou,Tr1,Tr2,Ha

Test          VILI                            Outcome CIN2+
                                                                             Included study
Parameter     Estimate         95% CI          Model      Range       Number locations
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Sensitivity          91.2   (87.8 - 94.6)        R      74.1 - 98.0     10   Ni,Ou,Tr1,Tr2
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Specificity          84.5   (81.3 - 87.8)        R      73.0 - 91.6     10   Ni,Ou,Tr1,Tr2
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
PPV                  12.9    (8.0 - 17.9)        R       3.5 - 33.9     10   Ni,Ou,Tr1,Tr2
                                                                             Ba,Br,Co,Ja,Ko1,Ko2,Mu,
NPV                  99.8   (99.7 - 99.9)        R      99.4 - 99.9     10   Ni,Ou,Tr1,Tr2

Test          VIAM                            Outcome CIN2+
                                                                               Included study
Parameter   Estimate           95%    CI       Model      Range       Number   locations
Sensitivity      67.0       (61.8 -   72.2)      F      64.6 - 73.2      3     Ko1,Ko2,Mu
Specificity      86.2       (82.4 -   90.0)      R      83.3 - 89.3      3     Ko1,Ko2,Mu
PPV               8.0        (5.4 -   10.7)      R       5.7 - 9.8       3     Ko1,Ko2,Mu
NPV              99.3       (98.7 -   99.8)      R      99.2 - 99.8      3     Ko1,Ko2,Mu

Test          HPV                             Outcome CIN2+
                                                                               Included study
Parameter   Estimate           95% CI          Model      Range       Number   locations
Sensitivity      65.8       (54.5 - 77.0)        R      48.4 - 80.2      5     Ko1,Ko2,Mu,Tr2,Ha
Specificity      87.3       (81.9 - 92.6)        R      61.2 - 94.6      5     Ko1,Ko2,Mu,Tr2,Ha
PPV              14.1       (10.2 - 18.0)        R       9.2 - 18.1      5     Ko1,Ko2,Mu,Tr2,Ha
NPV              99.1       (98.6 - 99.5)        R      96.7 - 99.7      5     Ko1,Ko2,Mu,Tr2,Ha

Test          Cytology                        Outcome CIN2+
Threshold     ASCUS+
                                                                               Included study
Parameter   Estimate           95% CI          Model      Range       Number   locations
Sensitivity      58.4       (43.5 - 73.2)        R      33.3 - 81.9      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity      90.0       (85.7 - 94.4)        R      76.2 - 98.5      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV              21.2       (13.1 - 29.3)        R       5.2 - 48.2      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV              98.6       (98.1 - 99.2)        R      95.3 - 99.3      6     Ja,Ko1,Mu,Tr1,Tr2,Ha

Test          Cytology                        Outcome CIN2+
Threshold     LSIL+
                                                                               Included study
Parameter   Estimate           95% CI         Model       Range       Number   locations
Sensitivity      50.1       (33.2 - 66.9)         R     23.8 - 77.9      6     Ja,Ko1,Ja,Mu,Tr1,Tr2,Ha
Specificity      94.2       (91.5 - 96.9)         R     88.6 - 99.1      6     Ja,Ko1,Ja,Mu,Tr1,Tr2,Ha
PPV              26.6       (16.3 - 37.0)         R      5.9 - 57.3      6     Ja,Ko1,Ja,Mu,Tr1,Tr2,Ha
NPV              98.3       (97.7 - 99.0)         R     93.9 - 99.3      6     Ja,Ko1,Ja,Mu,Tr1,Tr2,Ha




                                                                                                      129
Test        Cytology                    Outcome CIN2+
Threshold   HSIL+
                                                                         Included study
Parameter   Estimate       95% CI        Model      Range       Number   locations
Sensitivity      38.1   (22.4 - 53.7)      R      16.4 - 61.7      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity      99.1   (98.6 - 99.5)      R      97.7 - 99.7      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV              56.1   (35.4 - 76.8)      R      26.7 - 79.4      6     Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV              97.8   (97.0 - 98.7)      R      91.7 - 99.3      6     Ja,Ko1,Mu,Tr1,Tr2,Ha




                                                                                                130
6.1.8. Summary of the meta-analyses of the accuracy for CIN3+

Table 27. Summary of the meta-analyses of screening tests considering CIN3+ as outcome: pooled estimates
and confidence intervals, model of pooling (F=fixed; R=random effect model), range, number of study
locations and identification of studies include (studies reporting lowest and highest parameters are
respectively single and double underlined).
Test          VIA                            Outcome CIN3+
                                                                            Included study
Parameter     Estimate         95% CI         Model      Range       Number locations
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Sensitivity          82.9   (77.1 - 88.7)       R      58.3 - 94.6     11   Ni,Ou,Tr1,Tr2
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Specificity          84.2   (80.0 - 88.3)       R      73.8 - 94.3     11   Ni,Ou,Tr1,Tr2
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,Mu,
PPV                   6.8    (5.2 - 8.5)        R       2.7 - 16.6     13   Ni,Ou,Tr1,Tr2,Am,Bu
                                                                            Ba,Br,Co,Ja,Ko1,Ko2,Mu,
NPV                  99.7   (99.7 - 99.8)       R      99.3 - 99.9     11   Ni,Ou,Tr1,Tr2

Test          VILI                           Outcome CIN3+
                                                                           Included study
Parameter     Estimate         95% CI         Model      Range      Number locations
                                                                           Ba,Br,Co,Ja,Ko2,Mu,
Sensitivity          93.8   (90.6 - 97.1)       R      72.9 - 100.0   10   Ni,Ou,Tr1,Tr2
                                                                           Ba,Br,Co,Ja,Ko2,Mu,
Specificity          83.8   (80.5 - 87.1)       R      72.6 - 91.4    10   Ni,Ou,Tr1,Tr2
                                                                           Ba,Br,Co,Ja,Ko2,Mu,
PPV                   7.7    (5.0 - 10.3)       R       2.4 - 17.6    10   Ni,Ou,Tr1,Tr2
                                                                           Ba,Br,Co,Ja,Ko2,Mu,
NPV                  99.9   (99.9 - 100.0)      R      99.5 - 100.0   10   Ni,Ou,Tr1,Tr2

Test          VIAM                           Outcome CIN3+
                                                                              Included study
Parameter   Estimate           95% CI         Model      Range       Number   locations
Sensitivity      68.2       (61.8 - 74.7)       F      65.7 - 74.4      3     Ko1,Ko2,Mu
Specificity      85.9       (82.0 - 89.8)       R      82.8 - 89.1      3     Ko1,Ko2,Mu
PPV               5.2        (3.0 - 7.5)        R       3.2 - 6.6       3     Ko1,Ko2,Mu
NPV              99.5       (99.2 - 99.9)       R      99.3 - 99.9      3     Ko1,Ko2,Mu

Test          HPV                            Outcome CIN3+
                                                                              Included study
Parameter   Estimate           95% CI         Model      Range       Number   locations
Sensitivity      68.4       (61.5 - 75.4)       F      62.3 - 73.5      4     Ko1,Ko2,Mu,Tr2
Specificity      93.4       (92.2 - 94.6)       R      91.4 - 94.4      4     Ko1,Ko2,Mu,Tr2
PPV               9.1        (5.5 - 12.7)       R       5.8 - 13.1      4     Ko1,Ko2,Mu,Tr2
NPV              99.7       (99.5 - 99.9)       R      99.5 - 99.9      4     Ko1,Ko2,Mu,Tr2

Test          Cytology                       Outcome CIN3+
Threshold     ASCUS+
                                                                              Included study
Parameter   Estimate           95% CI         Model      Range       Number   locations
Sensitivity      63.0       (37.9 - 88.2)       R      35.6 - 96.4      5     Ja,Ko1,Mu,Tr1,Tr2
Specificity      92.3       (88.1 - 96.6)       R      86.3 - 98.2      5     Ja,Ko1,Mu,Tr1,Tr2
PPV              13.6        (8.1 - 19.0)       R       3.9 - 37.3      5     Ja,Ko1,Mu,Tr1,Tr2
NPV              99.5       (99.2 - 99.8)       R      98.9 - 99.9      5     Ja,Ko1,Mu,Tr1,Tr2

Test          Cytology                       Outcome CIN3+
Threshold     LSIL+
                                                                              Included study
Parameter   Estimate           95% CI         Model      Range       Number   locations
Sensitivity      56.1       (32.7 - 79.6)       R      26.7 - 89.3      5     Ja,Ko1,Mu,Tr1,Tr2
Specificity      94.5       (91.6 - 97.5)       R      87.3 - 98.8      5     Ja,Ko1,Mu,Tr1,Tr2
PPV              16.4        (9.6 - 23.2)       R       4.7 - 42.7      5     Ja,Ko1,Mu,Tr1,Tr2
NPV              99.4       (99.1 - 99.7)       R      98.8 - 99.8      5     Ja,Ko1,Mu,Tr1,Tr2



                                                                                                    131
Test        Cytology                    Outcome CIN3+
Threshold   HSIL+
                                                                         Included study
Parameter   Estimate       95% CI        Model      Range       Number   locations
Sensitivity      51.6   (32.0 - 71.1)      R      22.2 - 76.8      5     Ja,Ko1,Mu,Tr1,Tr2
Specificity      99.0   (98.4 - 99.5)      R      97.5 - 99.7      5     Ja,Ko1,Mu,Tr1,Tr2
PPV              42.7   (26.0 - 59.4)      R      20.6 - 57.4      5     Ja,Ko1,Mu,Tr1,Tr2
NPV              99.4   (99.1 - 99.6)      R      98.8 - 99.7      5     Ja,Ko1,Mu,Tr1,Tr2




                                                                                             132
6.1.9. Summary of the meta-analyses of the accuracy for cancer

Table 28. Summary of the meta-analyses of screening tests considering cervical cancer as outcome: pooled
estimates and confidence intervals, model of pooling (F=fixed; R=random effect model), range, number of
study locations and identification of studies include (studies reporting lowest and highest parameters are
respectively single and double underlined).
Test          VIA                               Outcome Cancer
                                                                               Included study
Parameter     Estimate 95% CI                   Model    Range          Number locations
                                                                               Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Sensitivity          89.1   (83.7 - 94.5)          R       60.0 - 100.0   12   Ni,Ou,Tr1,Tr2,Ha
                                                                               Ba,Br,Co,Ja,Ko1,Ko2,Mu,
Specificity          81.7   (77.1 - 86.3)          R       60.2 - 94.1    12   Ni,Ou,Tr1,Tr2,Ha
                                                                               Ba,Br,Co,Ja,Ko1,Ko2,Mu,
PPV                   2.5    (1.7 - 3.5)           R        0.3 - 12.4    14   Ni,Ou,Tr1,Tr2,Ha,Am,Bu
                                                                               Ba,Br,Co,Ja,Ko1,Ko2,Mu,
NPV                  99.9   (99.9 - 100.0)         R       99.9 - 100.0   12   Ni,Ou,Tr1,Tr2,Ha


Test          VILI                              Outcome Cancer
                                                                               Included study
Parameter     Estimate 95% CI                    Model   Range          Number locations
                                                                               Ba,Br,Co,Ja,Ko2,Mu,
Sensitivity          95.7   (91.8 - 99.7)          R       66.7 - 100.0   10   Ni,Ou,Tr1,Tr2
                                                                               Ba,Br,Co,Ja,Ko2,Mu,
Specificity          83.2   (79.8 - 86.5)          R       71.9 - 91.1    10   Ni,Ou,Tr1,Tr2
                                                                               Ba,Br,Co,Ja,Ko2,Mu,
PPV                   2.7    (1.7 - 3.7)           R        0.3 - 9.0     10   Ni,Ou,Tr1,Tr2
                                                                               Ba,Br,Co,Ja,Ko2,Mu,
NPV                 100.0 (100.0 - 100.0)          F      100.0 - 100.0   10   Ni,Ou,Tr1,Tr2

Test          VIAM                              Outcome Cancer
                                                                                  Included study
Parameter   Estimate                   95% CI    Model               Range Number locations
Sensitivity      81.4       (72.3 -   90.5)        F       74.1 -   100.0     3   Ko1,Ko2,Mu
Specificity      85.5       (81.5 -   89.6)        R       82.4 -   88.9      3   Ko1,Ko2,Mu
PPV               2.2        (0.6 -   3.8)         R        0.9 -   3.3       3   Ko1,Ko2,Mu
NPV              99.9       (99.7 -   100.0)       R       99.8 -   100.0     3   Ko,Ko2,Mu

Test          HPV                               Outcome Cancer
                                                                                  Included study
Parameter   Estimate                   95% CI    Model               Range Number locations
Sensitivity      71.8       (60.3 -   83.3)        F       61.5 -   85.7      5   Ko1,Ko2,Mu,Tr2,Ha
Specificity      85.9       (79.7 -   92.2)        R       57.3 -   94.0      5   Ko1,Ko2,Mu,Tr2,Ha
PPV               2.2        (0.7 -   3.8)         R        0.2 -   5.2       5   Ko1,Ko2,Mu,Tr2,Ha
NPV              99.9       (99.8 -   100.0)       R       99.8 -   100.0     5   Ko1,Ko2,Mu,Tr2,Ha

Test          Cytology                          Outcome Cancer
Threshold     ASCUS+
                                                                                  Included study
Parameter   Estimate                   95% CI    Model               Range Number locations
Sensitivity      75.8       (59.1 -   92.4)        R       40.0 -   100.0     6   Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity      88.6       (83.8 -   93.5)        R       72.3 -   97.7      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV               2.0        (0.7 -   3.3)         R        0.5 -   17.3      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV              99.9       (99.8 -   100.0)       R       99.6 -   100.0     6   Ja,Ko1,Mu,Tr1,Tr2,Ha




                                                                                                         133
Test        Cytology                        Outcome Cancer
Threshold   LSIL+
                                                                               Included study
Parameter   Estimate 95% CI                  Model   Range            Number   locations
Sensitivity      74.8 (52.2 -     97.5)        R       20.0 -   100.0    6     Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity      93.1 (89.8 -     96.5)        R       86.5 -   98.3     6     Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV               2.4   (0.6 -    4.3)         R        0.4 -   20.7     6     Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV              99.9 (99.9 -     100.0)       R       99.6 -   100.0    6     Ja,Ko1,Mu,Tr1,Tr2,Ha



Test        Cytology                        Outcome Cancer
Threshold   HSIL+
                                                                              Included study
Parameter   Estimate               95% CI    Model               Range Number locations
Sensitivity      69.8   (49.1 -   90.4)        R       20.0 -   100.0     6   Ja,Ko1,Mu,Tr1,Tr2,Ha
Specificity      98.2   (97.5 -   99.0)        R       96.6 -   99.5      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
PPV              10.4    (4.9 -   15.8)        R        3.6 -   28.3      6   Ja,Ko1,Mu,Tr1,Tr2,Ha
NPV              99.9   (99.8 -   100.0)       R       99.6 -   100.0     6   Ja,Ko1,Mu,Tr1,Tr2,Ha




                                                                                                      134
6.2. Meta-analyses of the relative sensitivity and specificity of
     cervical cancer screening tests
We will pool the ratio of the sensitivity for a given degree of cervical intraepithelial
neoplasia of a screen test over that of another test. The same will be done for the ratio of
specificities. Below follow a series of 18 possible comparisons of screen tests.

6.2.1. Relative sensitivity and specificity of VILI compared to VIA
                Outcome CIN1+                                                 Outcome CIN2+
                VILI/VIA                                                      VILI/VIA

     Bamako                                                        Bamako
  Brazzaville                                                   Brazzaville
     Conakry                                                       Conakry
       Jaipur                                                        Jaipur
    Kolkata 2                                                     Kolkata 2
     Mumbai                                                        Mumbai
     Niamey                                                        Niamey
Ouagadougou                                                   Ouagadougou
Trivandrum 1                                                  Trivandrum 1
Trivandrum 2                                                  Trivandrum 2

   Combined                                                      Combined
                .5       .67           1            1.5   2                   .5        .67           1            1.5    2
                                Sensitivity ratio                                              Sensitivity ratio
                Outcome CIN3+                                                 Outcome Cancer
                VILI/VIA                                                      VILI/VIA

     Bamako                                                        Bamako
  Brazzaville                                                   Brazzaville
     Conakry                                                       Conakry
       Jaipur                                                        Jaipur
    Kolkata 2                                                     Kolkata 2
     Mumbai                                                        Mumbai
     Niamey                                                        Niamey
Ouagadougou                                                   Ouagadougou
Trivandrum 1                                                  Trivandrum 1
Trivandrum 2                                                  Trivandrum 2

   Combined                                                      Combined
                .5       .67           1            1.5   2                   .5        .67           1            1.5    2
                                Sensitivity ratio                                              Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.143   1.110   1.177    8.931    0.000     10
Random |   1.185   1.082   1.297    3.675    0.000
Test for heterogeneity: Q= 73.540 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.112   1.081   1.144    7.415    0.000     10
Random |   1.105   1.048   1.165    3.709    0.000
Test for heterogeneity: Q= 23.790 on 9 degrees of freedom (p= 0.005)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.074   1.043   1.106    4.793    0.000     10
Random |   1.074   1.043   1.106    4.793    0.000
Test for heterogeneity: Q= 7.123 on 9 degrees of freedom (p= 0.624)




                                                                                                                         135
Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.013   0.989   1.036    1.060    0.289     10
Random |   1.013   0.989   1.036    1.060    0.289
Test for heterogeneity: Q= 6.952 on 9 degrees of freedom (p= 0.642)




                                                                      136
Specificity ratio (VILI/VIA)
                Outcome CIN1+                                                    Outcome CIN2+
                VILI/VIA                                                         VILI/VIA

     Bamako                                                           Bamako
  Brazzaville                                                      Brazzaville
     Conakry                                                          Conakry
       Jaipur                                                           Jaipur
    Kolkata 2                                                        Kolkata 2
     Mumbai                                                           Mumbai
     Niamey                                                           Niamey
Ouagadougou                                                      Ouagadougou
Trivandrum 1                                                     Trivandrum 1
Trivandrum 2                                                     Trivandrum 2

   Combined                                                         Combined
                .67       .8           1            1.25   1.5                   .67       .8            1            1.25   1.5
                                Specificity ratio                                                 Specificity ratio
                Outcome CIN3+                                                    Outcome Cancer
                VILI/VIA                                                         VILI/VIA

     Bamako                                                           Bamako
  Brazzaville                                                      Brazzaville
     Conakry                                                          Conakry
       Jaipur                                                           Jaipur
    Kolkata 2                                                        Kolkata 2
     Mumbai                                                           Mumbai
     Niamey                                                           Niamey
Ouagadougou                                                      Ouagadougou
Trivandrum 1                                                     Trivandrum 1
Trivandrum 2                                                     Trivandrum 2

   Combined                                                         Combined
                .67       .8           1            1.25   1.5                   .67       .8            1            1.25   1.5
                                Specificity ratio                                                 Specificity ratio



Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.994   0.990   0.998   -2.655    0.008     10
Random |   1.001   0.967   1.036    0.032    0.975
Test for heterogeneity: Q= 546.787 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.988   0.983   0.992   -5.253    0.000     10
Random |   0.996   0.962   1.031   -0.229    0.819
Test for heterogeneity: Q= 485.280 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.986   0.981   0.990   -6.087    0.000     10
Random |   0.994   0.962   1.027   -0.342    0.732
Test for heterogeneity: Q= 410.871 on 9 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.984   0.979   0.989   -6.609    0.000     10
Random |   0.993   0.962   1.025   -0.410    0.682
Test for heterogeneity: Q= 372.574 on 9 degrees of freedom (p= 0.000)




                                                                                                                             137
6.2.2. Relative sensitivity and specificity of VIAM compared to VIA
Sensitivity ratio (VIAM/VIA)
            Outcome CIN1+                                             Outcome CIN2+
            VIAM/VIA                                                  VIAM/VIA



Kolkata 1                                                 Kolkata 1
Kolkata 2                                                 Kolkata 2
 Mumbai                                                    Mumbai


Combined                                                  Combined
            .5       .67           1            1.5   2               .5        .67           1            1.5    2
                            Sensitivity ratio                                          Sensitivity ratio
            Outcome CIN3+                                             Outcome Cancer
            VIAM/VIA                                                  VIAM/VIA



Kolkata 1                                                 Kolkata 1
Kolkata 2                                                 Kolkata 2
 Mumbai                                                    Mumbai


Combined                                                  Combined
            .5       .67           1            1.5   2               .5        .67           1            1.5    2
                            Sensitivity ratio                                          Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.050   0.977   1.127    1.327    0.184       3
Random |   1.050   0.977   1.127    1.327    0.184
Test for heterogeneity: Q= 0.606 on 2 degrees of freedom (p= 0.739)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.036   0.926   1.159    0.622    0.534       3
Random |   1.036   0.926   1.159    0.622    0.534
Test for heterogeneity: Q= 0.185 on 2 degrees of freedom (p= 0.912)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.028   0.897   1.180    0.401    0.688       3
Random |   1.028   0.897   1.180    0.401    0.688
Test for heterogeneity: Q= 0.196 on 2 degrees of freedom (p= 0.906)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.999   0.966   1.034   -0.039    0.969      3
Random |   0.999   0.966   1.034   -0.039    0.969
Test for heterogeneity: Q= 0.074 on 2 degrees of freedom (p= 0.964)




                                                                                                                 138
Specificity ratio (VIAM/VIA)
            Outcome CIN1+                                                Outcome CIN2+
            VIAM/VIA                                                     VIAM/VIA



Kolkata 1                                                    Kolkata 1
Kolkata 2                                                    Kolkata 2
 Mumbai                                                       Mumbai


Combined                                                     Combined
            .67       .8           1            1.25   1.5               .67       .8            1            1.25   1.5
                            Specificity ratio                                             Specificity ratio
            Outcome CIN3+                                                Outcome Cancer
            VIAM/VIA                                                     VIAM/VIA



Kolkata 1                                                    Kolkata 1
Kolkata 2                                                    Kolkata 2
 Mumbai                                                       Mumbai


Combined                                                     Combined
            .67       .8           1            1.25   1.5               .67       .8            1            1.25   1.5
                            Specificity ratio                                             Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.999   0.991   1.007   -0.238    0.812       3
Random |   0.998   0.979   1.018   -0.179    0.858
Test for heterogeneity: Q= 11.544 on 2 degrees of freedom (p= 0.003)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.990   1.006   -0.498    0.619       3
Random |   0.997   0.978   1.016   -0.330    0.742
Test for heterogeneity: Q= 10.303 on 2 degrees of freedom (p= 0.006)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.990   1.006   -0.544    0.586       3
Random |   0.997   0.978   1.016   -0.363    0.716
Test for heterogeneity: Q= 9.703 on 2 degrees of freedom (p= 0.008)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.989   1.006   -0.601    0.548      3
Random |   0.996   0.977   1.015   -0.399    0.690
Test for heterogeneity: Q= 9.753 on 2 degrees of freedom (p= 0.008)




                                                                                                                     139
6.2.3. Relative sensitivity and specificity of HC2 compared to VIA
Sensitivity ratio (HPV/VIA)
               Outcome CIN1+                                                 Outcome CIN2+
               HPV/VIA                                                       HPV/VIA


   Kolkata 1                                                     Kolkata 1
   Kolkata 2                                                     Kolkata 2
    Mumbai                                                        Mumbai
Trivandrum 2                                                  Trivandrum 2
      Harare                                                        Harare


  Combined                                                      Combined
               .3          .5    .67            1   1.5   2                  .3           .5    .67            1   1.5    2
                                Sensitivity ratio                                              Sensitivity ratio
               Outcome CIN3+                                                 Outcome Cancer
               HPV/VIA                                                       HPV/VIA


   Kolkata 1                                                     Kolkata 1
                                                                 Kolkata 2
   Kolkata 2
                                                                  Mumbai
    Mumbai
                                                              Trivandrum 2
Trivandrum 2
                                                                    Harare


  Combined                                                      Combined
               .3          .5    .67            1   1.5   2                  .3           .5    .67            1   1.5    2
                                Sensitivity ratio                                              Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.764   0.712   0.820   -7.509    0.000       5
Random |   0.569   0.363   0.890   -2.468    0.014
Test for heterogeneity: Q= 119.271 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.971   0.900   1.047   -0.768    0.442       5
Random |   0.933   0.820   1.061   -1.062    0.288
Test for heterogeneity: Q= 8.553 on 4 degrees of freedom (p= 0.073)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.940   0.825   1.071   -0.928    0.353       4
Random |   0.956   0.781   1.169   -0.440    0.660
Test for heterogeneity: Q= 7.019 on 3 degrees of freedom (p= 0.071)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.850   0.711   1.016   -1.786    0.074      5
Random |   0.850   0.711   1.016   -1.786    0.074
Test for heterogeneity: Q= 1.500 on 4 degrees of freedom (p= 0.827)




                                                                                                                         140
Specificity ratio (HPV/VIA)
               Outcome CIN1+                                                   Outcome CIN2+
               HPV/VIA                                                         HPV/VIA


   Kolkata 1                                                       Kolkata 1
   Kolkata 2                                                       Kolkata 2
    Mumbai                                                          Mumbai
Trivandrum 2                                                    Trivandrum 2
      Harare                                                          Harare


  Combined                                                        Combined
               .67       .8           1            1.25   1.5                  .67       .8            1            1.25   1.5
                               Specificity ratio                                                Specificity ratio
               Outcome CIN3+                                                   Outcome Cancer
               HPV/VIA                                                         HPV/VIA


   Kolkata 1                                                       Kolkata 1
                                                                   Kolkata 2
   Kolkata 2
                                                                    Mumbai
    Mumbai
                                                                Trivandrum 2
Trivandrum 2
                                                                      Harare


  Combined                                                        Combined
               .67       .8           1            1.25   1.5                  .67       .8            1            1.25   1.5
                               Specificity ratio                                                Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.049   1.043   1.055   16.206    0.000       5
Random |   1.043   1.022   1.064    3.999    0.000
Test for heterogeneity: Q= 40.864 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.067   1.061   1.074   20.933    0.000       5
Random |   1.059   1.033   1.085    4.580    0.000
Test for heterogeneity: Q= 53.891 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.070   1.063   1.076   21.271    0.000       4
Random |   1.075   1.051   1.099    6.369    0.000
Test for heterogeneity: Q= 36.219 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.068   1.062   1.075   20.585    0.000      5
Random |   1.059   1.031   1.087    4.249    0.000
Test for heterogeneity: Q= 58.963 on 4 degrees of freedom (p= 0.000)




                                                                                                                           141
6.2.4. Relative sensitivity and specificity of cervical cytology (at
       ASCUS+) compared to VIA
Sensitivity ratio (Cytology at ASCUS+/VIA)

               Outcome CIN1+                                                  Outcome CIN2+
               Cytology at ASCUS+/VIA                                         Cytology at ASCUS+/VIA


      Jaipur                                                         Jaipur
   Kolkata 1                                                      Kolkata 1
    Mumbai                                                         Mumbai
Trivandrum 1                                                   Trivandrum 1
Trivandrum 2                                                   Trivandrum 2
      Harare                                                         Harare


  Combined                                                       Combined
               .3           .5    .67            1   1.5   2                  .3           .5    .67            1   1.5    2
                                 Sensitivity ratio                                              Sensitivity ratio
               Outcome CIN3+                                                  Outcome Cancer
               Cytology at ASCUS+/VIA                                         Cytology at ASCUS+/VIA


      Jaipur                                                         Jaipur

   Kolkata 1                                                      Kolkata 1
                                                                   Mumbai
    Mumbai
                                                               Trivandrum 1
Trivandrum 1
                                                               Trivandrum 2
Trivandrum 2                                                         Harare


  Combined                                                       Combined
               .3           .5    .67            1   1.5   2                  .3           .5    .67            1   1.5   2
                                 Sensitivity ratio                                              Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.748   0.707   0.791 -10.217     0.000       6
Random |   0.531   0.338   0.834   -2.748    0.006
Test for heterogeneity: Q= 280.537 on 5 degrees of freedom (p= 0.000)
Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.849   0.796   0.905   -5.003    0.000       6
Random |   0.770   0.640   0.926   -2.776    0.006
Test for heterogeneity: Q= 32.518 on 5 degrees of freedom (p= 0.000)
Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.950   0.887   1.017   -1.472    0.141       5
Random |   0.795   0.613   1.032   -1.726    0.084
Test for heterogeneity: Q= 29.929 on 4 degrees of freedom (p= 0.000)
Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.993   0.954   1.034   -0.327    0.744       6
Random |   0.988   0.935   1.044   -0.439    0.661
Test for heterogeneity: Q= 5.622 on 5 degrees of freedom (p= 0.345)




                                                                                                                          142
Specificity ratio (Cytology at ASCUS+/VIA)
               Outcome CIN1+                                                     Outcome CIN2+
               Cytology at ASCUS+/VIA                                            Cytology at ASCUS+/VIA


      Jaipur                                                            Jaipur
   Kolkata 1                                                         Kolkata 1
    Mumbai                                                            Mumbai
Trivandrum 1                                                      Trivandrum 1
Trivandrum 2                                                      Trivandrum 2
      Harare                                                            Harare


  Combined                                                          Combined
               .67       .8             1            1.25   1.5                  .67       .8             1            1.25   1.5
                                 Specificity ratio                                                 Specificity ratio
               Outcome CIN3+                                                     Outcome Cancer
               Cytology at ASCUS+/VIA                                            Cytology at ASCUS+/VIA


      Jaipur                                                            Jaipur

   Kolkata 1                                                         Kolkata 1
                                                                      Mumbai
    Mumbai
                                                                  Trivandrum 1
Trivandrum 1
                                                                  Trivandrum 2
Trivandrum 2                                                            Harare


  Combined                                                          Combined
               .67       .8             1            1.25   1.5                  .67       .8             1            1.25   1.5
                                 Specificity ratio                                                 Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.101   1.095   1.107   33.104    0.000       6
Random |   1.119   1.066   1.175    4.517    0.000
Test for heterogeneity: Q= 332.786 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.120   1.113   1.127   35.682    0.000       6
Random |   1.134   1.085   1.186    5.589    0.000
Test for heterogeneity: Q= 230.268 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.120   1.113   1.127   34.743    0.000       5
Random |   1.127   1.073   1.183    4.817    0.000
Test for heterogeneity: Q= 220.608 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.123   1.116   1.131   35.148    0.000      6
Random |   1.139   1.087   1.192    5.525    0.000
Test for heterogeneity: Q= 231.980 on 5 degrees of freedom (p= 0.000)




                                                                                                                              143
6.2.5. Relative sensitivity and specificity of cervical cytology (at LSIL+)
       compared to VIA
Sensitivity ratio (Cytology at LSIL+/VIA)
               Outcome CIN1+                                                         Outcome CIN2+
               Cytology at LSIL+/VIA                                                 Cytology at LSIL+/VIA


      Jaipur                                                                Jaipur
   Kolkata 1                                                             Kolkata 1
    Mumbai                                                                Mumbai
Trivandrum 1                                                          Trivandrum 1
Trivandrum 2                                                          Trivandrum 2
      Harare                                                                Harare


  Combined                                                              Combined
                     .25             .5      .67        1   1.5   2                  .25              .5       .67           1   1.5    2
                                      Sensitivity ratio                                                    Sensitivity ratio
               Outcome CIN3+                                                         Outcome Cancer
               Cytology at LSIL+/VIA                                                 Cytology at LSIL+/VIA


      Jaipur                                                                Jaipur

   Kolkata 1                                                             Kolkata 1
                                                                          Mumbai
    Mumbai
                                                                      Trivandrum 1
Trivandrum 1
                                                                      Trivandrum 2
Trivandrum 2                                                                Harare


  Combined                                                              Combined
               .25              .5       .67           1    1.5   2                  .25              .5       .67           1   1.5    2
                                     Sensitivity ratio                                                     Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.661   0.621   0.703 -13.152     0.000       6
Random |   0.433   0.246   0.761   -2.909    0.004
Test for heterogeneity: Q= 338.140 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.752   0.699   0.809   -7.651    0.000       6
Random |   0.645   0.500   0.833   -3.358    0.001
Test for heterogeneity: Q= 47.900 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.849   0.778   0.926   -3.680    0.000       5
Random |   0.708   0.535   0.937   -2.416    0.016
Test for heterogeneity: Q= 27.119 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.991   0.952   1.032   -0.425    0.671      6
Random |   0.961   0.878   1.052   -0.858    0.391
Test for heterogeneity: Q= 8.523 on 5 degrees of freedom (p= 0.130)



                                                                                                                                       144
Specificity ratio (Cytology at LSIL+/VIA)
               Outcome CIN1+                                                      Outcome CIN2+
               Cytology at LSIL+/VIA                                              Cytology at LSIL+/VIA


      Jaipur                                                             Jaipur
   Kolkata 1                                                          Kolkata 1
    Mumbai                                                             Mumbai
Trivandrum 1                                                       Trivandrum 1
Trivandrum 2                                                       Trivandrum 2
      Harare                                                             Harare


  Combined                                                           Combined
               .67        .8             1            1.25   1.5                  .67        .8             1            1.25   1.5
                                  Specificity ratio                                                  Specificity ratio
               Outcome CIN3+                                                      Outcome Cancer
               Cytology at LSIL+/VIA                                              Cytology at LSIL+/VIA


      Jaipur                                                             Jaipur

   Kolkata 1                                                          Kolkata 1
                                                                       Mumbai
    Mumbai
                                                                   Trivandrum 1
Trivandrum 1
                                                                   Trivandrum 2
Trivandrum 2                                                             Harare


  Combined                                                           Combined
               .67        .8             1            1.25   1.5                  .67        .8             1            1.25   1.5
                                  Specificity ratio                                                  Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.123   1.117   1.129   41.699    0.000       6
Random |   1.171   1.110   1.234    5.820    0.000
Test for heterogeneity: Q= 436.029 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.147   1.140   1.154   45.090    0.000       6
Random |   1.190   1.128   1.254    6.440    0.000
Test for heterogeneity: Q= 364.619 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.143   1.136   1.150   42.516    0.000       5
Random |   1.154   1.099   1.211    5.806    0.000
Test for heterogeneity: Q= 237.531 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.153   1.145   1.160   44.761    0.000      6
Random |   1.198   1.132   1.268    6.283    0.000
Test for heterogeneity: Q= 383.756 on 5 degrees of freedom (p= 0.000)




                                                                                                                                145
6.2.6. Relative sensitivity and specificity of cervical cytology (at HSIL+)
       compared to VIA
Sensitivity ratio (Cytology at HSIL+/VIA)
               Outcome CIN2+                                                       Outcome CIN3+
               Cytology at HSIL+/VIA                                               Cytology at HSIL+/VIA


      Jaipur                                                              Jaipur
   Kolkata 1                                                           Kolkata 1
    Mumbai
                                                                        Mumbai
Trivandrum 1
                                                                    Trivandrum 1
Trivandrum 2
      Harare                                                        Trivandrum 2


  Combined                                                            Combined
                     .25            .5     .67        1   1.5   2                        .25            .5     .67        1   1.5    2
                                  Sensitivity ratio                                                   Sensitivity ratio
               Outcome Cancer
               Cytology at HSIL+/VIA


      Jaipur
   Kolkata 1
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
                     .25            .5     .67        1   1.5   2
                                  Sensitivity ratio



Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.562   0.509   0.621 -11.350     0.000       6
Random |   0.462   0.310   0.688   -3.805    0.000
Test for heterogeneity: Q= 71.082 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.747   0.671   0.831   -5.344    0.000       5
Random |   0.660   0.499   0.872   -2.922    0.003
Test for heterogeneity: Q= 21.887 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.991   0.952   1.032   -0.425    0.671      6
Random |   0.961   0.878   1.052   -0.858    0.391
Test for heterogeneity: Q= 8.523 on 5 degrees of freedom (p= 0.130)




                                                                                                                                    146
Specificity ratio (Cytology at HSIL+/VIA)

               Outcome CIN2+                                                        Outcome CIN3+
               Cytology at HSIL+/VIA                                                Cytology at HSIL+/VIA


      Jaipur                                                               Jaipur
   Kolkata 1                                                            Kolkata 1
    Mumbai
                                                                         Mumbai
Trivandrum 1
                                                                     Trivandrum 1
Trivandrum 2
      Harare                                                         Trivandrum 2


  Combined                                                             Combined
               .67       .8            1              1.25     1.5                  .67        .8             1            1.25   1.5
                                  Specificity ratio                                                    Specificity ratio
               Outcome Cancer
               Cytology at HSIL+/VIA


      Jaipur
   Kolkata 1
    Mumbai
Trivandrum 1
Trivandrum 2
      Harare


  Combined
               .67       .8          1              1.25     1.5
                                  Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.190   1.184   1.197   61.282    0.000       6
Random |   1.252   1.171   1.340    6.520    0.000
Test for heterogeneity: Q= 696.712 on 5 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.185   1.178   1.192   57.974    0.000       5
Random |   1.209   1.133   1.291    5.728    0.000
Test for heterogeneity: Q= 499.212 on 4 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.198   1.191   1.205   60.942    0.000      6
Random |   1.268   1.178   1.365    6.319    0.000
Test for heterogeneity: Q= 759.400 on 5 degrees of freedom (p= 0.000)




                                                                                                                                  147
6.2.7. Relative sensitivity and specificity of VIAM compared to VILI
Sensitivity ratio (VIAM/VILI)
            Outcome CIN1+                                             Outcome CIN2+
            VIAM/VILI                                                 VIAM/VILI



Kolkata 2                                                 Kolkata 2

 Mumbai                                                    Mumbai



Combined                                                  Combined
            .5       .67           1            1.5   2               .5        .67           1            1.5    2
                            Sensitivity ratio                                          Sensitivity ratio
            Outcome CIN3+                                             Outcome Cancer
            VIAM/VILI                                                 VIAM/VILI



Kolkata 2                                                 Kolkata 2

 Mumbai                                                    Mumbai



Combined                                                  Combined
            .5       .67           1            1.5   2               .5        .67           1            1.5    2
                            Sensitivity ratio                                          Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.872   0.792   0.961   -2.760    0.006       2
Random |   0.872   0.792   0.961   -2.760    0.006
Test for heterogeneity: Q= 0.224 on 1 degrees of freedom (p= 0.636)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.892   0.780   1.021   -1.655    0.098       2
Random |   0.892   0.780   1.021   -1.655    0.098
Test for heterogeneity: Q= 0.017 on 1 degrees of freedom (p= 0.896)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.903   0.767   1.064   -1.218    0.223       2
Random |   0.903   0.767   1.064   -1.218    0.223
Test for heterogeneity: Q= 0.116 on 1 degrees of freedom (p= 0.733)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.000   0.966   1.035    0.000    1.000      2
Random |   1.000   0.966   1.035    0.000    1.000
Test for heterogeneity: Q= 0.000 on 1 degrees of freedom (p= 1.000)




                                                                                                                 148
Specificity ratio (VIAM/VILI)
            Outcome CIN1+                                                Outcome CIN2+
            VIAM/VILI                                                    VIAM/VILI



Kolkata 2                                                    Kolkata 2

 Mumbai                                                       Mumbai



Combined                                                     Combined
            .67       .8           1            1.25   1.5               .67       .8            1            1.25   1.5
                            Specificity ratio                                             Specificity ratio
            Outcome CIN3+                                                Outcome Cancer
            VIAM/VILI                                                    VIAM/VILI



Kolkata 2                                                    Kolkata 2

 Mumbai                                                       Mumbai



Combined                                                     Combined
            .67       .8           1            1.25   1.5               .67       .8            1            1.25   1.5
                            Specificity ratio                                             Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.027   1.018   1.037    5.596    0.000       2
Random |   1.027   1.017   1.037    5.483    0.000
Test for heterogeneity: Q= 1.027 on 1 degrees of freedom (p= 0.311)

Meta-analysis of the specificity ratio for outcome CIN2+

       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.030   1.020   1.040    5.909    0.000      2
Random |   1.030   1.020   1.040    5.909    0.000
Test for heterogeneity: Q= 0.749 on 1 degrees of freedom (p= 0.387)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.030   1.020   1.041    5.935    0.000       2
Random |   1.030   1.020   1.041    5.935    0.000
Test for heterogeneity: Q= 0.588 on 1 degrees of freedom (p= 0.443)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.031   1.021   1.041    5.999    0.000      2
Random |   1.031   1.021   1.041    5.999    0.000
Test for heterogeneity: Q= 0.537 on 1 degrees of freedom (p= 0.464)




                                                                                                                     149
6.2.8. Relative sensitivity and specificity of HC2 compared to VILI
 Sensitivity ratio (HPV/VILI)
               Outcome CIN1+                                                       Outcome CIN2+
               HPV/VILI                                                            HPV/VILI



   Kolkata 2                                                           Kolkata 2

    Mumbai                                                              Mumbai

Trivandrum 2                                                        Trivandrum 2




  Combined                                                            Combined
               .25             .5       .67           1   1.5   2                  .25              .5       .67           1   1.5    2
                                    Sensitivity ratio                                                    Sensitivity ratio
               Outcome CIN3+                                                       Outcome Cancer
               HPV/VILI                                                            HPV/VILI



   Kolkata 2                                                           Kolkata 2

    Mumbai                                                              Mumbai

Trivandrum 2                                                        Trivandrum 2




  Combined                                                            Combined
               .25             .5       .67           1   1.5   2                  .25              .5       .67           1   1.5    2
                                    Sensitivity ratio                                                    Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.408   0.360   0.462 -13.995     0.000       3
Random |   0.413   0.339   0.504   -8.684    0.000
Test for heterogeneity: Q= 4.976 on 2 degrees of freedom (p= 0.083)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.834   0.740   0.939   -3.006    0.003       3
Random |   0.834   0.740   0.939   -3.006    0.003
Test for heterogeneity: Q= 0.403 on 2 degrees of freedom (p= 0.818)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.855   0.748   0.977   -2.301    0.021       3
Random |   0.857   0.714   1.028   -1.659    0.097
Test for heterogeneity: Q= 3.707 on 2 degrees of freedom (p= 0.157)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.877   0.718   1.071   -1.289    0.197      3
Random |   0.877   0.718   1.071   -1.289    0.197
Test for heterogeneity: Q= 0.916 on 2 degrees of freedom (p= 0.633)




                                                                                                                                     150
Specificity ratio (HPV/VILI)
               Outcome CIN1+                                                   Outcome CIN2+
               HPV/VILI                                                        HPV/VILI



   Kolkata 2                                                       Kolkata 2

    Mumbai                                                          Mumbai

Trivandrum 2                                                    Trivandrum 2




  Combined                                                        Combined
               .67       .8           1            1.25   1.5                  .67       .8            1            1.25   1.5
                               Specificity ratio                                                Specificity ratio
               Outcome CIN3+                                                   Outcome Cancer
               HPV/VILI                                                        HPV/VILI



   Kolkata 2                                                       Kolkata 2

    Mumbai                                                          Mumbai

Trivandrum 2                                                    Trivandrum 2




  Combined                                                        Combined
               .67       .8           1            1.25   1.5                  .67       .8            1            1.25   1.5
                               Specificity ratio                                                Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.074   1.067   1.082   20.233    0.000       3
Random |   1.075   1.052   1.097    6.733    0.000
Test for heterogeneity: Q= 17.338 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.096   1.088   1.104   24.671    0.000       3
Random |   1.097   1.085   1.110   16.132    0.000
Test for heterogeneity: Q= 4.480 on 2 degrees of freedom (p= 0.106)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.096   1.088   1.105   24.509    0.000       3
Random |   1.098   1.084   1.112   14.720    0.000
Test for heterogeneity: Q= 5.327 on 2 degrees of freedom (p= 0.070)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.097   1.089   1.106   24.229    0.000      3
Random |   1.099   1.086   1.111   16.175    0.000
Test for heterogeneity: Q= 4.292 on 2 degrees of freedom (p= 0.117)




                                                                                                                           151
6.2.9. Relative sensitivity and specificity of cytology (at ASCUS+)
       compared to VILI
Sensitivity ratio (Cytology at ASCUS+/VILI)
               Outcome CIN1+                                                       Outcome CIN2+
               Cytology at ASCUS+/VILI                                             Cytology at ASCUS+/VILI


      Jaipur                                                              Jaipur

    Mumbai                                                              Mumbai

Trivandrum 1                                                        Trivandrum 1

Trivandrum 2                                                        Trivandrum 2



  Combined                                                            Combined
               .25             .5       .67           1   1.5   2                  .25             .5       .67           1   1.5    2
                                    Sensitivity ratio                                                   Sensitivity ratio
               Outcome CIN3+                                                       Outcome Cancer
               Cytology at ASCUS+/VILI                                             Cytology at ASCUS+/VILI


      Jaipur                                                              Jaipur

    Mumbai                                                              Mumbai

Trivandrum 1                                                        Trivandrum 1

Trivandrum 2                                                        Trivandrum 2



  Combined                                                            Combined
               .25             .5       .67           1   1.5   2                  .25             .5       .67           1   1.5   2
                                    Sensitivity ratio                                                   Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.808   0.752   0.868   -5.854    0.000       4
Random |   0.495   0.219   1.117   -1.695    0.090
Test for heterogeneity: Q= 284.509 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.848   0.787   0.914   -4.324    0.000       4
Random |   0.735   0.570   0.948   -2.374    0.018
Test for heterogeneity: Q= 21.633 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.949   0.897   1.005   -1.799    0.072       4
Random |   0.796   0.618   1.024   -1.772    0.076
Test for heterogeneity: Q= 19.809 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.998   0.954   1.044   -0.076    0.939      4
Random |   0.998   0.954   1.044   -0.076    0.939
Test for heterogeneity: Q= 0.939 on 3 degrees of freedom (p= 0.816)



                                                                                                                                    152
Specificity ratio (Cytology at ASCUS+/VILI)
               Outcome CIN1+                                                     Outcome CIN2+
               Cytology at ASCUS+/VILI                                           Cytology at ASCUS+/VILI


      Jaipur                                                            Jaipur

    Mumbai                                                            Mumbai

Trivandrum 1                                                      Trivandrum 1

Trivandrum 2                                                      Trivandrum 2



  Combined                                                          Combined
               .67        .8            1            1.25   1.5                  .67        .8            1            1.25   1.5
                                 Specificity ratio                                                 Specificity ratio
               Outcome CIN3+                                                     Outcome Cancer
               Cytology at ASCUS+/VILI                                           Cytology at ASCUS+/VILI


      Jaipur                                                            Jaipur

    Mumbai                                                            Mumbai

Trivandrum 1                                                      Trivandrum 1

Trivandrum 2                                                      Trivandrum 2



  Combined                                                          Combined
               .67        .8            1            1.25   1.5                  .67        .8            1            1.25   1.5
                                 Specificity ratio                                                 Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.136   1.128   1.143   37.525    0.000       4
Random |   1.152   1.091   1.216    5.116    0.000
Test for heterogeneity: Q= 190.222 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.157   1.148   1.165   38.570    0.000       4
Random |   1.162   1.092   1.236    4.760    0.000
Test for heterogeneity: Q= 200.978 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.159   1.151   1.168   38.512    0.000       4
Random |   1.164   1.094   1.239    4.776    0.000
Test for heterogeneity: Q= 197.259 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.162   1.153   1.171   38.186    0.000      4
Random |   1.166   1.094   1.242    4.731    0.000
Test for heterogeneity: Q= 195.714 on 3 degrees of freedom (p= 0.000)




                                                                                                                              153
6.2.10.   Relative sensitivity and specificity of cytology (at LSIL+)
      compared to VILI
Sensitivity ratio (Cytology at LSIL+/VILI)
               Outcome CIN1+                                                        Outcome CIN2+
               Cytology at LSIL+/VILI                                               Cytology at LSIL+/VILI


      Jaipur                                                               Jaipur

    Mumbai                                                               Mumbai

Trivandrum 1                                                         Trivandrum 1

Trivandrum 2                                                         Trivandrum 2



  Combined                                                             Combined
               .25              .5       .67           1   1.5   2                  .25              .5       .67           1   1.5    2
                                     Sensitivity ratio                                                    Sensitivity ratio
               Outcome CIN3+                                                        Outcome Cancer
               Cytology at LSIL+/VILI                                               Cytology at LSIL+/VILI


      Jaipur                                                               Jaipur

    Mumbai                                                               Mumbai

Trivandrum 1                                                         Trivandrum 1

Trivandrum 2                                                         Trivandrum 2



  Combined                                                             Combined
               .25              .5       .67           1   1.5   2                  .25              .5       .67           1   1.5    2
                                     Sensitivity ratio                                                    Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.783   0.727   0.844   -6.444    0.000       4
Random |   0.443   0.182   1.076   -1.799    0.072
Test for heterogeneity: Q= 293.712 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.802   0.739   0.870   -5.323    0.000       4
Random |   0.668   0.500   0.892   -2.731    0.006
Test for heterogeneity: Q= 23.683 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.852   0.785   0.926   -3.780    0.000       4
Random |   0.721   0.550   0.945   -2.370    0.018
Test for heterogeneity: Q= 17.397 on 3 degrees of freedom (p= 0.001)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.996   0.952   1.042   -0.162    0.871      4
Random |   0.996   0.952   1.042   -0.162    0.871
Test for heterogeneity: Q= 2.083 on 3 degrees of freedom (p= 0.555)



                                                                                                                                      154
Specificity ratio (Cytology at LSIL+/VILI)
               Outcome CIN1+                                                       Outcome CIN2+
               Cytology at LSIL+/VILI                                              Cytology at LSIL+/VILI


      Jaipur                                                              Jaipur

    Mumbai                                                              Mumbai

Trivandrum 1                                                        Trivandrum 1

Trivandrum 2                                                        Trivandrum 2



  Combined                                                            Combined
               .67        .8              1            1.25   1.5                  .67        .8             1            1.25   1.5
                                   Specificity ratio                                                  Specificity ratio
               Outcome CIN3+                                                       Outcome Cancer
               Cytology at LSIL+/VILI                                              Cytology at LSIL+/VILI


      Jaipur                                                              Jaipur

    Mumbai                                                              Mumbai

Trivandrum 1                                                        Trivandrum 1

Trivandrum 2                                                        Trivandrum 2



  Combined                                                            Combined
               .67        .8              1            1.25   1.5                  .67        .8             1            1.25   1.5
                                   Specificity ratio                                                  Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.146   1.139   1.154   41.073    0.000       4
Random |   1.165   1.092   1.242    4.659    0.000
Test for heterogeneity: Q= 276.628 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.170   1.161   1.178   42.409    0.000       4
Random |   1.176   1.096   1.261    4.513    0.000
Test for heterogeneity: Q= 271.368 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.173   1.164   1.181   42.352    0.000       4
Random |   1.178   1.097   1.265    4.519    0.000
Test for heterogeneity: Q= 267.468 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.176   1.168   1.185   42.130    0.000      4
Random |   1.180   1.098   1.269    4.488    0.000
Test for heterogeneity: Q= 265.510 on 3 degrees of freedom (p= 0.000)




                                                                                                                                 155
6.2.11.   Relative sensitivity and specificity of cytology (at HSIL+)
      compared to VILI
Sensitivity ratio (Cytology at HSIL+/VILI)
               Outcome CIN2+                                                       Outcome CIN3+
               Cytology at HSIL+/VILI                                              Cytology at HSIL+/VILI


      Jaipur                                                              Jaipur

    Mumbai                                                              Mumbai

Trivandrum 1                                                        Trivandrum 1

Trivandrum 2                                                        Trivandrum 2



  Combined                                                            Combined
               .1                          .5 .67     1   1.5   2                  .1                          .5 .67     1   1.5    2
                                  Sensitivity ratio                                                   Sensitivity ratio
               Outcome Cancer
               Cytology at HSIL+/VILI


      Jaipur

    Mumbai

Trivandrum 1

Trivandrum 2



  Combined
               .1                          .5 .67     1   1.5   2
                                  Sensitivity ratio



Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.627   0.562   0.700   -8.315    0.000       4
Random |   0.552   0.392   0.777   -3.400    0.001
Test for heterogeneity: Q= 24.066 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.749   0.672   0.835   -5.205    0.000       4
Random |   0.676   0.518   0.882   -2.886    0.004
Test for heterogeneity: Q= 13.487 on 3 degrees of freedom (p= 0.004)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.996   0.952   1.042   -0.162    0.871      4
Random |   0.996   0.952   1.042   -0.162    0.871
Test for heterogeneity: Q= 2.083 on 3 degrees of freedom (p= 0.555)




                                                                                                                                    156
Specificity ratio (Cytology at HSIL+/VILI)
               Outcome CIN2+                                                      Outcome CIN3+
               Cytology at HSIL+/VILI                                             Cytology at HSIL+/VILI


      Jaipur                                                             Jaipur

    Mumbai                                                             Mumbai

Trivandrum 1                                                       Trivandrum 1

Trivandrum 2                                                       Trivandrum 2



  Combined                                                           Combined
               .67        .8             1            1.25   1.5                  .67        .8             1            1.25   1.5
                                  Specificity ratio                                                  Specificity ratio
               Outcome Cancer
               Cytology at HSIL+/VILI


      Jaipur

    Mumbai

Trivandrum 1

Trivandrum 2



  Combined
               .67        .8             1            1.25   1.5
                                  Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.211   1.203   1.219   55.425    0.000       4
Random |   1.228   1.144   1.318    5.669    0.000
Test for heterogeneity: Q= 322.490 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.215   1.207   1.224   55.297    0.000       4
Random |   1.233   1.145   1.327    5.578    0.000
Test for heterogeneity: Q= 331.461 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.220   1.211   1.228   54.766    0.000      4
Random |   1.236   1.147   1.332    5.538    0.000
Test for heterogeneity: Q= 326.532 on 3 degrees of freedom (p= 0.000)




                                                                                                                                157
6.2.12.    Relative sensitivity and specificity of HC2 compared to
      VIAM
Sensitivity ratio (HPV/VIAM)
            Outcome CIN1+                                                   Outcome CIN2+
            HPV/VIAM                                                        HPV/VIAM



Kolkata 1                                                       Kolkata 1
Kolkata 2                                                       Kolkata 2
 Mumbai                                                          Mumbai


Combined                                                        Combined
            .25             .5       .67          1   1.5   2               .25              .5       .67          1   1.5    2
                                 Sensitvity ratio                                                 Sensitvity ratio
            Outcome CIN3+                                                   Outcome Cancer
            HPV/VIAM                                                        HPV/VIAM



Kolkata 1                                                       Kolkata 1
Kolkata 2                                                       Kolkata 2
 Mumbai                                                          Mumbai


Combined                                                        Combined
            .25             .5       .67          1   1.5   2               .25              .5       .67          1   1.5    2
                                 Sensitvity ratio                                                 Sensitvity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.497   0.435   0.568 -10.262     0.000       3
Random |   0.497   0.435   0.568 -10.262     0.000
Test for heterogeneity: Q= 1.976 on 2 degrees of freedom (p= 0.372)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.901   0.783   1.036   -1.461    0.144       3
Random |   0.898   0.770   1.048   -1.365    0.172
Test for heterogeneity: Q= 2.391 on 2 degrees of freedom (p= 0.302)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.025   0.877   1.199    0.314    0.753       3
Random |   1.025   0.877   1.199    0.314    0.753
Test for heterogeneity: Q= 0.244 on 2 degrees of freedom (p= 0.885)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.892   0.726   1.095   -1.096    0.273      3
Random |   0.892   0.726   1.095   -1.096    0.273
Test for heterogeneity: Q= 0.622 on 2 degrees of freedom (p= 0.733)



                                                                                                                             158
Specificity ratio (HPV/VIAM)
            Outcome CIN1                                                 Outcome CIN2+
            HPV/VIAM                                                     HPV/VIAM



Kolkata 1                                                    Kolkata 1
Kolkata 2                                                    Kolkata 2
 Mumbai                                                       Mumbai


Combined                                                     Combined
            .67       .8           1            1.25   1.5               .67       .8            1            1.25   1.5
                            Specificity ratio                                             Specificity ratio
            Outcome CIN3+                                                Outcome Cancer
            HPV/VIAM                                                     HPV/VIAM



Kolkata 1                                                    Kolkata 1
Kolkata 2                                                    Kolkata 2
 Mumbai                                                       Mumbai


Combined                                                     Combined
            .67       .8           1            1.25   1.5               .67       .8           1             1.25   1.5
                            Specificity ratio                                             Sensitvity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.059   1.052   1.066   16.195    0.000       3
Random |   1.061   1.050   1.072   10.928    0.000
Test for heterogeneity: Q= 4.208 on 2 degrees of freedom (p= 0.122)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.074   1.066   1.082   19.521    0.000       3
Random |   1.082   1.055   1.109    6.130    0.000
Test for heterogeneity: Q= 21.463 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.075   1.067   1.083   19.588    0.000       3
Random |   1.083   1.055   1.112    5.874    0.000
Test for heterogeneity: Q= 23.771 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.075   1.067   1.083   19.311    0.000      3
Random |   1.083   1.054   1.114    5.648    0.000
Test for heterogeneity: Q= 25.097 on 2 degrees of freedom (p= 0.000)




                                                                                                                     159
6.2.13.   Relative sensitivity and specificity of cytology at (ASCUS+)
      compared to VIAM
Sensitivity ratio (Cytology at ASCUS+/VIAM)
            Outcome CIN1+                                                   Outcome CIN2+
            Cytology at ASCUS+/VIAM                                         Cytology at ASCUS+/VIAM



Kolkata 1                                                       Kolkata 1

 Mumbai                                                          Mumbai



Combined                                                        Combined
            .25            .5       .67           1   1.5   2               .25            .5       .67           1   1.5    2
                                Sensitivity ratio                                               Sensitivity ratio
            Outcome CIN3+                                                   Outcome Cancer
            Cytology at ASCUS+/VIAM                                         Cytology at ASCUS+/VIAM



Kolkata 1                                                       Kolkata 1

 Mumbai                                                          Mumbai



Combined                                                        Combined
            .25            .5       .67          1    1.5   2               .25            .5       .67          1    1.5    2
                                Sensitvity ratio                                                Sensitvity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.389   0.338   0.446 -13.357     0.000       2
Random |   0.396   0.313   0.501   -7.709    0.000
Test for heterogeneity: Q= 2.707 on 1 degrees of freedom (p= 0.100)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.800   0.683   0.936   -2.785    0.005       2
Random |   0.797   0.486   1.307   -0.899    0.368
Test for heterogeneity: Q= 9.851 on 1 degrees of freedom (p= 0.002)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.876   0.734   1.044   -1.478    0.139       2
Random |   0.863   0.573   1.301   -0.702    0.483
Test for heterogeneity: Q= 5.393 on 1 degrees of freedom (p= 0.020)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.868   0.688   1.095   -1.194    0.233      2
Random |   0.859   0.598   1.235   -0.822    0.411
Test for heterogeneity: Q= 2.420 on 1 degrees of freedom (p= 0.120)



                                                                                                                            160
Specificity ratio (Cytology at ASCUS+/VIAM)
            Outcome CIN1                                                  Outcome CIN2+
            Cytology at ASCUS+/VIAM                                       Cytology at ASCUS+/VIAM



Kolkata 1                                                     Kolkata 1

 Mumbai                                                        Mumbai



Combined                                                      Combined
            .67       .8            1            1.25   1.5               .67       .8            1            1.25   1.5
                             Specificity ratio                                             Specificity ratio
            Outcome CIN3+                                                 Outcome Cancer
            Cytology at ASCUS+/VIAM                                       Cytology at ASCUS+/VIAM



Kolkata 1                                                     Kolkata 1

 Mumbai                                                        Mumbai



Combined                                                      Combined
            .67       .8            1            1.25   1.5               .67       .8            1            1.25   1.5
                             Specificity ratio                                             Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.074   1.063   1.084   14.479    0.000       2
Random |   1.061   0.948   1.188    1.033    0.302
Test for heterogeneity: Q= 131.356 on 1 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.100   1.089   1.112   18.493    0.000       2
Random |   1.091   0.990   1.202    1.755    0.079
Test for heterogeneity: Q= 89.243 on 1 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.102   1.090   1.113   18.489    0.000       2
Random |   1.093   0.995   1.200    1.865    0.062
Test for heterogeneity: Q= 80.622 on 1 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.101   1.090   1.113   18.050    0.000      2
Random |   1.093   0.999   1.197    1.931    0.053
Test for heterogeneity: Q= 73.535 on 1 degrees of freedom (p= 0.000)




                                                                                                                      161
6.2.14.   Relative sensitivity and specificity of cytology (at LSIL+)
      compared to VIAM
Sensitivity ratio (Cytology at LSIL+/VIAM)
            Outcome CIN1+                                                    Outcome CIN2+
            Cytology at LSIL+/VIAM                                           Cytology at LSIL+/VIAM



Kolkata 1                                                        Kolkata 1

 Mumbai                                                           Mumbai



Combined                                                         Combined
                  .25            .5     .67        1   1.5   2               .25             .5       .67          1   1.5    2
                                  Sensitvity ratio                                                Sensitvity ratio
            Outcome CIN3+                                                    Outcome Cancer
            Cytology at LSIL+/VIAM                                           Cytology at LSIL+/VIAM



Kolkata 1                                                        Kolkata 1

 Mumbai                                                           Mumbai



Combined                                                         Combined
            .25             .5       .67          1    1.5   2               .25             .5       .67          1   1.5    2
                                 Sensitvity ratio                                                 Sensitvity ratio



Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.315   0.269   0.369 -14.396     0.000       2
Random |   0.325   0.218   0.484   -5.528    0.000
Test for heterogeneity: Q= 6.228 on 1 degrees of freedom (p= 0.013)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.689   0.579   0.821   -4.182    0.000       2
Random |   0.681   0.386   1.202   -1.324    0.185
Test for heterogeneity: Q= 10.591 on 1 degrees of freedom (p= 0.001)
Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.740   0.607   0.902   -2.981    0.003      2
Random |   0.732   0.478   1.119   -1.442    0.149
Test for heterogeneity: Q= 4.590 on 1 degrees of freedom (p= 0.032)
Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.775   0.600   1.001   -1.953    0.051      2
Random |   0.770   0.539   1.101   -1.433    0.152
Test for heterogeneity: Q= 1.942 on 1 degrees of freedom (p= 0.163)




                                                                                                                             162
Specificity ratio (Cytology at LSIL+/VIAM)
            Outcome CIN1+                                                  Outcome CIN2+
            Cytology at LSIL+/VIAM                                         Cytology at LSIL+/VIAM



Kolkata 1                                                      Kolkata 1

 Mumbai                                                         Mumbai



Combined                                                       Combined
            .67        .8            1            1.25   1.5               .67        .8            1            1.25   1.5
                              Specificity ratio                                              Specificity ratio
            Outcome CIN3+                                                  Outcome Cancer
            Cytology at LSIL+/VIAM                                         Cytology at LSIL+/VIAM



Kolkata 1                                                      Kolkata 1

 Mumbai                                                         Mumbai



Combined                                                       Combined
            .67        .8            1            1.25   1.5               .67        .8            1            1.25   1.5
                              Specificity ratio                                              Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.105   1.095   1.114   21.854    0.000       2
Random |   1.103   1.050   1.158    3.915    0.000
Test for heterogeneity: Q= 29.888 on 1 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.134   1.124   1.145   26.046    0.000       2
Random |   1.133   1.095   1.173    7.165    0.000
Test for heterogeneity: Q= 12.952 on 1 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.136   1.125   1.147   26.048    0.000       2
Random |   1.135   1.102   1.170    8.248    0.000
Test for heterogeneity: Q= 9.816 on 1 degrees of freedom (p= 0.002)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.137   1.126   1.148   25.785    0.000      2
Random |   1.137   1.105   1.169    9.010    0.000
Test for heterogeneity: Q= 8.101 on 1 degrees of freedom (p= 0.004)




                                                                                                                        163
6.2.15.   Relative sensitivity and specificity of cytology (at HSIL+)
      compared to VIAM
Sensitivity ratio (Cytology at HSIL+/VIAM)
            Outcome CIN2+                                                    Outcome CIN3+
            Cytology at HSIL+/VIAM                                           Cytology at HSIL+/VIAM



Kolkata 1                                                        Kolkata 1

 Mumbai                                                           Mumbai



Combined                                                         Combined
                       .5         .67            1     1.5   2                      .5      .67              1       1.5    2
                                   Sensitvity ratio                                               Sensitvity ratio
            Outcome Cancer
            Cytology at HSIL+/VIAM



Kolkata 1

 Mumbai



Combined
                .5          .67            1          1.5    2
                                  Sensitvity ratio



Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.618   0.512   0.746   -5.027    0.000       2
Random |   0.606   0.324   1.132   -1.571    0.116
Test for heterogeneity: Q= 11.066 on 1 degrees of freedom (p= 0.001)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.706   0.575   0.866   -3.332    0.001       2
Random |   0.692   0.428   1.118   -1.505    0.132
Test for heterogeneity: Q= 5.415 on 1 degrees of freedom (p= 0.020)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.775   0.600   1.001   -1.953    0.051      2
Random |   0.770   0.539   1.101   -1.433    0.152
Test for heterogeneity: Q= 1.942 on 1 degrees of freedom (p= 0.163)




                                                                                                                           164
Specificity ratio (Cytology at HSIL+/VIAM)
            Outcome CIN2+                                                  Outcome CIN3+
            Cytology at HSIL+/VIAM                                         Cytology at HSIL+/VIAM



Kolkata 1                                                      Kolkata 1

 Mumbai                                                         Mumbai



Combined                                                       Combined
            .67       .8             1            1.25   1.5               .67       .8             1            1.25   1.5
                              Specificity ratio                                              Specificity ratio
            Outcome Cancer
            Cytology at HSIL+/VIAM



Kolkata 1

 Mumbai



Combined
            .67       .8             1            1.25   1.5
                              Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.166   1.156   1.176   33.879    0.000       2
Random |   1.166   1.152   1.180   24.364    0.000
Test for heterogeneity: Q= 1.928 on 1 degrees of freedom (p= 0.165)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.169   1.158   1.179   33.955    0.000       2
Random |   1.169   1.150   1.187   19.180    0.000
Test for heterogeneity: Q= 3.121 on 1 degrees of freedom (p= 0.077)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.171   1.160   1.181   33.646    0.000      2
Random |   1.170   1.149   1.192   16.979    0.000
Test for heterogeneity: Q= 3.902 on 1 degrees of freedom (p= 0.048)




                                                                                                                        165
6.2.16.   Relative sensitivity and specificity of cytology (at ASCUS+)
      compared to HC2
Sensitivity ratio (Cytology at ASCUS+/HPV)
               Outcome CIN1+                                                 Outcome CIN2+
               Cytology at ASCUS+/HPV                                        Cytology at ASCUS+/HPV


   Kolkata 1                                                     Kolkata 1

    Mumbai                                                        Mumbai

Trivandrum 2                                                  Trivandrum 2

      Harare                                                        Harare



  Combined                                                      Combined
               .5       .67             1           1.5   2                  .5           .67          1                1.5    2
                                 Sensitvity ratio                                               Sensitvity ratio
               Outcome CIN3+                                                 Outcome Cancer
               Cytology at ASCUS+/HPV                                        Cytology at ASCUS+/HPV



   Kolkata 1                                                     Kolkata 1

                                                                  Mumbai
    Mumbai
                                                              Trivandrum 2
Trivandrum 2
                                                                    Harare



  Combined                                                      Combined
               .5       .67             1           1.5   2                  .5     .67         1           1.5     2
                                 Sensitvity ratio                                                Sensitvity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.791   0.723   0.864   -5.166    0.000       4
Random |   0.854   0.704   1.036   -1.603    0.109
Test for heterogeneity: Q= 9.239 on 3 degrees of freedom (p= 0.026)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.865   0.787   0.950   -3.019    0.003       4
Random |   0.883   0.780   0.999   -1.971    0.049
Test for heterogeneity: Q= 4.223 on 3 degrees of freedom (p= 0.238)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.929   0.793   1.088   -0.913    0.361       3
Random |   0.915   0.742   1.130   -0.824    0.410
Test for heterogeneity: Q= 3.406 on 2 degrees of freedom (p= 0.182)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.076   0.854   1.355    0.618    0.537      4
Random |   1.076   0.854   1.355    0.618    0.537
Test for heterogeneity: Q= 1.537 on 3 degrees of freedom (p= 0.674)



                                                                                                                              166
Specificity ratio (Cytology at ASCUS+/HPV)
               Outcome CIN1+                                                    Outcome CIN2+
               Cytology at ASCUS+/HPV                                           Cytology at ASCUS+/HPV


   Kolkata 1                                                        Kolkata 1

    Mumbai                                                           Mumbai

Trivandrum 2                                                     Trivandrum 2

      Harare                                                           Harare



  Combined                                                         Combined
               .67       .8            1            1.25   1.5                  .67       .8            1            1.25   1.5
                                Specificity ratio                                                Specificity ratio
               Outcome CIN3+                                                    Outcome Cancer
               Cytology at ASCUS+/HPV                                           Cytology at ASCUS+/HPV



   Kolkata 1                                                        Kolkata 1

                                                                     Mumbai
    Mumbai
                                                                 Trivandrum 2
Trivandrum 2
                                                                       Harare



  Combined                                                         Combined
               .67       .8            1            1.25   1.5                  .67       .8            1            1.25   1.5
                                Specificity ratio                                                Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.030   1.024   1.035   10.472    0.000       4
Random |   1.052   0.996   1.110    1.815    0.070
Test for heterogeneity: Q= 229.935 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.028   1.022   1.034    9.646    0.000       4
Random |   1.057   1.000   1.117    1.957    0.050
Test for heterogeneity: Q= 231.817 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.024   1.018   1.030    8.046    0.000       3
Random |   1.008   0.956   1.064    0.311    0.756
Test for heterogeneity: Q= 151.373 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.027   1.021   1.033    8.569    0.000      4
Random |   1.061   1.000   1.125    1.966    0.049
Test for heterogeneity: Q= 229.069 on 3 degrees of freedom (p= 0.000)




                                                                                                                            167
6.2.17.   Relative sensitivity and specificity of cytology (at LSIL+)
      compared to HC2
Sensitivity ratio (Cytology at LSIL+/HPV)
               Outcome CIN1+                                                      Outcome CIN2+
               Cytology at LSIL+/HPV                                              Cytology at LSIL+/HPV


   Kolkata 1                                                          Kolkata 1

    Mumbai                                                             Mumbai

Trivandrum 2                                                       Trivandrum 2

      Harare                                                             Harare



  Combined                                                           Combined
                       .5      .67               1       1.5   2                    .5           .67            1              1.5    2
                                     Sensitivity ratio                                                 Sensitivity ratio
               Outcome CIN3+                                                      Outcome Cancer
               Cytology at LSIL+/HPV                                              Cytology at LSIL+/HPV



   Kolkata 1                                                          Kolkata 1

                                                                       Mumbai
    Mumbai
                                                                   Trivandrum 2
Trivandrum 2
                                                                         Harare



  Combined                                                           Combined
                     .5       .67               1        1.5   2                    .5     .67          1           1.5    2
                                     Sensitivity ratio                                                 Sensitivity ratio


Meta-analysis of the sensitivity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.569   0.511   0.635 -10.116     0.000       4
Random |   0.663   0.456   0.964   -2.152    0.031
Test for heterogeneity: Q= 28.786 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.712   0.635   0.798   -5.845    0.000       4
Random |   0.755   0.559   1.019   -1.838    0.066
Test for heterogeneity: Q= 18.654 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.842   0.711   0.997   -1.991    0.046       3
Random |   0.816   0.609   1.093   -1.366    0.172
Test for heterogeneity: Q= 5.744 on 2 degrees of freedom (p= 0.057)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.013   0.796   1.291    0.108    0.914      4
Random |   1.013   0.796   1.291    0.108    0.914
Test for heterogeneity: Q= 2.532 on 3 degrees of freedom (p= 0.470)



                                                                                                                                     168
Specificity ratio (Cytology at LSIL+/HPV)
               Outcome CIN1+                                                      Outcome CIN2+
               Cytology at LSIL+/HPV                                              Cytology at LSIL+/HPV


   Kolkata 1                                                          Kolkata 1

    Mumbai                                                             Mumbai

Trivandrum 2                                                       Trivandrum 2

      Harare                                                             Harare



  Combined                                                           Combined
               .67        .8             1            1.25   1.5                  .67       .8             1             1.25     1.5
                                  Specificity ratio                                                  Specificity ratio
               Outcome CIN3+                                                      Outcome Cancer
               Cytology at LSIL+/HPV                                              Cytology at LSIL+/HPV



   Kolkata 1                                                          Kolkata 1

                                                                       Mumbai
    Mumbai
                                                                   Trivandrum 2
Trivandrum 2
                                                                         Harare



  Combined                                                           Combined
               .67        .8             1            1.25   1.5                  .67       .8           1             1.25     1.5
                                  Specificity ratio                                                  Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.046   1.041   1.052   17.114    0.000       4
Random |   1.116   1.054   1.182    3.780    0.000
Test for heterogeneity: Q= 296.609 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.048   1.042   1.053   17.110    0.000       4
Random |   1.127   1.058   1.200    3.701    0.000
Test for heterogeneity: Q= 351.989 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.040   1.035   1.046   14.024    0.000       3
Random |   1.037   1.014   1.060    3.177    0.001
Test for heterogeneity: Q= 30.599 on 2 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.049   1.043   1.055   16.166    0.000      4
Random |   1.136   1.059   1.218    3.585    0.000
Test for heterogeneity: Q= 373.645 on 3 degrees of freedom (p= 0.000)




                                                                                                                                  169
6.2.18.   Relative sensitivity and specificity of cytology (at HSIL+)
      compared to HC2
Sensitivity ratio (Cytology at HSIL+/HPV)
               Outcome CIN2+                                                       Outcome CIN3+
               Cytology at HSIL+/HPV                                               Cytology at HSIL+/HPV


   Kolkata 1                                                           Kolkata 1
    Mumbai
                                                                        Mumbai
Trivandrum 2
                                                                    Trivandrum 2
      Harare



  Combined                                                            Combined
               .1            .25            .5 .67    1   1.5   2                  .1            .25            .5 .67    1   1.5    2
                                   Sensitvity ratio                                                    Sensitvity ratio
               Outcome Cancer
               Cytology at HSIL+/HPV


   Kolkata 1

    Mumbai

Trivandrum 2

      Harare



  Combined
               .1            .25            .5 .67    1   1.5   2
                                   Sensitvity ratio


Meta-analysis of the sensitivity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.629   0.545   0.725   -6.390    0.000       4
Random |   0.560   0.286   1.096   -1.693    0.090
Test for heterogeneity: Q= 64.346 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the sensitivity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.822   0.692   0.976   -2.231    0.026       3
Random |   0.786   0.562   1.099   -1.408    0.159
Test for heterogeneity: Q= 7.301 on 2 degrees of freedom (p= 0.026)

Meta-analysis of the sensitivity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.013   0.796   1.291    0.108    0.914      4
Random |   1.013   0.796   1.291    0.108    0.914
Test for heterogeneity: Q= 2.532 on 3 degrees of freedom (p= 0.470)




                                                                                                                                    170
Specificity ratio (Cytology at HSIL+/HPV)
               Outcome CIN2+                                                     Outcome CIN3+
               Cytology at HSIL+/HPV                                             Cytology at HSIL+/HPV


   Kolkata 1                                                         Kolkata 1
    Mumbai
                                                                      Mumbai
Trivandrum 2
                                                                  Trivandrum 2
      Harare



  Combined                                                          Combined
               .67       .8         1              1.25     1.5                  .67        .8            1            1.25   1.5
                                 Specificity ratio                                                 Specificity ratio
               Outcome Cancer
               Cytology at HSIL+/HPV


   Kolkata 1

    Mumbai

Trivandrum 2

      Harare



  Combined
               .67      .8         1            1.25      1.5
                                 Specificity ratio


Meta-analysis of the specificity ratio for outcome CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.067   1.062   1.072   26.029    0.000       4
Random |   1.170   1.092   1.253    4.478    0.000
Test for heterogeneity: Q= 497.486 on 3 degrees of freedom (p= 0.000)

Meta-analysis of the specificity ratio for outcome CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.060   1.054   1.065   22.298    0.000       3
Random |   1.061   1.052   1.070   13.944    0.000
Test for heterogeneity: Q= 5.013 on 2 degrees of freedom (p= 0.082)

Meta-analysis of the specificity ratio for outcome cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    1.070   1.065   1.076   24.988    0.000      4
Random |   1.187   1.096   1.286    4.194    0.000
Test for heterogeneity: Q= 584.614 on 3 degrees of freedom (p= 0.000)




                                                                                                                              171
6.2.19.    Summary of the meta-analyses of the relative accuracy of
      screening tests
Table 29. Pooled relative sensitivity and specificity of 5 screening tests relative to each other with respect to
detection of CIN1+, CIN2+, CIN3+ or cancer (* indicates ratios which do not include unity, indicating
statistically significant differences between tests).
                                                Relative sensitivity & CI              Relative specificity & CI
                           Number
                           of study
Test combination  Outcome locations Model Ratio               lower upper           Model    Ratio lower upper
VILI/VIA          CIN1+       10     R    1.19                 1.08 1.30 *           R       1.00 0.97 1.04
                  CIN2+              R    1.11                 1.05 1.17 *           R       1.00 0.96 1.03
                  CIN3+              F    1.07                 1.04 1.11 *           R       0.99 0.96 1.03
                  Cancer             F    1.01                 0.99 1.04             R       0.99 0.96 1.03
VIAM/VIA          CIN1+        3     F    1.05                 0.98 1.13             R       1.00 0.98 1.02
                  CIN2+              F    1.04                 0.93 1.16             R       1.00 0.98 1.02
                  CIN3+              F    1.03                 0.90 1.18             R       1.00 0.98 1.02
                  Cancer             F    1.00                 0.97 1.03             R       1.00 0.98 1.02
HC2/VIA           CIN1+        4     R    0.57                 0.36 0.89 *           R       1.04 1.02 1.06 *
                  CIN2+              R    0.93                 0.82 1.06             R       1.06 1.03 1.09 *
                  CIN3+              R    0.96                 0.78 1.17             R       1.08 1.05 1.10 *
                  Cancer             R    0.85                 0.71 1.02             R       1.06 1.03 1.09 *
Pap (ASCUS+)/VIA CIN1+         5     R    0.53                 0.34 0.83 *           R       1.12 1.07 1.18 *
                  CIN2+              R    0.77                 0.64 0.93 *           R       1.13 1.09 1.19 *
                  CIN3+              R    0.80                 0.61 1.03             R       1.13 1.07 1.18 *
                  Ca                 R    0.99                 0.94 1.04             R       1.14 1.09 1.19 *
Pap (LSIL+)/VIA   CIN1+        5     R    0.43                 0.25 0.76 *           R       1.17 1.11 1.23 *
                  CIN2+              R    0.65                 0.50 0.83 *           R       1.19 1.13 1.25 *
                  CIN3+              R    0.71                 0.54 0.94 *           R       1.15 1.10 1.21 *
                  Ca                 R    0.96                 0.88 1.05 *           R       1.20 1.13 1.27 *
Pap (HSIL+)/VIA   CIN2+        5     R    0.46                 0.31 0.69 *           R       1.25 1.17 1.34 *
                  CIN3+              R    0.66                 0.50 0.87 *           R       1.21 1.13 1.29 *
                  Ca                 R    0.96                 0.88 1.05 *           R       1.27 1.18 1.37 *
VIAM/VILI         CIN1+        2     F    0.87                 0.79 0.96 *           F       1.03 1.02 1.04 *
                  CIN2+              F    0.89                 0.78 1.02             F       1.03 1.02 1.04 *
                  CIN3+              F    0.90                 0.77 1.06             F       1.03 1.02 1.04 *
                  Ca                 F    1.00                 0.97 1.04             F       1.03 1.02 1.04 *
HC2/VILI          CIN1+        3     R    0.41                 0.34 0.50 *           R       1.08 1.05 1.10 *
                  CIN2+              F    0.83                 0.74 0.94 *           R       1.10 1.09 1.11 *
                  CIN3+              R    0.86                 0.71 1.03             R       1.10 1.08 1.11 *
                  Ca                 F    0.88                 0.72 1.07             R       1.10 1.09 1.11 *
Pap (ASCUS+)/VILI CIN1+        4     R    0.50                 0.22 1.12             R       1.15 1.09 1.22 *
                  CIN2+              R    0.74                 0.57 0.95 *           R       1.16 1.09 1.24 *
                  CIN3+              R    0.80                 0.62 1.02             R       1.16 1.09 1.24 *
                  Ca                 F    1.00                 0.95 1.04             R       1.17 1.09 1.24 *
Pap (LSIL+)/VILI  CIN1+        4     R    0.44                 0.18 1.08             R       1.17 1.09 1.24 *
                  CIN2+              R    0.67                 0.50 0.89 *           R       1.18 1.10 1.26 *
                  CIN3+              R    0.72                 0.55 0.95 *           R       1.18 1.10 1.27 *
                  Ca                 F    1.00                 0.95 1.04             R       1.18 1.10 1.27 *
Pap (HSIL+)/VILI  CIN2+        4     R    0.55                 0.39 0.78 *           R       1.23 1.14 1.32 *
                  CIN3+              R    0.68                 0.52 0.88 *           R       1.23 1.15 1.33 *



                                                                                                             172
                  Ca          F   1.00   0.95   1.04   R   1.24   1.15   1.33 *
HC2/VIAM          CIN1+   3   F   0.50   0.44   0.57   R   1.06   1.05   1.07
                  CIN2+       F   0.90   0.78   1.04   R   1.08   1.06   1.11
                  CIN3+       F   1.03   0.88   1.20   R   1.08   1.06   1.11
                  Ca          R   0.89   0.73   1.10   R   1.08   1.05   1.11
Pap (ASCUS+)/VIAM CIN1+   2   R   0.40   0.31   0.50   R   1.06   0.95   1.19
                  CIN2+       R   0.80   0.49   1.31   R   1.09   0.99   1.20
                  CIN3+       R   0.86   0.57   1.30   R   1.09   1.00   1.20
                  Ca          R   0.86   0.60   1.24   R   1.09   1.00   1.20
Pap (LSIL+)/VIAM CIN1+    2   R   0.33   0.22   0.48   R   1.10   1.05   1.16
                  CIN2+       R   0.68   0.39   1.20   R   1.13   1.10   1.17
                  CIN3+       R   0.73   0.48   1.12   R   1.14   1.10   1.17
                  Ca          R   0.77   0.54   1.10   R   1.14   1.11   1.17
Pap (HSIL+)/VIAM CIN2+    2   R   0.61   0.32   1.13   R   1.17   1.15   1.18
                  CIN3+       R   0.69   0.43   1.12   R   1.17   1.15   1.19
                  Ca          R   0.77   0.54   1.10   R   1.17   1.15   1.19
Pap (ASCUS+)/HC2 CIN1+    4   R   0.85   0.70   1.04   R   1.05   1.00   1.11
                  CIN2+       F   0.87   0.79   0.95   R   1.06   1.00   1.12
                  CIN3+       R   0.92   0.74   1.13   R   1.01   0.96   1.06
                  Ca          F   1.08   0.85   1.36   R   1.06   1.00   1.13
Pap (LSIL+)/HC2   CIN1+   4   R   0.66   0.46   0.96   R   1.12   1.05   1.18
                  CIN2+       R   0.76   0.56   1.02   R   1.13   1.06   1.20
                  CIN3+       R   0.82   0.61   1.09   R   1.04   1.01   1.06
                  Ca          F   1.01   0.80   1.29   R   1.14   1.06   1.22
Pap (HSIL+)/HC2   CIN2+   4   R   0.56   0.29   1.10   R   1.17   1.09   1.25
                  CIN3+       R   0.79   0.56   1.10   R   1.06   1.05   1.07
                  Ca          F   1.01   0.80   1.29   R   1.19   1.10   1.29




                                                                         173
6.3. Summary ROC curves

The simultaneous variation of sensitivity and specificity over the different study locations is
assessed by plotting the false positive rate (complement of the specificity) against the
sensitivity. Using sROC regression [Moses, 1987; Arbyn, 2002] we can obtain a smoothed
curve through the observed points. We have limited the sROC regression analyses to VIA
and VILI for which we have respectively 12 and 10 study points.

Figure 7 shows the observed sensitivity against the observed FPR and the smoothed sROC
over a limited proportion of the ROC-space considering CIN2+ as outcome. It clearly
shows a few exceptional points. In Conakry, a simultaneously outlying high sensitivity
(91%) and specificity (94%) were observed; whereas in Kolkata 1, a very low sensitivity
(62%) and an intermediate specificity (82%) were found. In Harare, the lowest specificity
(64%) was found in spite of only an intermediate sensitivity (76%).

                       VIA
                       Outcome=CIN2+
                  1
                                   Co                          Tr1       Ou
                                                                        Ja
                                        Ba Tr2                     Br
                 .8                       Ko2
                                                                                         Ha

                                  Ni
 Sensitivity




                                               Mu      Ko1
                 .6

                 .4

                 .2

                  0
                        0                 .1             .2                    .3                .4
                                                 FPR = 1- Specificity

Figure 7. Partial summary ROC curve (sROC): observed sensitivity against observed false positive rate
(indicated by the first 3 letters of the 12 included study locations); fitted sensitivity and 95% CI obtained by
an SROC regression; for VIA considering CIN2+ as outcome.


Figure 8 shows the complete sROC curve running from (0,0) to (1,1). The area under this
curve occupies 89.2% (CI: 84.9% to 92.4%) of the total ROC space. Figure 9 and Figure
10 display respectively the partial and complete sROC curve describing the accuracy of
VILI for CIN2. Figure 11 contains the accuracy points and partial sROC curves for both,
VIA and VILI in one plot. The red sROC curve, describing the accuracy of VILI jumps
abruptly under the blue VIA curve at the left part of the plot (in the vertical zone where
FPR≈ 0.1). This downward part of the curve is located beyond observed data points.
Therefore the area under the curve (AUC) is not really representative for the observed range
of accuracy. For this reason, the area under the VILI curve is nearly equal to the area under
the VIA curve, in spite of the fact that most VILI points are situated at left and above the



                                                                                                              174
VIA points. We prefer using the partial AUC considering only observed data points. The
partial AUC was 16.9 % for VIA and the 95% CI (15.0% to 18.4%) includes the value for
VILI (17.5%). In this particular case, even the difference in partial AUC can not describe
appropriately the contrast in accuracy between both tests appropriately, since most VILI
data points are situated in a narrow range near the point where the sROC jumps downward
and no points are located around the downward part of the curve.
We constructed forest plots for the other outcomes. Interested readers can contact us if they
wish to obtain them.
                  VIA
                  Outcome=CIN2+
                1

               .8
Sensitivity




               .6

               .4

               .2

                0
                     0     .1    .2        .3 .4 .5 .6 .7                 .8   .9    1
                                             FPR = 1- Specificity

Figure 8. Complete sROC curve describing the relation between the FPR and sensitivity for the same 12
study locations as in Figure 7.

                    VILI
                    Outcome=CIN2+
                1                   Co Br
                                     Ba                         Ou
                                  Ni                   Tr1
                                                                Ja
                                            Ko2
                                            Tr2
               .8                                 Mu
Sensitivity




               .6

               .4

               .2

                0
                     0                .1            .2               .3
                                            FPR = 1- Specificity

Figure 9. Partial sROC curve describing the relation between the FPR and the sensitivity of VILI considering
CIN2+ as outcome.




                                                                                                        175
                         VILI
                         Outcome=CIN2+
                 1

                .8
 Sensitivity




                .6

                .4

                .2

                 0
                         0       .1   .2    .3 .4 .5 .6 .7                    .8     .9      1
                                              FPR = 1- Specificity

Figure 10. Complete sROC curve describing the describing the same relation between the FPR and
sensitivity for the 10 study locations plotted in Figure 9.


                                      VIA                                   VILI
                     1

                  .8
 Sensitivity




                  .6

                  .4

                  .2

                     0
                             0              .1             .2                      .3                  .4
                                                   FPR = 1- Specificity
Figure 11. Relation between sensitivity and FPR of VIA (blue x-points and interrupted line) and VILI (red
circles and full line) for CIN2+. The points represent respectively 12 VIA studies and 10 VILI studies. The
smoothed curves are obtained using sROC regression.




                                                                                                        176
Table 30. Area under the sROC curve (AUC) obtained by integration of the surface under the complete
sROC-regression curve.
           Test Outcome           AUC           95% CI
           VIA CIN2+              0.892       0.849       0.924
                CIN3+             0.912       0.878       0.937
           VILI CIN2+             0.906       0.863       0.936
                CIN3+             0.895        0.85        0.93


Table 31. Area under the partial sROC curves for respectively VIA obtained by integration over the range of
observed FPR values for VILI (between 8.3% and 30.0%).
                                 Partial
           Test Outcome           AUC           95% CI
           VIA CIN2+              0.169       0.150       0.184
           VILI CIN2+             0.175       0.134       0.201




                                                                                                       177
6.4. Influence of study characteristics on the prevalence of
     disease

The overall prevalence of cervical disease by category of severity is documented in Table
32. The relation between the prevalence of cervical disease and age group is plotted in
Figure 12.
The relation between CIN2+ and age is further detailed by study setting in Figure 13.
Overall, the prevalence of CIN2+, CIN3+ and cancer increased modestly with age. After
the age of 60 the slope of the curve increased substantially. A marked increase of CIN2+
prevalence, in the older age groups, could be observed in Brazzaville, Conakry and Kolkata
1. In Harare the prevalence of CIN2+ was higher than in the other settings. Here, the
prevalence decreased until the age group 50-54 and increased thereafter.
There was no important change by study phase (see Table 33).
Table 32. Prevalence of cervical intra-epithelial neoplasia and invasive cervical cancer and 95% CI.
                        Category    Prevalence            95% CI
                         CIN1+         9.0%           8.8%     9.2%
                         CIN2+         2.5%           2.4%     2.7%
                         CIN3+         1.3%           1.2%     1.4%
                         Cancer       0.48%           0.43%    0.53%


Table 33. Prevalence of CIN2+ by study phase.
                        Period     Prevalence              95% CI
                             1              2.8%          2.6%            3.0%
                             2              2.2%          2.1%            2.4%
                             3              2.6%          2.4%            2.8%


                        CIN 1                                   CIN 2
                        CIN 3                                   Cancer

              .2




             .15
Prevalence




              .1




             .05




              0
                   30     35        40       45            50            55      60   65
                                                  Age group

Figure 12. Relation between prevalence of cervical neoplasia by category of disease and by 5-year age
group.



                                                                                                        178
                         CIN 2+
                         .
                                                                                           Ko1
                    .3                                                                     Br




                    .2
     Prevalence




                                                                                Br   Br
                                                                                     Co
                                                                                     Ko1
                    .1
                                                                    Br      Co
                                                                            Ba
                          Br                                Br              Ko1
                                  Br      Br
                                          Ba       Br               Ko1
                                                                    Co
                                 Ba       Ko1
                                          Co       Ko1     Ba       Ba
                                 Ko1               Ba
                                                   Ko2
                                                    Ja     Ko1
                                                           Co
                                                            Ja               Ja
                          Ja               Ja
                                          Ko2      Co      Ko2      Ko2     Ko2
                          Co
                          Ba     Co
                                  Ja
                                 Ko2                                 Ja              Ko2   Ko2
                     0
                         25       30      35       40   45 50               55       60    65
                                                     Age group

                         CIN 2+
                         .
                    .3



                    .2
     Prevalence




                          Ha      Ha                                            Ha
                    .1                                                                     Tr2
                                           Ha      Ha                                Mu
                                                                            Ou       Tr1
                                                                    Ha      Tr1
                                          Ou       Ou
                                                   Tr1     Ha
                                                           Tr1
                                                           Ou       Tr1     Mu       Tr2   Tr1
                         Tr1      Tr1
                                  Ou      Tr1      Mu               Tr2     Tr2
                         Tr2      Mu
                                  Tr2     Mu       Tr2     Mu
                                                           Tr2      Mu
                                                                    Ni
                                                                    Ou
                         Ou       Ni      Tr2      Ni      Ni
                         Mu
                         Ni               Ni                                    Ni   Ni    Ni
                     0
                         25       30      35       40   45 50               55       60    65
                                                     Age group


Figure 13. Relation between the prevalence of CIN2+ and age group by setting.




                                                                                                 179
6.5. Influence of study covariates on test characteristics
6.5.1. Variation of the test positivity rate by age group

The variation of test results by age is illustrated for all five studied screening tests in a
series of line plots (see Figure 14-Figure 16) and assessed statistically using Pearson's chi
square test and a trend test [Sasieni, 1996]. The variation by age in VIA-test positivity rate
was not homogenous over the different study locations. The variation by age was
significant in most settings, with the exception of Niamey, Harare and Busia. A significant
increase in test positivity with increasing age was noticed (p value for trend test <0.05) in
Brazzaville, Conakry and Trivandrum. In Conakry in particular, a remarkable age trend
was found, with VIA test positivity increasing from 2% in the age group 25-29 to 33%
among women 60-64 years old. On the other hand, a significant decrease was found in
Kolkata 1 and 2, Mumbai, Harare, Ambilikai and Accra.
                             VIA                                                                                  VIA
                             .                                                                                    .
                        .4                                                                                   .4
                                                                    Br    Co                                                  Ou
                                                                          Br                                                                             Tr1
                                                                                                                        Ou                                     Tr1
Test positiviity rate




                                                                                     Test positiviity rate




                                                               Br                                                                   Ou
                        .3                     Ja
                                                        Br                                                   .3                              Ou    Tr1
                                   Ja
                                   Br    Ja    Br                                                                                            Tr1
                             Ja
                             Br          Br                                                                             Tr1
                                   Ko1                  Ja                                                                          Tr1
                                         Ko1                                                                      Ou          Tr1
                                                               Ja
                        .2                                          Co                                       .2   Tr1
                                                                                                                  Mu
                                                                    Ja                                                        Mu                         Ou
                                                                          Ko1                                           Mu                         Ou
                                                               Co                                                                                              Ko2
                                         Ba    Ko1                  Ba                                                  Ko2
                                   Ba          Ba       Ko1
                                                        Co    Ko1                                                             Ko2
                                                                    Ko1                                                             Mu
                                                                                                                                    Ko2      Mu
                        .1                              Ba                                                   .1                              Ko2         Mu    Ni
                                         Co    Co              Ba                                                                                  Mu    Ni    Mu
                             Ba                                                                                   Ni    Ni    Ni    Ni       Ni    Ni
                                                                                                                                                   Ko2   Ko2
                                   Co
                             Co
                        0                                                                                    0
                             25    30    35    40       45     50   55    60    65                                25    30    35    40       45     50   55    60    65
                                                     Age group                                                                            Age group
                             VIA                                                                                  VIA
                             .                                                                                    .
                                   Ha                               Ha
                                                                                                             .4
                             Ha
                        .4               Ha
                                               Ha
Test positiviity rate




                                                                                     Test positiviity rate




                                                        Ha
                                                                                                             .3
                        .3                                     Ha

                                               Bu                         Tr2
                                   Bu    Bu                                                                  .2
                        .2   Tr2                                                                                  Ac          Ch
                                                                                                                                    Ch
                                                                                                                                    Ka
                                                                                                                        Ch
                                                                                                                        Ac    Ka
                                   Tr2                                                                                                       Ac
                                                                                                                                             Ch
                                                                                                                        Ph
                                                                                                                        Ka    Ph    Pa
                                   Am    Am    Tr2                                                                      Pa    Pa
                                                                                                                              Ac    Ac
                                                                                                                                    Ph       Ka
                                         Tr2                  Tr2
                                                        Tr2         Tr2                                      .1
                        .1   Bu                Am
                                                                                                                                             Pa
                                                                                                                                             Ph
                                                        Am                Am
                                                              Am    Am
                        0                                                                                    0
                             25    30    35    40       45     50   55    60    65                                25    30    35    40       45     50   55    60    65
                                                     Age group                                                                            Age group



Figure 14. Variation in test positivity rate of VIA by age group and study setting. Settings are identified by
the first 2 characters.


The changes by age in VILI positivity rate were generally smaller than for VIA, but these
changes were still significant in Brazzaville, Conakry, Mumbai, Ouagadougou and
Trivandrum 1. In Conakry the same spectacular increase over age could be discerned as
already remarked for VIA. The change in VIAM positivity rate was homogenous in the
three locations where it was evaluated, decreasing slightly by age until the age group 50-59
and increasing among women older than 60 years.
The variation in HC2 positivity rate was limited in the four Indian sites (Kolkata 1 & 2,
Mumbai and Trivandrum): between 7 and 9% between 30-54 years. In Harare, the HPV


                                                                                                                                                                     180
positivity rate was very high. Half of the women between 25 and 29 years old were HC2-
positive. The rate decreased to 23% among women of 45-49 years. After that age an
increase was noticed.
Cytological positivity changed significantly over age groups in all settings where it was
evaluated and for all cytological cutoffs, with the exception of the HSIL rate in Trivandrum
2 and Harare. In general, cytological rates increased slightly with age. The continuous
increase by age observed in Kolkata 1 is notable.

Table 34. Variation of the VIA test positivity rate by 5-year age group and by study location (computed only
for the groups representing at least 50 women). Variation is assessed statistically by Pearson's chi-square test
and a trend test.
                                      5-year age group (first year of interval)
                                                                                   chi2 Trend Direction
Setting      Total          25     30    35    40    45    50    55    60    65 (Pearson) test  trend
Bamako       5552 %              11.2% 12.9% 12.1% 9.1% 7.4% 12.7%                0.02    0.08
                   N              1687 1346 1106 822 393 181
Brazzaville   6935 %       24.3% 26.4% 24.6% 26.4% 28.8% 30.0% 33.5% 32.0%        0.02    0.00    +
                   N        1008 1498 1413 1321 878 483 230              97
Conakry      8627 %         2.3% 4.6% 7.9% 7.7% 11.7% 14.5% 19.1% 32.9%           0.01    0.00    +
                   N         880 2283 1902 1519 1175 557 241             70
Jaipur       5786 %        24.4% 27.0% 26.6% 27.7% 22.7% 20.2% 16.8%              0.00    0.06
                   N        1126 1696 1223 859 498 253 131
Kolkata 1    5894 %              22.8% 20.6% 13.6% 12.2% 11.3% 10.7% 15.4%        0.00    0.00     -
                   N              2697 1299 801 576 238 169 104
Kolkata 2    8080 %              12.6% 12.7% 11.4% 10.6% 6.3% 7.0% 17.7%          0.00    0.00     -
                   N              3709 1938 1072 749 337 183             73
Mumbai       4004 %              16.2% 16.7% 11.1% 10.6% 7.2% 9.8%                0.00    0.00     -
                   N                616 1081 937 698 405 215
Niamey       2534 %         6.4% 5.8% 6.3% 5.8% 5.6% 5.9%                         0.99    0.96
                   N         141 676 646 600 302 118
Ouagadougou 2051 %         21.4% 30.2% 33.3% 29.9% 27.7% 15.9% 17.2%              0.00    0.60
                   N         556 430 429 318 191             69    58
Trivandrum 1 4457 %        18.1% 23.8% 21.0% 22.1% 25.8% 28.1% 32.2% 30.5% 24.1% 0.00     0.00    +
                   N         166 513 1098 894 841 445 301 141                  58
Trivandrum 2 4759 %        18.1% 14.7% 11.6% 12.7% 10.4% 10.8% 10.0% 22.2%        0.02    0.07
                   N           72 715 1111 1067 891 548 289              54
Harare       2206 %        40.0% 44.5% 39.5% 35.1% 33.6% 29.0%                    0.06    0.04     -
                   N         880 488 392 242 110             62
Ambilikai    31317 %             12.7% 12.0% 8.5% 5.2% 2.6% 1.9% 5.6%             0.00    0.00     -
                   N             12946 5886 4267 3648 2532 1949          89
Busia        2295 %              21.4% 20.8% 21.9%                                0.67    0.92
                   N              1074 946 128
Roi-Et       1990 %              12.8% 13.7% 14.3% 8.3% 7.7%                      0.03    0.98
                   N              2257 1987 1572 169
Accra        3665 %        16.1% 14.0% 10.6% 11.3% 13.7%                          0.00    0.00     -
                   N        1016 953 928 635 124




                                                                                                            181
                             VILI                                                                           VILI
                             .                                                                              .
                        .4                                               Co                            .4
                                                                                                                          Ou

                                                                                                            Mu     Ou           Ou
Test positiviity rate




                                                                               Test positiviity rate
                        .3          Ja           Ja                                                    .3                              Ou         Tr1   Tr1
                             Ja            Ja                                                                                                           Ni
                                                        Ja   Ja    Br    Br
                                                                                                                                      Tr1   Tr1
                                                                   Co                                                                                   Ko2
                                                                                                                                                        Mu
                                                                   Ja                                       Ou     Tr1    Mu
                        .2                                                                             .2   Tr1
                                                                                                            Tr2
                                                                                                                   Mu     Tr1   Tr1
                                                                                                                                Mu
                             Br     Br                       Co                                                                                   Ou
                                                                                                                                                  Ko2
                                                        Br   Br                                                    Tr2          Tr2
                                           Ba
                                           Br           Co                                                         Ko2    Ko2         Tr2   Ou          Tr2
                                    Ba           Br
                                                 Ba                Ba                                                     Tr2   Ko2   Ko2
                                                                                                                                      Mu
                             Ba            Co    Co          Ba                                                                             Tr2
                                                                                                                                            Mu
                                                        Ba                                                                Ni          Ni    Ko2   Mu
                                                                                                                                                  Ni
                                                                                                                                                  Tr2
                        .1          Co
                                                                                                       .1   Ni
                                                                                                                   Ni           Ni          Ni
                             Co


                        0                                                                              0
                             25     30     35    40     45   50    55    60                                 25     30     35    40     45   50    55    60
                                                 Age group                                                                      Age group
                             VIAM                                                                           HC2
                             .                                                                              .
                                                                                                            Ha
                        .5
                                                                                                                   Ha

                                                                                                                          Ha
                        .4                                                                             .4
Test positiviity rate




                                                                               Test positiviity rate
                                                                                                                                            Ha

                        .3                                                                             .3
                                                                                                                                Ha
                             Mu                                                                                                        Ha         Ha
                                    Ko1    Ko1                           Mu
                        .2                 Mu                                                          .2
                                    Mu
                                                                         Ko1
                                                                         Ko2
                                                 Mu
                                                 Ko1   Ko1
                                    Ko2    Ko2         Mu                                                                                               Ko2
                                                 Ko2   Ko2         Ko1                                                                            Mu    Ko1
                        .1                                   Mu
                                                             Ko1   Mu                                  .1          Mu
                                                                                                                   Tr2                Mu    Ko2   Tr2
                                                                                                                                                  Ko2   Mu
                                                             Ko2   Ko2                                      Tr2    Ko1    Tr2
                                                                                                                          Ko1
                                                                                                                          Mu    Mu
                                                                                                                                Tr2   Ko1
                                                                                                                                      Tr2   Tr2
                                                                                                                                            Ko1
                                                                                                                   Ko2    Ko2   Ko2
                                                                                                                                Ko1   Ko2   Mu    Ko1   Tr2
                                                                                                            Mu
                        0                                                                              0
                             25     30     35    40     45   50    55    60                                 25     30     35    40     45   50    55    60
                                                 Age group                                                                      Age group



Figure 15. Variation in test positivity rate of VILI, VIAM and HPV detection using the HC2 assay, by age
group and study setting. Settings are identified by the first 2 characters.

                             Cytology, ASCUS+                                                               Cytology, LSIL+
                             .                                                                              .
                        .4                                               Ko1                           .4
Test positiviity rate




                                                                               Test positiviity rate




                        .3   Ha     Ha
                                           Ha                Ha
                                                             Ko1                                       .3                                               Ko1
                                                                   Ko1
                                                 Ha
                                                                         Tr1
                        .2                             Ko1
                                                             Tr1
                                                                                                       .2                                         Ko1   Tr1
                                                 Ko1   Tr1                                                                            Tr1   Ko1
                                                                                                                                            Tr1
                                                 Tr1               Tr1                                                          Tr1               Tr1
                                                       Ha                                                   Ha            Ha
                                           Tr1                                                                     Ha     Tr1
                                           Ko1                     Ha
                             Tr1    Tr1                                                                                               Ko1   Ha
                        .1          Ko1
                                     Ja    Ja    Ja
                                                        Ja   Ja    Ja    Tr2
                                                                                                       .1   Tr1    Tr1          Ko1
                                                                                                                                Ha                Ja    Tr2
                                                                         Mu                                                      Ja         Ja          Mu
                                                             Tr2                                                          Ko1
                                                                   Mu
                                                                   Tr2                                              Ja
                                                                                                                   Ko1     Ja         Ja
                                                 Tr2
                                                 Mu    Tr2   Mu                                                                 Tr2   Tr2   Tr2
                                                                                                                                            Mu    Tr2
                                                                                                                                                  Mu
                             Ja     Tr2
                                    Mu     Tr2
                                           Mu          Mu                                                          Tr2          Mu    Ha
                                                                                                                                      Mu
                                                                                                                   Mu     Tr2
                                                                                                                          Mu
                             Tr2
                             Mu                                                                             Ja
                                                                                                            Tr2
                                                                                                            Mu                                    Ha
                        0                                                                              0
                             25     30     35    40     45   50    55    60                                 25     30     35    40     45   50    55    60
                                                 Age group                                                                      Age group
                             Cytology, HSIL+
                             .
                        .4
Test positiviity rate




                        .3


                        .2
                                                                         Ko1


                        .1                                   Ko1   Ko1
                                                                         Mu
                                                                         Tr1
                                                             Ha          Tr2
                                           Ha    Ha
                                                 Ko1   Ko1         Tr1
                             Ha
                             Tr1    Ha           Mu    Tr1   Mu
                                                             Tr1   Mu
                                                                   Tr2
                                    Tr1
                                    Tr2
                                    Ko1    Ko1
                                           Tr1
                                           Tr2
                                           Mu    Tr1
                                                 Tr2
                                                  Ja   Tr2
                                                       Mu
                                                       Ha
                                                        Ja   Tr2
                                                             Ja
                             Ja
                             Mu
                             Tr2     Ja
                                    Mu      Ja                     Ja
                                                                   Ha
                        0
                             25     30     35    40     45   50    55    60
                                                 Age group



Figure 16. Variation in test positivity rate of the Pap smear, defined at 3 different cutoffs (ASCUS+, LSIL+
and HSIL+) by age group and study setting. Settings are identified by the first 2 characters.




                                                                                                                                                        182
Table 35. Variation of the prevalence of HC2 positivity by 5-year age group in four Indian locations and in
Harare (computed only for groups representing at least 50 women). Variation is assessed statistically by
Pearson's chi-square test and a trend test.
                         5-year age group (first year of interval)
                                                                                              chi2   Trend Direction
Setting       Total        25    30    35    40    45    50                       55    60 (Pearson) test   trend
Kolkata 1 & 2 22737 % 4.8% 7.1% 6.7% 6.7% 6.7% 7.1%                            8.6% 12.2%        0.10 0.13
Mumbai,
Trivandrum 2         N     84 5979 4411 3302 2494 1346                           746     189
Harare          2206 % 49.7% 46.6% 39.9% 26.1% 22.7% 33.3%                                            0.00       0.00    -
                     N   884   489   398   245   110     63




6.5.2. Variation of the test positivity rate by time period

We subdivided the study subjects in three period groups based on the tertiles of the
screening date or the rank number in the Zimbabwe data file. The change of the test
positivity rate by time period and study location is shown in Figure 17. Important
significant period effects can be noticed for the visual screening methods. In general, the
positivity rate of VIA and VILI dropped over time.
The Hybrid Capture II positivity rate remained remarkably constant over time (see Table
36). In the Indian trials a significant but relatively weak period effect was observed. The
time trend of HC2 positivity in Harare was insignificant.

Changes in cytological positivity rates were less important than for the direct visual
methods but, nevertheless, the period variation was most often statistically significant.

Table 36. Change in prevalence of HC2 positivity by period in the Indian study location and Harare.
                                             Period
                                                                                chi2              Direction
Setting                  Total          1            2               3       (Pearson) Trend test  trend
Kolkata 1 & 2, Mumbai,
Trivandrum 2               18554          6.2%        7.3%            7.3%        0.03         0.03          +
Harare                      2199         44.5%       43.4%           40.1%        0.20         0.08




                                                                                                                   183
                             VIA                                                        VIA
                             .                                                          .
                             Br                                                         Ou
                                                                                   .4

                                                                                        Tr1
Test positiviity rate




                                                           Test positiviity rate
                        .4                                                         .3

                             Ko1                                                                                   Ou
                                                                                                                   Tr1
                              Ja
                        .3
                                      Ja                                           .2                      Ou
                                                                                                           Tr1
                                                     Ja                                                            Ko2
                        .2   Ba                                                         Mu                         Mu
                             Co                     Ko1                                                    Mu
                                                                                                           Ko2
                                                    Br
                                     Ko1
                                     Br                                            .1   Ko2
                        .1           Ba              Ba
                                                                                        Ni
                                                                                                            Ni     Ni
                                     Co
                                                     Co
                        0                                                          0
                             1        2              3                                  1                   2      3
                                    Period                                                                Period
                             VIA                                                        VILI
                             .                                                          .
                                      Ha             Ha                            .4
                        .4
                                                                                        Ja
Test positiviity rate




                                                           Test positiviity rate
                             Ha                                                    .3                       Ja
                        .3
                                                                                                                   Ja
                                      Bu
                             Bu                                                         Ba
                                                                                   .2   Co
                        .2                                                                                  Br     Br
                                                     Bu                                 Br
                             Tr2     Tr2
                             Am                      Tr2                                                    Co
                                                                                                            Ba
                        .1           Am
                                                     Am                            .1                              Ba
                                                                                                                   Co


                        0                                                          0
                             1        2              3                                  1                   2      3
                                    Period                                                                Period



                             VILI                                                       VIAM
                             .                                                          .
                             Ou
                                                                                   .5
                        .4
                                                                                   .4
Test positiviity rate




                                                           Test positiviity rate




                        .3   Tr1

                                                     Ou
                                                                                   .3   Ko1

                        .2   Mu       Ou            Tr1
                                                    Mu
                                                    Ko2
                             Tr2     Tr1
                                     Tr2
                                                                                   .2
                                     Mu
                                     Ko2                                                Mu                         Mu
                             Ko2                     Tr2                                                   Mu      Ko2
                                                                                                                   Ko1
                                                                                                           Ko1
                             Ni                      Ni                                                    Ko2
                        .1            Ni                                           .1   Ko2


                        0                                                          0
                             1        2              3                                  1                   2      3
                                    Period                                                                Period
                             HC2                                                        Cytology, LSIL+
                             .                                                          .
                             Ha
                                      Ha                                           .4
                                                     Ha
                        .4
Test positiviity rate




                                                           Test positiviity rate




                                                                                   .3
                        .3

                                                                                   .2
                        .2
                                                                                                           Ha
                                                                                                           Tr1     Tr1
                                                                                        Tr1
                                                                                        Ha
                                                                                         Ja
                                                                                        Ko1
                                                                                                                   Ha
                        .1           Mu
                                                                                   .1
                             Tr2     Ko1            Ko1
                                                    Mu
                                                    Ko2
                                     Tr2            Tr2                                                    Ko1     Ko1
                             Mu
                             Ko2     Ko2                                                                   Tr2
                                                                                        Tr2
                                                                                        Mu
                             Ko1                                                                            Ja
                                                                                                           Mu      Mu
                                                                                                                   Tr2
                                                                                                                   Ja
                        0                                                          0
                             1        2              3                                  1                   2      3
                                    Period                                                                Period


Figure 17. Variation of the test positivity rate by period and by study location.




                                                                                                                   184
6.5.3. Influence of age, period and study setting on the PPV

We used a logistic model to assess the impact of age group, time period (defined by the
tertiles of the screening date), and study location on the positive predictive value,
considering CIN2 or worse disease as outcome.

In Table 37, we show the results of the logistic regression describing the relation of the
PPV of VIA for CIN2+. It shows, first of all, the PPV0 for the base case, this means the
fitted PPV in age group 30-34, in the first period in Bamako is 13%.
Table 37. Multivariate variation of the PPV for CIN2+ of VIA by age group, period and study location.

               Basic PPV                   13.3%
               Age groupa        RR            95% CI
               30                  1
               35                1.07       0.93      1.22
               40                1.26       1.09      1.46
               45                1.41       1.20      1.65
               50                1.61       1.32      1.94
               55                2.54       2.12      3.00
               60                2.64       2.00      3.35
               Period            RR             95% CI
               1                   1
               2                 1.49       1.33      1.68
               3                 1.87       1.68      2.07
               Setting           RR             95% CI
               Bamako              1
               Brazzaville       0.77       0.62        0.95
               Conakry           1.00       0.79        1.26
               Jaipur            0.16       0.11        0.23
               Kolkata 1         0.42       0.32        0.55
               Kolkata 2         0.22       0.16        0.31
               Mumbai            0.36       0.26        0.51
               Niamey            0.36       0.20        0.64
               Ouagadougou       0.42       0.29        0.59
               Trivandrum 1      0.43       0.33        0.55
               Trivandrum 2      0.41       0.30        0.56
               Harare            0.67       0.50        0.88
               Ambilikai         0.41       0.33        0.51

The PPV increases with age and period. The change by period was significant. The PPV of
VIA was highest in Bamako, Brazzaville and Conakry. The interaction between setting and
age was significant. However for simplicity we only showed the main effects.

We can compare the relative risks for the study locations with the forest plot showing the
meta-analysis of the PPV of VIA for CIN2+ presented in chapter 6.1.1. To assist the reader
we redisplay this forest plot below.


a
 Women of 20-24 years were excluded from the logistic regression since this age group was not enrolled in
all studies.


                                                                                                        185
                VIA, Outcome=CIN2+


     Bamako
  Brazzaville
     Conakry
       Jaipur
    Kolkata 1
    Kolkata 2
     Mumbai
     Niamey
Ouagadougou
Trivandrum 1
Trivandrum 2
      Harare
    Ambilikai
       Busia

    Combined
                  0            .1            .2           .3            .4            .5   .6
                                                         PPV

Figure 18. Forest plot showing the PPV of VIA for CIN2+ observed in 14 study locations.


The results from the logistic regression targeting the PPV of the other tests are shown in
Table 38,Table 39 and Table 40. Remark that the PPV of the HC2, contrary to the other
tests, does not vary by period.




                                                                                             186
Table 38. Multivariate variation of the PPV for CIN2+ of VILI by age group, period and study location

                     Basic PPV                      16.0%
                     Age group           RR             95% CI
                     30                    1
                     35                  1.16        0.97      1.36
                     40                  1.32        1.11      1.55
                     45                  1.41        1.18      1.68
                     50                  1.45        1.16      1.79
                     55                  2.13        1.73      2.57
                     60                  2.08        1.50      2.75
                     Period              RR              95% CI
                     1                     1
                     2                   1.20        1.05      1.37
                     3                   1.40        1.22      1.59
                     Setting             RR              95% CI
                     Bamako                1
                     Brazzaville         1.45        1.22        1.72
                     Conakry             0.70        0.56        0.87
                     Jaipur              0.14        0.10        0.20
                     Kolkata 2           0.20        0.14        0.27
                     Mumbai              0.33        0.24        0.45
                     Niamey              0.33        0.20        0.53
                     Ouagadougou         0.40        0.29        0.56
                     Trivandrum 1        0.52        0.41        0.67
                     Trivandrum 2        0.35        0.26        0.48


Table 39. Multivariate variation of the PPV for CIN2+ of the HC2 test by age group, period and study
location

                      Basic PPV                        7.9%
                      Age group           RR         Upper       lower
                      30                   1
                      35                  1.04        0.74        1.45
                      40                  1.73        1.23        2.39
                      45                  1.17        0.74        1.81
                      50                  1.14        0.65        1.92
                      55                  1.78        0.97        3.08
                      60                  3.05        1.35        5.81
                      Period              RR         Upper       lower
                      1                    1
                      2                   0.98        0.71        1.34
                      3                   0.95        0.69        1.30
                      Setting             RR         Upper       lower
                      Kolkata 1            1
                      Kolkata 2           1.14        0.71        1.77
                      Mumbai              1.62        1.02        2.50
                      Trivandrum 2        1.80        1.15        2.72
                      Harare              2.18        1.47        3.13




                                                                                                        187
Table 40. Multivariate variation of the PPV for CIN2+ of cytology (at cutoff LSIL+) by age group, period
and study location.

                      Basic PPV                       4.6%
                      Age group            RR             95% CI
                      30                     1
                      35                  0.81        0.53      1.24
                      40                  1.51        1.01      2.23
                      45                  1.17        0.74      1.82
                      50                  1.08        0.64      1.77
                      55                  1.68        0.97      2.85
                      60                  1.73        0.89      3.25
                      Period               RR             95% CI
                      1                      1
                      2                   1.10        0.81      1.50
                      3                   1.19        0.87      1.61
                      Setting              RR             95% CI
                      Jaipur                 1
                      Kolkata 1            2.02       1.11        3.55
                      Mumbai              10.67       6.90       14.48
                      Trivandrum 1        3.24        1.86        5.36
                      Trivandrum 2        6.78        4.05       10.28
                      Harare               7.00       4.22       10.50




                                                                                                       188
6.5.4. Influence of study characteristics on the sensitivity and
       specificity of screen tests

The effect of the 5-year age group (restricted to women between 30 and 64), the study
phase (1, 2 or 3) or the study location on sensitivity and specificity was explored using
logistic regression. The sensitivity did not vary by age. A period effect was noticed for
VIA, with higher sensitivity in the third study phase. The sensitivity always differed by
study location. Almost all effects are significant when prediction of absence of disease
(specificity) is explored. There was one exception, the specificity of HC2 was not
influenced by study phase. As already noticed by exploring the forest plots, we notice also
here a simultaneously outlying high sensitivity and specificity in Conakry and the opposite
low sensitivity and specificity are found in Kolkata 1 and Mumbai.
For VILI, we remark simultaneous low sensitivity and specificity in Kolkata 1 & 2,
Mumbai and Trivandrum II. The sensitivity of HC2 was considerably higher in Harare,
compared with the Indian settings.

Table 41. Variation of the sensitivity (at left) and specificity (at right) of VIA for presence or absence of
CIN2+, according to age group, period or study setting, assessed by multivariate logistic regression. Non-
significant effects are omitted.
VIA, accuracy for CIN2+
Basic sensitivity                 75.8%                     Basic specificity                 84.8%
Age group               RR           95% CI                 Age group            RR              95% CI
30                                                          30                   1.00
35                                                          35                   1.01        1.00       1.02
40                                                          40                   1.02        1.01       1.03
45                                                          45                   1.02        1.01       1.03
50                                                          50                   1.03        1.02       1.04
55                                                          55                   1.03        1.01       1.05
60                                                          60                   0.98        0.94       1.02
Period                  RR           95% CI                 Period               RR              95% CI
1                          1                                1                      1
2                       1.03     0.96        1.10           2                    1.09        1.09       1.10
3                       1.14     1.08        1.18           3                    1.09        1.08       1.09
Setting                 RR            95%                   Setting              RR              95% CI
Bamako                     1                                Bamako                 1
Brazzaville             0.98     0.85        1.08           Brazzaville          0.75        0.72       0.78
Conakry                 1.17     1.07        1.24           Conakry              1.05        1.03       1.06
Jaipur                  1.10     0.89        1.22           Jaipur               0.75        0.72       0.78
Kolkata 1               0.77     0.61        0.92           Kolkata 1            0.85        0.83       0.88
Kolkata 2               0.87     0.67        1.04           Kolkata 2            0.98        0.96       1.00
Mumbai                  0.71     0.52        0.90           Mumbai               0.95        0.92       0.97
Niamey                  0.79     0.47        1.06           Niamey               1.07        1.05       1.09
Ouagadougou             1.20     1.01        1.28           Ouagadougou          0.70        0.66       0.74
Trivandrum 1            1.13     1.00        1.21           Trivandrum 1         0.77        0.74       0.80
Trivandrum 2            0.99     0.80        1.13           Trivandrum 2         0.96        0.94       0.99
Harare                  0.88     0.70        1.03           Harare               0.57        0.53       0.62




                                                                                                            189
Table 42. Variation of the sensitivity and specificity of VILI for presence or absence of CIN2+, according to
age group, period or study setting, assessed by multivariate logistic regression.
Sensitivity and specificity of VILI for CIN2+            VILI
Basic sensitivity                   97.0%                Basic specificity                 86.7%
Age group                 RR         95% CI              Age group           RR              95% CI
30                                                       30                    1
35                                                       35                  0.99        0.98      1.00
40                                                       40                  1.00        0.99      1.01
45                                                       45                  1.01        0.99      1.02
50                                                       50                  1.01        1.00      1.03
55                                                       55                  1.01        0.99      1.02
60                                                       60                  0.92        0.87      0.96
Period                    RR         95% CI              Period              RR              95% CI
1                                                        1                   1.00
2                                                        2                   1.04        1.04      1.05
3                                                        3                   1.04        1.04      1.05
Setting                   RR         95% CI              Setting             RR              95% CI
Bamako                     1                             Bamako                1
Brazzaville               0.98     0.90    1.01          Brazzaville         1.00        0.98        1.01
Conakry                   1.00     0.93    1.02          Conakry             1.01        0.99        1.02
Jaipur                    0.89     0.68    0.98          Jaipur              0.79        0.76        0.81
Kolkata 2                 0.84     0.62    0.96          Kolkata 2           0.96        0.94        0.98
Mumbai                    0.76     0.51    0.91          Mumbai              0.93        0.90        0.95
Niamey                    0.93     0.64    1.01          Niamey              1.03        1.01        1.05
Ouagadougou               1.01     0.86    1.03          Ouagadougou         0.75        0.71        0.79
Trivandrum 1              0.94     0.80    1.00          Trivandrum 1        0.89        0.86        0.91
Trivandrum 2              0.82     0.60    0.95          Trivandrum 2        0.96        0.94        0.98


Table 43. Variation of the sensitivity and specificity of the Hybrid Capture II assay for presence or absence
of CIN2+, according to age group, period or study setting, assessed by multivariate logistic regression.
Sensitivity and specificity of HC2 for CIN2+             HC2
Basic sensitivity                   48.4%                Basic specificity                 91.3%
RR                        RR         95% CI              Age group           RR              95% CI
30                                                       30                    1
35                                                       35                  1.01        1.00      1.02
40                                                       40                  1.03        1.01      1.04
45                                                       45                  1.02        1.01      1.03
50                                                       50                  1.01        0.99      1.03
55                                                       55                  1.00        0.97      1.02
60                                                       60                  0.97        0.90      1.01
Period                    RR         95% CI              Period              RR              95% CI
1                                                        1
2                                                        2
3                                                        3
Setting                   RR         95% CI              Setting             RR              95% CI
Kolkata 1                 1.00                           Kolkata 1             1
Kolkata 2                 1.15    1.02     1.23          Kolkata 2           1.03        1.02        1.04
Mumbai                    1.13    0.99     1.22          Mumbai              1.02        1.00        1.03
Trivandrum 2              1.13    1.00     1.22          Trivandrum 2        1.03        1.02        1.04
Harare                    1.24    1.17     1.28          Harare              0.70        0.66        0.74



                                                                                                            190
Table 44. Variation of the sensitivity and specificity of the Pap smear (at cutoff LSIL+) for presence or
absence of CIN2+, according to age group, period or study setting, assessed by multivariate logistic
regression.
Sensitivity and cytology at LSIL+ for CIN2+              Cytology, LSIL+
Basic sensitivity                 16.6%                  Basic specificity                 94.8%
Age                      RR        95% CI                Age group              RR           95% CI
30                        1                              30                      1
35                      0.46    17.24    0.90            35                     0.98     0.97      0.99
40                      1.01     0.82    1.10            40                     0.97     0.95      0.98
45                      0.96     0.56    1.09            45                     0.96     0.95      0.98
50                      1.01     0.65    1.12            50                     0.94     0.92      0.96
55                      1.00     0.55    1.12            55                     0.95     0.92      0.97
60                      1.07     0.61    1.17            60                     0.88     0.83      0.93
Period                   RR        95% CI                Period                 RR           95% CI
1                                                        1                       1
2                                                        2                      1.03     1.02      1.03
3                                                        3                      1.03     1.02      1.03
Setting                  RR        95% CI                Setting                RR           95% CI
Jaipur                    1                              Jaipur                  1
Kolkata 1               0.72    13.43    1.03            Kolkata 1              0.97     0.96        0.98
Mumbai                  1.05     0.78    1.14            Mumbai                 1.05     1.04        1.05
Trivandrum 1            1.15     1.07    1.19            Trivandrum 1           0.94     0.92        0.96
Trivandrum 2            1.07     0.85    1.15            Trivandrum 2           1.04     1.03        1.04
Harare                  1.05     0.79    1.14            Harare                 0.96     0.93        0.98




                                                                                                            191
6.5.5. Influence of study characteristics on the diagnostic odds ratio
       using multi-variate SROC-regression analysis

The logistic regression allowed us to assess the influence of study characteristics on each
dichotomous diagnostic parameter separately. By using sROC-regression we can evaluate
the impact of covariates simultaneously on sensitivity, specificity and overall accuracy.
The sROC regression analysis is restricted to the same study covariates assessed in the
previous sub-chapters, which are available for all included studies: 5-year age group, the
study phase (study period subdivided in tertiles), and the study location.

In Table 45 we show the coefficients of significant terms included in the linear sROC
regression equation describing the relation between D and S (which are the difference [D]
and the sum [S] of the logits of the true and false positivity rates). We only document the
accuracy of VIA, VILI, HC2 and cytology (at the cutoff LSIL) for CIN2+. Interested
readers can contact us to obtain tables concerning the accuracy of VIAM, cytology at other
cutoffs, and the accuracy for other outcomes.

The prediction of presence or absence of CIN2+ was influenced significantly by the study
phase and study location when VIA, VILI, VIAM or cytology was used. The age group
never influenced test accuracy. The HC2 assay was the only screening test whose accuracy
did not vary significantly by study period.

Table 45. Coefficients of terms included in the sROC regression equation, t-test for significance of the
hypothesis that coefficients are zero and 95% confidence interval around the estimate of the coefficient.
VIA, reference setting = Bamako
Term                 Coef.    Std.er           t          P>t             (95% CI)
S                        0.26    0.05           4.75            0.00      0.15        0.37
Period 2                 0.83    0.16           5.05            0.00      0.50        1.15
Period 3                 1.04    0.16           6.69            0.00      0.74        1.35
Brazzaville             -1.22    0.37          -3.28            0.00     -1.96       -0.48
Conakry                  0.98    0.43           2.29            0.02      0.13        1.84
Jaipur                  -2.21    0.50          -4.39            0.00     -3.20       -1.21
Kolkata 1               -1.51    0.37          -4.10            0.00     -2.24       -0.78
Kolkata 2               -0.94    0.41          -2.29            0.03     -1.76       -0.12
Mumbai                  -1.34    0.37          -3.65            0.00     -2.07       -0.61
Niamey                   0.11    0.54           0.20            0.85     -0.97        1.18
Ouagadougou             -1.34    0.63          -2.14            0.04     -2.59       -0.10
Trivandrum 1            -1.71    0.42          -4.02            0.00     -2.55       -0.86
Trivandrum 2            -0.50    0.44          -1.12            0.26     -1.37        0.38
Harare                  -2.69    0.43          -6.22            0.00     -3.55       -1.83
Intercept                3.24    0.30          10.70            0.00      2.64        3.85




                                                                                                            192
VILI, reference country = Burkina Faso
Term                         Coef.        Std.er       t           P>t     95% CI
S                                0.38          0.10         3.65    0.00 0.17 0.59
Period 2                         0.46          0.28         1.64    0.11 -0.10 1.02
Period 3                         0.73          0.25         2.87    0.01 0.22 1.24
Congo                            2.41          0.88         2.75    0.01 0.65 4.17
Guinea                           2.10          0.94         2.22    0.03 0.20 3.99
India                            0.67          0.89         0.75    0.46 -1.12 2.45
Mali                             2.44          0.91         2.66    0.01 0.60 4.27
Niger                            2.30          1.10         2.08    0.04 0.08 4.51
Constant                         1.74          0.85         2.06    0.04 0.05 3.44

VIAM, reference setting = Kolkata 1
Term                         Coef.        Std.er       t           P>t     95% CI
S                                0.11          0.11         0.99    0.33 -0.12 0.34
Period 2                         0.46          0.24         1.96    0.06 -0.02 0.95
Period 3                         0.59          0.25         2.38    0.02 0.08 1.10
Kolkata 2                        0.63          0.26         2.42    0.02 0.10 1.16
Mumbai                          -0.03          0.23        -0.15    0.88 -0.50 0.43
Constant                         2.15          0.25         8.60    0.00 1.64 2.66

HC2 (reference setting = Kolkata 1)
Term                          Coef.       Std.er       t           P>t      95% CI
S
Kolkata 2                         0.94         0.34         2.78   0.01 0.25 1.62
Mumbai                            0.40         0.33         1.22   0.23 -0.27 1.08
Trivandrum 2                      0.88         0.31         2.81   0.01 0.25 1.52
Harare                           -2.69         0.53        -5.09   0.00 -3.75 -1.62
Constant                          4.48         0.43        10.39   0.00 3.61 5.35



Cytology at cutoff LSIL+ (reference setting=Jaipur)
Term                          Coef.        Std.er      t           P>t       95% CI
S                                 0.19          0.10        1.91    0.06   -0.01 0.38
Period 2                          0.55          0.28        1.92    0.06   -0.02 1.12
Period 3                          0.76          0.28        2.68    0.01    0.19 1.33
Kolkata 1                        -1.41          0.45       -3.10    0.00   -2.31 -0.50
Mumbai                            1.87          0.47        3.97    0.00    0.92 2.81
Trivandrum 1                     -0.39          0.51       -0.77    0.44   -1.42 0.63
Trivandrum 2                      1.59          0.46        3.49    0.00    0.68 2.51
Harare                           -0.85          0.49       -1.73    0.09   -1.83 0.14
Constant                          3.31          0.51        6.52    0.00    2.29 4.33

The interpretation of the sROC-regression coefficients is not straightforward. Let us take
the example of the first table concerning VIA. The coefficient of the S term is different
from zero. This means that the accuracy (diagnostic odds ratio=DOR) depends on a latent
cutoff even when in theory VIA is a dichotomous test. The accuracy of VIA in the first
period in Bamako is taken as reference. The diagnostic odds ratio increases in the second
and third period. This means that the area under the sROC curve is greater in last two


                                                                                         193
periods than in the first period. The accuracy of VIA (DOR) is greater in Conakry and
Niamey than in Bamako. In the other settings, the DOR is lower. The relative size of an
effect can be computed by taking the anti-log of the effect. For instance: the DOR in
Conakry is e0.98= 2.7 (95% CI: e0.13 or 1.1 to e1.84 or 6.3).


6.6. Correlations between tests

The rank correlation between the respective evaluated screening tests is shown in Table 46.
Table 46. Correlation between screening tests and colposcopy assessed with the rank correlation coefficient
of Spearman. (*Spearman coefficient not significantly different from 0).
                   VIA         VILI       VIAM         HC2      Cytology Colposcopy
VIA                 -          0.83        0.86       0.07*      0.18*      0.36
VILI                -            -         0.63       -0.02*      0.11      0.74
VIAM                -            -           -         0.04       0.08      0.64
HC2                 -            -           -           -        0.16      0.21
Cytology            -            -           -           -          -       0.11
Colposcopy          -            -           -           -          -         -

The degree of correlation is high to very high for all visual testing methods: VIAM, VILI,
VIAM and colposcopy. The correlations between the other tests are substantially lower.
The coefficients of correlation between HC2 and VIA, between HC2 and VILI, and
between cytology (LSIL+) and VIA were not significantly different from zero.



6.7. PPV of colposcopy triage

Using a "see & treat strategy", requires treatment of all eligible VIA-positive women. This
strategy was applied in Ghana and Thailand. In all other settings a "see-triage-treat"
strategy was applied using colposcopy to decide which women to treat.
The forest plot of the colposcopy positivity rate among VIA-positive women ,defined at
low- and high-grade colposcopy, is shown in Figure 19. The pooled "low-grade+" rate was
64.7% (CI: 53.4% to 76.1%). The rate varied over a broad range. The two outlying high
rates were at Jaipur (92%) and Ambilikai (93%). The positivity rate defined at high-grade
or worse was substantially lower and varied less; its pooled value was 18.4% (CI: 14.7% to
22.0%).
The PPVs of a low-grade colposcopy result for the four outcomes CIN1+, CIN2+, CIN3+
and cancer are shown in Figure 20. For comparison, we also show the PPV of VIA
without colposcopy triage. By adding colposcopy triage the PPV is increased by 59%, 13%
and 62% when the outcomes CIN2+, CIN3+ or cancer respectively are considered.




                                                                                                        194
Table 47. PPV of VIA and of VIA followed by colposcopy, where the cutoff for a positive colposcopy result
is determined at low-grade or worse.

                     VIA           VIA + & colposcopy triage
Outcome     PPV        95% CI       PPV        95% CI            Ratio      95% CI
CIN1+         30.6    21.1    40.0    45.3    32.5       18.1     1.48     1.54    0.45
CIN2+         11.8     9.1    14.6    18.8    13.5       24.0     1.59     1.48    1.64
CIN3+          5.3     4.0     6.6     6.0     4.1        7.8     1.13     1.03    1.18
Cancer         2.1     1.6     2.5     3.4     2.4        4.5     1.62     1.50    1.80




                                                                                                     195
Figure 19. Meta-analysis of the test positivity rate for colposcopy, applied to VIA-positive women, defined
as low-grade colposcopy or worse (at left) or high-grade colposcopy (at right).

                Colposcopy at cut-off low-grade                                            Colposcopy at cut-off high-grade
                Among VIA+ women                                                           Among VIA+ women

     Bamako                                                                     Bamako
  Brazzaville                                                                Brazzaville
     Conakry                                                                    Conakry
       Jaipur                                                                     Jaipur
    Kolkata 1                                                                  Kolkata 1
    Kolkata 2                                                                  Kolkata 2
     Mumbai                                                                     Mumbai
     Niamey                                                                     Niamey
Ouagadougou                                                                Ouagadougou
Trivandrum 1                                                               Trivandrum 1
Trivandrum 2                                                               Trivandrum 2
      Harare                                                                     Harare
    Ambilikai                                                                  Ambilikai
       Busia                                                                      Busia
   Combined                                                                   Combined
                0     .1   .2    .3   .4    .5     .6   .7   .8   .9   1                   0     .1   .2    .3   .4    .5     .6   .7   .8   .9    1
                                      Positivity rate                                                            Positivity rate




Meta-analysis of the colposcopy test positivity rate (low-grade+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.792   0.786   0.798 254.401     0.000     14
Random |   0.647   0.534   0.761   11.206    0.000
Test for heterogeneity: Q= 3703.764 on 13 degrees of freedom (p= 0.000)


Meta-analysis of the colposcopy test positivity rate (high-grade+)
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.163   0.157   0.170   51.762    0.000     14
Random |   0.184   0.147   0.220    9.790    0.000




                                                                                                                                                  196
Figure 20. PPV of low-grade colposcopy applied to VIA-positive women for presence of CIN1+, CIN2+,
CIN3+ or cancer.
                Colposcopy at cut-off low-grade, outcome=CIN1+                            Colposcopy at cut-off low-grade, outcome=CIN2+
                Among VIA+ women                                                          Among VIA+ women

     Bamako                                                                    Bamako
  Brazzaville                                                               Brazzaville
     Conakry                                                                   Conakry
       Jaipur                                                                    Jaipur
    Kolkata 1                                                                 Kolkata 1
    Kolkata 2                                                                 Kolkata 2
     Mumbai                                                                    Mumbai
     Niamey                                                                    Niamey
Ouagadougou                                                               Ouagadougou
Trivandrum 1                                                              Trivandrum 1
Trivandrum 2                                                              Trivandrum 2
      Harare                                                                    Harare
    Ambilikai                                                                 Ambilikai
       Busia                                                                     Busia
   Combined                                                                  Combined
                0    .1   .2    .3   .4    .5 .6     .7   .8     .9   1                   0    .1    .2   .3   .4    .5   .6   .7    .8     .9    1
                                          PPV                                                                       PPV
                Colposcopy at cut-off low-grade, outcome=CIN3+                            Colposcopy at cut-off low-grade, outcome=Cancer
                Among VIA+ women                                                          Among VIA+ women

     Bamako                                                                    Bamako
  Brazzaville                                                               Brazzaville
     Conakry                                                                   Conakry
       Jaipur                                                                    Jaipur
    Kolkata 1                                                                 Kolkata 1
    Kolkata 2                                                                 Kolkata 2
     Mumbai                                                                    Mumbai
     Niamey                                                                    Niamey
Ouagadougou                                                               Ouagadougou
                                                                          Trivandrum 1
Trivandrum 1                                                              Trivandrum 2
Trivandrum 2                                                                    Harare
    Ambilikai                                                                 Ambilikai
       Busia                                                                     Busia
   Combined                                                                  Combined
                 0   .1    .2   .3   .4    .5   .6   .7   .8     .9   1                   0     .1   .2   .3   .4    .5   .6   .7    .8     .9    1
                                          PPV                                                                       PPV



Meta-analysis of the PPV of low-grade colposcopy for CIN1+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.436   0.427   0.445   94.046    0.000     14
Random |   0.453   0.325   0.581    6.928    0.000
Test for heterogeneity: Q= 2355.179 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of low-grade colposcopy for CIN2+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.103   0.097   0.109   33.758    0.000     14
Random |   0.188   0.135   0.240    7.038    0.000
Test for heterogeneity: Q= 800.461 on 13 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of low-grade colposcopy for CIN3+
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.034   0.031   0.038   17.868    0.000     13
Random |   0.060   0.041   0.078    6.435    0.000
Test for heterogeneity: Q= 203.365 on 12 degrees of freedom (p= 0.000)

Meta-analysis of the PPV of low-grade colposcopy for cancer
       | Pooled       95% CI         Asymptotic      No. of
Method |     Est   Lower   Upper z_value p_value     studies
-------+----------------------------------------------------
Fixed |    0.010   0.008   0.012    9.889    0.000     14
Random |   0.034   0.024   0.045    6.343    0.000
Test for heterogeneity: Q= 207.181 on 13 degrees of freedom (p= 0.000)




                                                                                                                                                 197
6.8. Treatment of VIA-positive cases

The data file containing results from the Zimbabwe trial did not contain treatment
information. Some treatment data were available for the multi-center cross-sectional study,
but these were incomplete and lacked for some settings. Therefore, we considered only
four studies (Ambilikai, Busia, Roi-Et and Accra) to evaluate treatment rate and
compliance.
Table 48 shows the number of women per category of final cervical status and the
percentage of them that was treated. More than 80% of women with known CIN2+ status
in Ambilikai and Busia got treatment. In Thailand and Ghana more than 90% of VIA-
positive women were treated. In Ambilikai 91% of treated women received cryotherapy.

Table 48. Percentage of women treated per final cervical status and per setting.
                Ambilikai               Busia              Roi-Et                  Accra
Final status   N % treated         N      % treated    N     % treated     N       % treated
CIN 1          1745    72.1%           68     80.9%
CIN 2           153    81.7%           19     94.7%
CIN 3            71    81.7%           10     80.0%
Cancer           67    80.6%            2      0.0%
VIA+                                                    798      92.5%      484          90.3%



Table 49 shows the proportion of women treated with cryotherapy who received screening
and treatment on the same day. This percentage was very low in Kenya, since women had
to be referred to the hospital for further diagnosis, which was sometimes at a considerable
distance from the health centers where VIA screening took place. In the other settings
between 71% and 82% received cryotherapy the same day.

Table 49. Percentage of women receiving cryotherapy, treated the same day as VIA screening
                                     % same
                         N treated day
               Ambilikai        2355     76.7%
               Busia             116      3.4%
               Roi-Et            738     82.2%
               Accra             437     70.5%



The experiences of women and the occurrence of secondary effects of cryotherapy are
documented in detail in the Thai and Ghanaian demonstration projects, summarized in
Table 17 and Table 19. The main issues of the interviews are further summarized in Table
50.

It can be concluded that cryotherapy offered to VIA-positive women the same day as
screening is highly accepted and quite safe. Pain during or just after cryotherapy was the
most noticed secondary effect (40% in Thailand, 23% in Ghana), which was most often
mild (79% in Roi-Et and 86% in Accra). Only in 2% in Roi-Et and 3% in Accra was pain
considered severe. In 2% of treated women some minor blood loss occurred. In Thailand,
83% and 93% of treated women presented at the follow-up visits at 3 and 12 months,
respectively, after treatment. In Ghana these proportions were 77% and 55%.


                                                                                                 198
199
Table 50. Main answers extracted from the Thai and Ghanaian treatment questionnaire (see Table 17 and
Table 19).

                                                                      Thailand         Ghana
Question                          Definition of the denominator (N)      N     Percent   N   Percent
Experience about testing
Satisfaction about being tested   Tested woman                            5742     99.9%     3621       79.8%
Woman will recommend VIA
testing to others                 Women with negative VIA result          5122     99.8%     3115       99.2%

Experience at the moment of treatment
Pain reported by provider      Treated women                               756     39.6%      412        22.6%
Pain was mild                  Treated women reporting pain                290     79.0%       90        85.6%
Pain was moderate              Treated women reporting pain                290     18.3%       90        12.2%
Pain was severe                Treated women reporting pain                290      2.8%       90         2.2%
An analgesic drug was given    Treated women reporting pain                746      6.2%      422         1.7%
Bleeding after cryo            Treated women                               748      1.7%      400         2.0%
Bleeding was mild              Treated women reporting bleeding             11    100.0%        5       100.0%

Problem visit of a health structure
Women contacted health service
after cryo                       Treated women                             756      4.4%      439        1.1%
                                 Women having contacted a health
The visit: related to the cryo   service                                    33     21.2%         -           -
Reason of problem visit:         Women having contacted a health
bleeding related to menses       service                                    33      9.1%         -           -
Reason of problem visit:         Women having contacted a health
bleeding unrelated to menses     service                                    33     12.1%         -           -
Reason of problem visit:
pain/cramping unrelated to       Women having contacted a health
menses                           service                                    33     27.3%         -           -
Reason of problem visit was:     Women having contacted a health
abnorm vaginal discharge         service                                    34     44.1%         -           -
Reason of problem visit:         Women having contacted a health
chills/hot sweats/fever          service                                    35      2.9%         -           -
Reason of problem visit: another Women having contacted a health
problem                          service                                    36      2.8%         -           -

Planned follow-up visit at 3 months
Attended at the visit           Treated women                              756     83.2%      439       77.2%
Had pain or cramping not        Treated women presenting at 3M FU
associated with menses          visit                                      626     13.6%      316       10.1%
Less menstrual blood loss since
cryo                            Treated women at 3M FU visit               552      5.6%      337        5.9%
More menstrual blood loss since
cryo                            Treated women at 3M FU visit               552      4.3%      337       14.5%
Shorter menses                  Treated women at 3M FU visit               552      4.3%      337        5.0%
Longer menses                   Treated women at 3M FU visit               552      3.1%      337       11.0%
More cramping                   Treated women at 3M FU visit               552     10.0%      337        8.0%
Less cramping                   Treated women at 3M FU visit               552      1.4%      337        9.5%
Abnormal vaginal discharge      Treated women at 3M FU visit               628      0.5%      310        5.5%
Woman will recommend VIA
testing to others               Treated women at 3M FU visit               627     97.9%      335       98.5%




                                                                                                     200
                                                                   Thailand         Ghana
Question                       Definition of the denominator (N)      N     Percent   N   Percent




Compliance with recommendation concerning sexual hygiene
Woman had sex within 4W post-
treatment                      Treated women at 3M FU visit            459    30.9%   229    14.4%
No condom use if sex within 4W
post-treatment                 Having had sex <4W post-treatment       142    10.6%    32     3.1%
Condom use all the time if sex
within 4W post-treatment       Having had sex <4W post-treatment       142    79.6%    30    86.7%


Planned follow-up at 12 months after treatment
Attended at follow-up         Treated women                            756    93.5%   439    54.9%
Suspect for cancer at VIA     Treated women, attending at 12
examination                   month visit                              704     0.1%   232     0.0%

VIA positive                   Treated women, at 12 month visit        704     5.7%   232     2.6%




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7. Discussion

The ACCP trials have provided a mass of new data, which we have tried to pool and to
synthesize using meta-analytical methods.

We can conclude the following:

VILI was 10% more sensitive as a screening test than VIA, but had the same specificity;
therefore, it seems to be the preferred visual inspection method to detect high-grade CIN in
developing countries. This quite spectacular result was only documented in one study, but
it was a very large one involving multiple centers. The good triage results of VILI,
compared to VIAM and cytology, reported in the Kenyan study give some corroboration.
Nevertheless, it is recommended to conduct more research, by unrelated researchers to
confirm the findings of the cross-sectional multi-center study conducted by IARC.

The inter-study variation of VIA accuracy parameters was very wide, which might reflect
its low reproducibility . This is further suggested by the inconsistent relation between VIA
positivity and age. The accuracy of VIA increased significantly by study period. It also
increased in Trivandrum II and Kolkata II, where the examinations were done by the same
teams as in Trivandrum 1 and Kolkata 1. These findings suggest an impact of experience,
training and supervision.

VIAM requires an additional device but does not show better test characteristics than VIA.
Therefore, in low-resource settings, VILI and VIA appear to be preferable screening
methods.

The significant correlation between all visual screening methods (VIA, VIAM, VILI) with
colposcopy, which is intrinsically integrated in the gold standard definition, may have
contributed to inflating their sensitivity and specificity.

The hybrid capture II showed an unexpectedly low sensitivity (66%) for high-grade CIN in
the five Indian settings. There are not many publications where the accuracy of HC2 is
documented without verification bias in developing countries. In all retrieved studies, a
substantially higher sensitivity was reported. In a Chinese rural area, Belinson [2001] found
a sensitivity of HC2 for CIN2+ of 95% and a specificity of 89%. In a study conducted by
De Vuyst in Nairobi (Kenya), a PCR system was used to detect HPV, followed by typing
for high-risk types, which yielded a sensitivity of 94% (and a specificity of 69%). Also in
the Harare study, which is included in our meta-analysis, considerably higher sensitivity
(80%) was reported for HC2 (the specificity was 61%) [University of Zimbabwe, 2001].
In a small study conducted in South Kivu, with complete histological gold standard
verification, all histologically confirmed CIN2 and CIN3 were detected by HPV testing
using GP5+/6+ PCR followed by enzyme-immunoassay [Arbyn, 2000].
Table 51 shows the accuracy parameters of HC2 and PCR tests for the detection of CIN2+
and CIN3+ in the framework of primary screening for cervical cancer. It is derived from a
Cochrane review that is currently being finalized where the test performance of HPV
testing is compared with cytology screening [Koliopoulos, 2006; Arbyn, 2005]. Figure 1
shows the forest plot representing the variation of the sensitivity of HC2 for CIN2+. From


                                                                                         202
both the table and the forest plot the outlying low sensitivity values reported for the Indian
studies become clear.

Table 51. Sensitivity, specificity, positive predictive value, negative predictive value of HC2 or HPV DNA
tests based on PCR to detect CIN2+ or CIN3+; prevalence of CIN2+ and CIN4+, assessed in the framework
of primary screening for cervical cancer.


Study                        Country            HPV test Outcome   Sense Specie PPV NPV Prev
Kuhn, 2000                   South-Africa       HC2     CIN2+       0.88   0.80 0.12 1.00 0.033
Ratnam, 2000                 Canada             HC2     CIN2+      0.83 0.88 0.17 0.99 0.029
Clavel, 2001 (C. Cyt arm)    France             HC2     CIN2+       1.00   0.90 0.18     1.00   0.021
Clavel, 2001 (LBC arm)       France             HC2     CIN2+       1.00   0.91 0.15     1.00   0.016
Coste, 2003                  France             HC2     CIN2+       0.95   0.85 0.13     1.00   0.023
Cuzick, 2003                 UK                 HC2     CIN2+       0.97   0.93 0.11     1.00   0.009
Belinson, 2003               China              HC2     CIN2+       0.97   0.80 0.18     1.00   0.044
Petry, 2003                  Germany            HC2     CIN2+       0.98   0.95 0.11     1.00   0.006
Salmeron, 2003               Mexico             HC2     CIN2+       0.93   0.93 0.15     1.00   0.013
Sankaranarayanan, K1 2004    India              HC2     CIN2+       0.46   0.92 0.10     0.99   0.018
Sankaranarayanan, M 2004     India              HC2     CIN2+       0.66   0.94 0.16     0.99   0.018
Sankaranarayanan, T2 2004    India              HC2     CIN2+       0.64   0.95 0.17     0.99   0.017
Blumenthal, 2001             Zimbabwe           HC2     CIN2+       0.81   0.61 0.19     0.87   0.100
Sankaranarayanan, 2005       India              HC2     CIN2+                   0.11
Sarion, 2005                 Brazil-Argentina   HC2     CIN2+       0.83   0.84 0.07     1.00 0.015
Bigras,2005                  Switzerland        HC2     CIN2+       0.97   0.92 0.09     1.00 0.006
             Pooled                             HC2     CIN2+       0.90   0.87

Syrjanen, 2002               Russia             HC2     CIN3+       0.97                        0.009
Petry, 2003                  Germany            HC2     CIN3+       0.97   0.95   0.09   1.00   0.005
Sherman, 2003                Costa Rica         HC2     CIN3+       0.64   0.86   0.04   1.00   0.008
Sankaranarayanan, K1 2004    India              HC2     CIN3+       0.64   0.92   0.06   1.00   0.009
Sankaranarayanan, M 2005     India              HC2     CIN3+       0.74   0.94   0.13   1.00   0.013
Sankaranarayanan, T2 2005    India              HC2     CIN3+       0.62   0.94   0.13   1.00   0.013
Sarion, 2005                 Brazil-Argentina   HC2     CIN3+       0.97   0.84   0.04   1.00   0.008
Pan, 2003                    China              HC2     CIN3+       0.98   0.84   0.12   1.00   0.022
             Pooled                                                 0.85   0.90

Cuzick, 1995                 UK                 PCR     CIN2+       0.75   0.96   0.42   0.99   0.040
Cuzick, 1999                 UK                 PCR     CIN2+       0.64   0.99   0.42   1.00   0.015
Schneider, 2000              Germany            PCR     CIN2+       0.95   0.96   0.36   1.00   0.025
Oh, 2001                     South-Korea        PCR     CIN2+       0.78   0.99   0.78   0.99   0.039
Paraskevaidis, 2001          Greece             PCR     CIN2+       0.89   0.79   0.11   1.00   0.029
Agorastos, 2005              Greece             PCR     CIN2+       0.75   0.97   0.08   1.00   0.003
             Pooled                                                 0.81   0.95

Cuzick 1999                  UK                 PCR     CIN2+       0.74   0.99 0.42 1.00 0.012
Kulasingam 2002              US                 PCR     CIN2+       0.89   0.86 0.14 1.00 0.021
            Pooled                                                  0.83   0.89




                                                                                                        203
                             HC2, testcutoff >1pg/mL
                             Outcome: CIN2+


               Kuhn, 2000

             Ratnam, 2000

            Belinson, 2001

          Blumenthal, 2001

              Clavel, 2001

            Belinson, 2003

              Coste, 2003

              Cuzick, 2003

                Pan, 2003

               Petry, 2003

Sankaranarayanan, K1, 2004

 Sankaranarayanan, M, 2004

Sankaranarayanan, T2, 2004

              Bigras, 2005

              Sarian, 2005




                Combined



                              0       .1      .2       .3   .4      .5         .6   .7   .8   .9          1
                                                                 Sensitivity

Figure 21. Estimation of the sensitivity of the Hybrid Capture II assay for detection of CIN2+ in the
framework of primary screening, pooled from 12 studies using a random effect model. Pooled sensitivity:
90% (95% CI: 86-94%). Q test for heterogeneity=139,5, 14 df, p=0.000.


Possible explanations for this low sensitivity could be: contamination of the sample by
acetic acid or Lugol’s iodine or deterioration of the sample due to exposure at high
temperature. Contamination of the sample by acetic acid or Lugol’s iodine is unlikely
since, according to the protocol, the sample for HC2 was collected before application of
vinegar or iodine solution. A laboratory testing problem, is also unlikely because of the
high concordance between the Indian results and those performed in a specialized
virological French laboratory on a random subsample [Sankaranarayanan, 2004d].
Existence of other HPV types not included in the hrHPV DNA HC2 cocktail is another
possibility which merits further examination. Finally, misclassification of the outcome
could explain the low accuracy of HC2.
It is known that colposcopy followed by biopsy taken from colposcopically suspect lesions
is not a perfect gold standard. In this study, all visual inspection methods yielded highly
correlated results, which might explain – as mentioned earlier - the high apparent accuracy
(sensitivity and specificity) of the visual methods. The test sensitivity of colposcopy itself
was not evaluated in the ACCP trials. Belinson [2001] found a sensitivity of colposcopy for
CIN2+ of 81%.
The inter-study and inter-period variation in HC2 test positivity and accuracy was narrow
and most often non-significant, which most probably reflects high reproducibility,
independent of training or experience.

Among all evaluated tests, cytology showed the lowest sensitivity, even at the lowest
cytological cutoff (58% for CIN2+). We have inserted the sensitivity/specificity values in a
sROC curve containing the data of a previously published meta-analyses of the accuracy of



                                                                                                      204
the Pap smear [Fahey, 1995; Nanda, 2000]. We see that the data points from the multi-
center and the Zimbabwe trial all belong to the cloud of points from Fahey's meta-analysis.



                           VIA
                           Outcome=CIN2+

                      1



                      .8



                      .6
 Sensitivity




                      .4



                      .2



                      0
                           0.0    0.1      0.2   0.3   0.4    0.5       0.6   0.7    0.8     0.9      1.0
                                                       FPR = 1- Specificity

Figure 22. Summary ROC curve displaying the relation between the false positive rate and the sensitivity of
cytology for the outcome of CIN2+ (derived from the meta-analysis of Fahey [1995]). The values from the
five Indian settings of the multi-center cross-sectional study are added as blue squares; the point
corresponding with the Harare study is added as a green triangle.



There are still a few issues which we mention here for future exploration:

               •   Inclusion of the data from three other ACCP trials, after primary publication of the
                   results:
                       o The See and Treat randomized trial, conducted in South Africa by
                            EngenderHealth in collaboration with Columbia University (New York) and
                            the University of Cape Town.
                       o The trial conducted by PAHO, in San Martin (Peru) comparing different
                            screening test and triage combinations.
                       o Multi-arm RCT, conducted in Osmanabad (India) by IARC.
               •   Analysis of the second see & treat demonstration project, conducted in Amasaman
                   (Ghana), and further analysis of the completed Busia study.
               •   Assessment of the accuracy of combinations of screening tests.
               •   Multi-level and Bayesian hierarchical meta-analyses to differentiate better between
                   individual, provider, study setting, country and supervising agency effects.
               •   Cost-effectiveness analyses: of different screening options, combinations of tests,
                   triage and treatment procedures.
               •   The impact of possible gold standard misclassification using external data
                   documenting the accuracy of colposcopy and histology of biopsies.


                                                                                                        205
   •   Pooling of other published studies targeting cervical cancer screening in developing
       countries. We obtained recently the registration of the title of a future systematic
       Cochrane review. Moreover a grant was awarded to the Scientific Institute of
       Public Health in Brussels by the Gynaecological Cancer Cochrane Collaboration to
       finalize a meta-analysis on screening methods applicable in developing countries.
   •   Continued surveillance of longitudinal indicators from the Ambilikai and
       Osmanabad RCTs. In fact, the results of this type of study will give more clear
       answers on screening and treatment efficacy in terms of incidence and mortality
       reduction, under the condition that registration of cancer cases and deaths is
       sufficiently complete and that cause of death certification is accurate and balanced
       according to the screening arms. Contamination of the randomized groups (other
       screening/treatment/vaccination interventions affecting incidence of cervix cancer)
       can become another danger that can bias study results. The outcome of five
       European randomized screening trials comparing cytology screening with HPV or
       combined cytology/HPV screening will be pivotal for deciding on a possible shift
       from the Pap smear to the HPV test as first choice screening method in Europe. All
       these trials will allow observation of a reduced incidence of CIN2, CIN3 or cancer
       among screen-negatives in the HPV arm 3 to 5 years after initial screening (Davies,
       2005).
   •   Definition of future screening strategies in a context where probably HPV
       vaccination will be introduced progressively, which is expected to protect
       vaccinated teenagers against anogenital cancer within a few decades but which
       meanwhile will not affect current trends in the cohorts of women who are already
       15 years and older.

An enormous quantity of new knowledge has become available from the studies which we
have analyzed in the current report, but the definitive answers on how to define the best
screening and treatment policies can not yet be given. We hope therefore that researchers
will continue their work in cervical cancer screening to complete this picture in the near
future.



8. Acknowledgements

We acknowledge all the researchers and data managers for the provision of the individual
data files, in particular, the collaborators of Dr. R. Sankaranarayanan, Mr. R. Muwonge and
Dr. C. Mahé for the data from the trials coordinated by IARC (Lyon), Mrs. Joyce Erickson
Kristen Lewis (PATH, Seattle) for the data from Kenya and Mrs. Robbyn Lewis
(JHPIEGO, Baltimore) who provided data from Zimbabwe, Thailand and Ghana.
Moreover, we want to express our gratitude to Ms. Jacqueline Sherris (PATH) who invited
us to conduct this pooled analysis and who facilitated the contacts with the data providers .

All studies, with the exception of the Zimbabwean trial, were funded by the Bill & Melinda
Gates Foundation through the Alliance for Cervical Cancer Prevention. Financial support
for the Zimbabwe study came from the JHPIEGO Corporation and an affiliate of The Johns
Hopkins University through funds from the US Agency for International Development
(USAID Office of Population, Center for Population, Health and Nutrition, Global Bureau,
under the terms of Cooperative Agreement Number CCP-3069-A-00-3020-00) .



                                                                                         206
207
9. Abbreviations

AA: acetic acid
ACCP: Alliance for Cervical Cancer Prevention
AdenoCa: adenocarcinoma
AGC: atypical glandular cells
AGUS: atypical squamous cells of unspecified significance
AIS: Adenocarcinoma in situ
ASC: atypical squamous cells
ASC-US: atypical squamous cells of unspecified significance
ASC-H: atypical squamous cells, cannot rule out HSIL
AUC: area under the curve
AW: acetowhite
Ca: cancer
CI: 95% confidence interval
CIN: cervical intra-epithelial lesion
CP: conventional Papanicolaou smear
CT: cytotechnologist
DNA: Desoxyribo-nucleic acid
DOR: diagnostic odds ratio
DVI: direct visual inspection
ECC: endocervical curettage
FN: false negative
FNR: false negative rate (= complement of sensitivity; FNR = 1 - SE)
FP: false positive
FU: follow-up
HC2: Hybrid Capture-2 assay
HPV: human papillomavirus
hrHPV: high risk HPV type
HSIL: high-grade squamous intra-epithelial lesion
IARC: International Agency for Research in Cancer
JHPIEGO: John Hopkins Program for International Education of Gynecologists and
           Obstetricians
LBC: liquid based cytology
LEEP: loop electrosurgical excision procedure
lrHPV: low risk HPV type
LSIL: low-grade squamous intra-epithelial lesion
NPV: negative predictive value
OR: odds ratio
PAHO: PanAmerican Health Organization
PATH: Program for Appropriate Technology in Health
RCT: randomized controlled trial
RLU: Relative Light Units
ROC-curve: Receiver Operational Characteristic curve
RR: relative risk
SBLB: satisfactory but limited by
SCJ: squamocolumnar junction
SE: sensitivity


                                                                                 208
SIL: squamous intra-epithelial lesion
SP: specificity
sROC-curve: summary Receiver Operational Characteristic curve

T+ rate: proportion of test positives
TBS: The Bethesda System
TBS91: The Bethesda System (version 1991)
TBS01: The Bethesda System (version 2001)
TN: true negative
TP: true positive
TZ: transformation zone
VIA: visual inspection after application of acetic acid
VIAM: visual inspection after application of acetic acid with magnification
VILI: visual inspection after application of Lugol’s iodine
WNL: within normal limits




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2000; 107: 33-8.

Womack SD, Chirenje Z, Gaffikin L, Blumenthal PD, McGrath JA, Chipato T et al. HPV-
based cervical cancer screening in a population at high risk for HIV infection. Int J Cancer
2000; 85: 206-10.

Yang BH, Bray FI, Parkin DM, Sellors JW, Zhang Z-F. Cervical cancer as a priority for
prevention in different world regions : an evaluation using years of life lost. Int J Cancer
2004; 109: 418-24.

Zhang J, Yu KF. What is the relative risk: a method of correcting the odds ratio in cohort
studies of common outcomes. JAMA 1998; 280: 1690-1.


11. Annexes


11.1. Data files and statistical syntax files
• Directories: /xls/metaanalysis/via/sankar (1st multi-center cross-sectional study) and
  /xls/metaanalysis/via/accp/ (last 5 studies).
• Primary data files:
    1. Cross-sectional multi-center study: /xls/metaanalysis/via/sankar/crossdata.dta
    2. Ambilikai RCT: /xls/metaanalysis/via/accp/ambi/ambidata.dta
    3. Zimbabwe study: /xls/metaanalysis/via/accp/zimb/zimb.dta
    4. Kenya study: (3 files)
        /xls/metaanalysis/via/accp/kenya/kenya10nov04/metaanalysis_WKCCPP_Nov8.dta;
        ellie_meta_nov_04.dta ; /xls/metaanalysis/via/accp/kenya/providers.dta


                                                                                               213
   5. Thai study: /xls/metaanalysis/via/accp/thai
      via.init.cry.ref.prob1_2.ffol.oy.12_11_01.sav
   6. Ghana study: /xls/metaanalysis/via/accp/ghana/ghana i_v_c_f_o_r_p_08-04-
      04_5.sav


11.2. Abstracts from the included separate published studies
11.2.1.        Cross-sectional multi-country study (5 publications)

Sankaranarayanan R, Wesley R, Thara S, Dhakad N, Chandralekha B, Sebastian P et
al. Test characteristics of visual inspection with 4% acetic acid (VIA) and Lugol's
iodine (VILI) in cervical cancer screening in Kerala, India. Int J Cancer 2003b; 106:
404-8.

Simple and inexpensive methods based on visual examination of the cervix are currently
being investigated as alternative methods of cervical screening. The test characteristics of
visual inspection with 4% acetic acid (VIA), and Lugol's iodine (VILI) and conventional
cytology were investigated in a cross-sectional study involving 4,444 women aged 25 to 65
years in Kerala, India. While detection of any acetowhite area constituted a low-threshold
positive VIA, detection of well-defined, opaque acetowhite lesions close to or touching the
squamocolumnar junction constituted a high-threshold positive VIA test. Detection of
definite yellow iodine non-uptake areas in the transformation zone close to or touching the
squamocolumnar junction constituted a positive VILI test. Cytology was considered
positive if reported as atypia or worse lesions. All screened women were evaluated by
colposcopy and biopsies were directed in 1,644 women (37.0%), which allowed the direct
estimation of sensitivity, specificity and predictive values. The reference diagnosis was
based on a combination of histology and/or colposcopy. True disease status was defined as
CIN 2 and worse lesions. A total of 149 (3.4%) women had CIN 2 or worse lesions. The
sensitivities of low-threshold VIA, high-threshold VIA, VILI and cytology to detect CIN 2
or worse disease were 88.6%, 82.6%, 87.2% and 81.9%, respectively; the corresponding
specificities were 78.0%, 86.5%, 84.7% and 87.8%. Our results indicate that VIA and VILI
are suitable alternate screening tests to cytology for detecting cervical neoplasia in low-
resource settings

Sankaranarayanan R, Shastri SS, Basu P, Mahé C, Mandal R, Amin G. The role of
low-level magnification in visual inspection with acetic acid for the early detection of
cervical neoplasia. Cancer Detect Prev 2004a; 28: 345-51.

Several studies have investigated the accuracy of naked eye visual inspection with acetic
acid (VIA) in the early detection of cervical neoplasia. It is not clear whether low-level (2-
4x) magnification (VIAM) can improve the sensitivity and specificity of VIA. The accuracy
of both VIA and VIAM, provided by independent health workers, were evaluated in three
cross-sectional studies involving 18,675 women aged 25-65 years in Kolkata and Mumbai
in India. All screened women were investigated with colposcopy and biopsies were
obtained based on colposcopy findings. The final disease status was based on the reference
standard of histology (if biopsies had been taken) or colposcopy. Data from the studies
were pooled to calculate the test characteristics for the detection of high-grade squamous
intraepithelial lesions (HSIL). 14.1% and 14.2% were positive on testing with VIA and
VIAM respectively. Two hundred twenty-nine were diagnosed with HSIL and 68 with


                                                                                          214
invasive cancer. The pooled sensitivity, specificity, positive and negative predictive values
for VIA in detecting high-grade squamous intraepithelial lesions (HSIL) were 60.3% (95%
CI: 53.6-66.7), 86.8% (95% CI: 86.3-87.3), 5.9% (95% CI: 5.0-7.0), and 99.4% (95% CI:
99.2-99.5), respectively. The values were 64.2% (95% CI: 57.6-70.4), 86.8% (95% CI:
86.2-87.3), 6.3% (95% CI: 5.3-7.3) and 99.4% (95% CI: 99.3-99.6), respectively, for
VIAM. Low-level magnification did not improve the test performance of naked eye
visualization of acetic acid impregnated uterine cervix.

Sankaranarayanan R, Basu P, Wesley RS, Mahé C, Keita N, Mbalawa CCG et al.
Accuracy of visual screening for cervical neoplasia: results from an IARC multi-
center study in India and Africa. Int J Cancer 2004c; 110: 907-13.

Visual inspection-based screening tests, such as visual inspection with 4% acetic acid
(VIA) and with Lugol's iodine (VILI), have been proposed as alternatives to cytology in
mass screening programs. To date, there is only limited information on the accuracy of
these tests in detecting High-grade Squamous Intraepithelial Lesions (HSIL). Eleven cross-
sectional studies involving 56,939 women aged 25-65 years were conducted in Burkina
Faso, Congo, Guinea, India, Mali and Niger to evaluate the accuracy of VIA and VILI
performed by health workers. A common protocol and questionnaire was used. For final
diagnosis, all women were investigated with colposcopy and biopsies were taken when
necessary. Data from the studies were pooled to calculate sensitivity, specificity and
predictive values of the tests for the detection of HSIL. Of the screened women, 16.1% and
16.4% were positive on examination using, respectively, VIA and VILI; 1,063 were
diagnosed with HSIL. The pooled sensitivity, specificity, positive and negative predictive
values for VIA were 76.8% (95% CI: 74.2-79.4%), 85.5% (95% CI: 85.2-85.8%), 9.4%
(95% CI:8.8-10.8%) and 99.5% (95% CI:99.4-99.6%), respectively. The values were
91.7% (95% CI: 89.7-93.4%), 85.4% (95% CI: 85.1-85.7%), 10.9% (95% CI: 10.2-11.6%)
and 99.8% (95% CI:99.7-99.9%), respectively for VILI. The range of sensitivity and
specificity for VIA was 56.1-93.9% and 74.2-93.8%, respectively, between studies and
were 76.0-97.0 % and 73.0-91.3% for VILI. VILI had a significantly higher sensitivity than
VIA in detecting HSIL, but specificity was similar. VILI appears to be a more accurate
visual test for use in screening and treatment programs in low-resource settings.

Sankaranarayanan R, Chatterji R, Shastri SS, Basu P, Mahé C, Muwonge R et al.
Accuracy of human papillomavirus testing in primary screening of cervical neoplasia:
results from a multi-center study in India. Int J Cancer 2004d; 112: 341-7.

The knowledge that cervical neoplasia are caused by human papillomavirus (HPV)
infection has led to the evaluation of its role in screening. We evaluated the accuracy of
HPV testing by Hybrid capture II (HC II) method in detecting cervical intraepithelial
neoplasia grade 2 and 3 (CIN 2 and 3) lesions in 4 cross-sectional studies with common
protocol and questionnaire in 3 different locations (Kolkata, Mumbai and Trivandrum) in
India. These studies involved 18,085 women aged 25-65 years. The reference standard for
final diagnosis was a combination of colposcopy/biopsy. All women were investigated with
colposcopy and 3,116 received directed biopsy. The sensitivity of HPV testing for detecting
CIN 2-3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied
from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Retesting of
298 randomly chosen denatured samples in France revealed an agreement rate of 85.9% and
a kappa-value of 0.72. Although HPV testing seems to be a promising approach for cervical
cancer prevention, a large range in sensitivity was observed in our study, possibly due to


                                                                                         215
variations in the quality of specimen collection and reference standards. A higher sensitivity
was associated with the center performing the test well. Further developments in terms of
more reproducible, less expensive and less sophisticated testing are essential to make the
test feasible and effective in low-resource settings.


Sankaranarayanan R, Thara S, Sharma A, Roy C, Shastri S, Mahe C et al. Accuracy
of conventional cytology: results from a multi-center screening study in India. J Med
Screen 2004e; 11: 77-84.

OBJECTIVE: We conducted a multi-center cross-sectional study in India to evaluate the
accuracy of conventional cytology to detect high-grade squamous intraepithelial lesions
(HSIL). SETTING: Cross-sectional studies in Jaipur, Kolkata, Mumbai and Trivandrum,
India, during 1999-2003. METHODS: A common protocol and questionnaire were used to
test 22,663 women aged 25-65 years with conventional cytology in five cross-sectional
studies. Three thresholds were used to define test positivity: atypical squamous cells of
uncertain significance (ASCUS), low-grade squamous intra-epithelial lesion (LSIL), or
HSIL. All screened women were investigated with colposcopy, and biopsies were taken
when necessary. The reference standard for final disease status was histology or negative
colposcopy. Data from the studies were pooled to evaluate the test characteristics for the
detection of histologically confirmed HSIL. RESULTS: The test positivity rates of cytology
were 8.8% at ASCUS, 6.2% at LSIL and 1.8% at HSIL thresholds, and 355 women had
histologically confirmed HSIL while 74 had invasive cancer. The pooled sensitivity,
specificity, positive and negative predictive values at ASCUS threshold were 64.5%,
92.3%, 11.8% and 99.4% respectively. The corresponding values at LSIL threshold were
58.0%, 94.9%, 15.2% and 99.3%, while at the HSIL threshold they were 45.4%, 99.2%,
46.3% and 99.1%. The sensitivity varied between 37.8-81.3% at ASCUS, 28.9-76.9% at
LSIL and 24.4-72.3% at HSIL thresholds. A significantly low sensitivity was observed in
women aged 25-39 years (p<0.001). The wide variation in sensitivity across study sites
persisted even after age standardization. CONCLUSION: The sensitivity of cytology varied
widely between the study sites. Findings from our study and other reviews indicate that
sustained efforts in improving sampling, preparation and reading of cytological specimens
and improvements in clinical judgment are essential to achieve concurrently high sensitivity
and specificity.




11.2.2.        Zimbabwe study (3 publications)

University of Zimbabwe/JHPIEGO Cervical Cancer Project, Anonymous. Visual
inspection with acetic acid for cervical-cancer screening: test qualities in a primary-
care setting. Lancet 1999; 353: 869-73.

BACKGROUND: Naked-eye visual inspection of the cervix with acetic-acid wash (VIA),
or cervicoscopy, is an alternative to cytology in screening for cervical cancer in poorly
resourced locations. We tested the sensitivity, specificity, and predictive value of VIA done
by nurse-midwives in a less-developed country. METHODS: Women were screened by six
trained nurse-midwives in a two-phase, cross-sectional study at 15 primary-care clinics in
Zimbabwe. VIA and Pap smears were done concurrently, and their sensitivity and


                                                                                          216
specificity compared. Colposcopy, with biopsy as indicated, was used as the reference test
to allow a direct comparison of the test unaffected by verification bias. FINDINGS: 10934
women were screened. In phase II, 2148 (97.5%) of the 2203 participants for whom there
was a screening result also had a reference test result. Also in phase II, VIA was more
sensitive but less specific than cytology. Sensitivity (95% CI) was 76.7% (70.3-82.3) for
VIA and 44.3% (37.3-51.4) for cytology. Specificity was 64.1% (61.9-66.2) for VIA and
90.6% (89.2-91.9) for cytology. INTERPRETATION: The high sensitivity of VIA shows
that the test could be valuable in detection of precancerous lesions of the cervix. However,
there are costs to the patient and system costs associated with high numbers of false-
positive results, so attention should be given to improving the specificity of VIA.


Womack SD, Chirenje ZM, Blumenthal PD, Gaffikin L, McGrath JA, Chipato T et al.
Evaluation of a human papillomavirus assay in cervical screening in Zimbabwe.
BJOG 2000; 107: 33-8.

OBJECTIVE: To determine the utility of an assay for high risk genital human
papillomavirus (HPV) in cervical screening in Zimbabwe, Africa. DESIGN: Cross-
sectional study. SETTING: Harare, Zimbabwe. POPULATION: Zimbabwe women (n =
2,140), 25 to 55 years old, recruited in clinics in Chitungwiza and Greater Harare.
METHODS: Genital specimens were assessed for HPV, using the HPV DNA test Hybrid
Capture II (probe B). Further assessment of the women was conducted using colposcopy
and biopsy as indicated. High grade squamous intraepithelial lesions were diagnosed in 215
women. Colposcopy and/or biopsy showed low grade lesions in 346 women. RESULTS:
The overall prevalences were: 42 x 7% for HPV, 10% for high grade squamous
intraepithelial lesions and 16% for low grade lesions. Prevalence for HPV decreased
significantly with increase in age (P for trend < 0 x 0001) and increased significantly with
increasing disease severity, from 35% in normal women, to 53% in women with low grade
lesions and 81% in women with high grade lesions (P for trend < 0 x 001). In specimens
positive for HPV, the amount was 14-fold higher in women with high grade lesions
compared with normal women. In screening for high grade lesions the assay for HPV had a
sensitivity of 81% (CI 75%-86%); sensitivity for low grade lesions was 64% (CI 60%-
68%). Specificity was 62% (CI 59%-64%) for high grade lesions and 65% (CI 62%-67%)
for low grade lesions. The positive predictive value was 19% (CI 17%-22%) for high grade
lesions and 39% (CI 36%-42%) for low grade lesions. CONCLUSION: For high grade
squamous intraepithelial lesions the sensitivity of the Hybrid Capture II HPV DNA test was
high, but the specificity was relatively low. The test may therefore be most useful in
conjunction with other screening tests.


Blumenthal PD, Graffikin L, Chirenje ZM. Adjunctive testing for cervical cancer in
low resource settings with visual inspection, HPV, and the Pap smear. Int J Gynaecol
Obstet 2001; 72: 47-53.

OBJECTIVE: To test whether the performance of visual inspection using acetic acid (VIA)
could be improved through adjunctive testing and to determine whether the combination of
visual inspection of the cervix and HPV testing could prove useful for identifying those at
highest risk of cervical precancer. METHODS: Between October 1995 and August 1997,
2199 women willing to be screened for cervical cancer in peri-urban clinics in Harare,
Zimbabwe received VIA, Pap smear and HPV as screening tests. The presence or absence


                                                                                        217
of (pre)cancer was confirmed via colposcopy with biopsy as indicated for >97% of all
women. Computerized simulations of sequential testing scenarios provided estimates of the
joint (net) test qualities of different paired combinations of the three tests and allowed for
comparisons with the individual test qualities. RESULTS: Using HGSIL/CIN II-III as the
reference threshold of disease, the net sensitivity and specificity of VIA and HPV when
used sequentially were 63.6 and 81.9%, respectively, compared to 43.3 and 91%,
respectively, when Pap smears were followed by HPV testing. VIA followed by the Pap
smear yielded a net sensitivity of 37.5% and net specificity of 94.3%. CONCLUSIONS:
For programs with limited resources but with the capacity for HPV testing, sequential
testing involving the use of VIA followed by HPV could yield fewer false positives than the
use of VIA alone at a cost of relatively few additional false negatives.


11.2.3.        Ambilikai RCT (2 publications)

Sankaranarayanan R, Rajkumar R, Arrossi S, Theresa R, Esmy PO, Mahe C et al.
Determinants of participation of women in a cervical cancer visual screening trial in
rural south India. Cancer Detect Prev 2003a; 27: 457-65.

The efficacy of a single round of screening of visual inspection with acetic acid (VIA) on
cervical cancer incidence and mortality is investigated in a cluster randomized controlled
trial in south India. Women aged 30-59 years in 113 clusters in Dindigul District were
randomized to VIA screening by nurses (57 clusters, 48,225 eligible women) and to a
control group (56 clusters, 30,167 women). 30,577 (63.4%) eligible women participated in
screening. Younger, educated, married, multiparous, low-income women and those who
have had tubal sterilization had a higher compliance with screening. Of the 2069 women
diagnosed with CIN and invasive cancer, 1498 (72.4%) received treatment. Young women,
those who practiced contraception and women with high-grade precursor lesions and
invasive cancers were more likely to comply with treatment. In summary, our study
indicates that women accept screening with VIA by nurses and a moderate level of
compliance with screening and treatment can be reached through appropriate service
delivery systems including health education activities, personal invitations, clinics in
proximity to the target women, and testing and treatment in the same session. Our results
imply that integration of screening activities with primary health services seems to have the
potential to replicate most of these service delivery conditions in routine programs


Sankaranarayanan R, Rajkumar R, Theresa R, Esmy PO, Mahe C, Bagyalakshmi KR
et al. Initial results from a randomized trial of cervical visual screening in rural south
India. Int J Cancer 2004b; 109: 461-7.

The impact of a single round of screening of visual inspection with acetic acid (VIA) on
cervical cancer incidence and mortality was investigated in a cluster randomized trial in
south India. Women 30-59 years of age in 113 clusters in Dindigul District were
randomized to VIA screening (57 clusters, 48,225 women) by nurses and to a control group
(56 clusters, 30,167 women). 30,577 eligible women were screened between May 2000 and
April 2003; 2,939 (9.6%) screen-positive women were investigated with colposcopy by
nurses and 2,777 (9.1%) women had biopsy. CIN 1 was diagnosed in 1,778 women, CIN 2-
3 lesions were found in 222, and there were 69 screen detected invasive cervical cancers.
The detection rates of lesions per 1,000 screened women were 58.2 for CIN 1, 7.3 for CIN


                                                                                          218
2-3, and 2.3 for invasive cancer. The detection rate of high-grade lesions in our study was
2-3-fold higher than those observed in repeatedly screened populations in developed
countries. 71% of women with CIN 1 and 80% of those with CIN 2-3 lesions accepted
cryotherapy provided by nurses and surgical treatment by mid-level clinicians. Overall, 97
and 34 incident cervical cancer cases were observed in the intervention and control arms,
respectively. The intervention arm accrued 124,144 person years and the control arm
accrued 90,172 during the study period. The age standardized cervical cancer incidence
rates were 92.4/100,000 person-years in the intervention and 43.1/100,000 in the control
arms. In the screened arm, 35.0% of cases were in Stage I as opposed to none in the control
arm. The preliminary findings from our study indicate that not only is a VIA-based
screening program feasible, safe and acceptable to a population in rural settings, it also
results in early detection of cervical neoplasia.


11.2.4.        Kenya study
Not published yet.


11.2.5.        Thailand demonstration project

Gaffikin L, Blumenthal PD, Emerson M, Limpaphayom K. Safety, acceptability, and
feasibility of a single-visit approach to cervical-cancer prevention in rural Thailand: a
demonstration project. Lancet 2003; 361: 814-20.

BACKGROUND: To increase screening and treatment coverage, innovative approaches to
cervical-cancer prevention are being investigated in rural Thailand. We assessed the value
of a single-visit approach combining visual inspection of the cervix with acetic acid wash
(VIA) and cryotherapy. METHODS: 12 trained nurses provided services in mobile (village
health center-based) and static (hospital-based) teams in four districts of Roi-et Province,
Thailand. Over 7 months, 5999 women were tested by VIA. If they tested positive, after
counseling about the benefits, potential risks, and probable side-effects they were offered
cryotherapy. Data measuring safety, acceptability, feasibility, and effort to implement the
program were gathered. FINDINGS: The VIA test-positive rate was 13.3% (798/5999), and
98.5% (609/618) of those eligible accepted immediate treatment. Overall, 756 women
received cryotherapy, 629 (83.2%) of whom returned for their first follow-up visit. No
major complications were recorded, and 33 (4.4%) of those treated returned for a perceived
problem. Only 17 (2.2%) of the treated women needed clinical management other than
reassurance about side-effects. Both VIA and cryotherapy were highly acceptable to the
patients (over 95% expressed satisfaction with their experience). At their 1-year visit, the
squamocolumnar junction was visible to the nurses, and the VIA test-negative rate was
94.3%. INTERPRETATION: A single-visit approach with VIA and cryotherapy seems to
be safe, acceptable, and feasible in rural Thailand, and is a potentially efficient method of
cervical-cancer prevention in such settings.




                                                                                         219
11.2.6.        Ghana demonstration project

Gaffikin L, Lauterbach M, Emerson M, Lewis R. Safety, acceptability, and feasibility
of a single visit approach to cervical cancer prevention: results from a demonstration
project in Ghana. JHPIEGO Publication, Baltimore, November 2004, pp 1-42.

A demonstration project to assess a single visit approach (SVA) to cervical cancer
prevention was implemented in Ghana from March 2001 to July 2003. The SVA approach
links visual inspection of the cervix with acetic acid (VIA) with an offer of immediate
treatment or referral, as indicated. The objective of this demonstration project was to assess
the safety, acceptability, feasibility and programmatic effort (SAFE) of this approach.
VIA has been established as a viable testing option for low-resource settings. Cryotherapy
was selected as the treatment of choice for this project because it: 1) has a cure rate
comparable to other commonly performed procedures; 2) is easy to learn, does not require
electricity, requires few consumables, and has a long history in the scientific literature of
low complication rates; and 3) has an established, safe, and effective performance record
with non-physicians in developed countries.
The project was implemented in a phased approach, beginning in an urban setting and then
expanding to a rural setting. The first phase of this demonstration project was implemented
in an urban regional hospital, located in the capital city, Accra. Beginning the project in an
urban center helped ensure the presence of a functional referral network for cases requiring
advanced diagnosis and management prior to commencing screening services. The second
phase of this demonstration project, involving expansion of services to a rural site, will be
described in a subsequent report.
The project protocol required that test-positive, treatment-eligible women were offered
immediate cryotherapy and counseled about the benefits, potential risks, and likely side
effects of treatment. Women ineligible for treatment, that is, whose lesions exceeded 75%
of the cervical surface area or who had suspect cervical cancer, were referred. Data
measuring safety, acceptability and feasibility of the single visit approach were collected.
During the 18-month recruitment period at Ridge Hospital, 3,665 women were tested for
cervical precancer using VIA. The overall VIA test-positive rate at Ridge Hospital was
3.2%.
Among test-positive, treatment-eligible women for whom data are available, 70.1 %
accepted the offer of immediate cryotherapy. In total, 439 women accepted the offer of
cryotherapy and, of those, 76.8% returned for their first follow-up visit. There were no
major complications, and fewer than 6% of those treated returned to the project facility for
any perceived problem. Only 4% of those treated required any management other than
reassurance for side effects. Both VIA and cryotherapy were highly acceptable to women--
more than 98% were satisfied with the experience--and 1 year after treatment the
squamocolumnar junction (SCJ) was clearly visible for the majority of the women who
returned, yielding a 1-year VIA test-negative rate of 96.7%.
A single visit approach linking VIA testing with the offer of immediate treatment (or
referral) of test-positive cases is safe, acceptable and feasible in low resource settings such
as Ghana. This report describes the key results of this demonstration project involving an
alternative, field-based, resource-appropriate approach to cervical cancer prevention.




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11.3. Comprehensive table with characteristics of the included
    studies

In the framework of an ongoing meta-analysis of published studies on cervical cancer
screening in developing countries, we constructed comprehensive tables containing all
study characteristics. From those tables we extracted the rows containing data from the
ACCP studies (see Table 52 to Table 57).




                                                                                          221
Table 52. Characteristics of the study population.

Study        Publications                     Country        Study        Study population               Inclusion criteria                Exclusion criteria            Study    Age range
                                                            location                                                                                                      size
Cross-       Sankaranarayanan et al. Int J    B-Fasso    Ouagadougou,     Apparently healthy,             Consecutive series recruited     Pregnancy, hysterectomy,      58679    25-65y.
sectional    Cancer 2003; 106: 404-408        Congo      Brazzaville,     ambulant, symptomatic           opportunistically from           previous treatment for
multi-       Sankaranarayanan et al. Int J    Guinea     Conakry,         women. Women were               resident populations.            cervical cancer or CIN.
country      Cancer 2004;110: 907-913         Mali       Bamako,          encouraged to attend open       Women in Kolkata B &
Study        Sankaranarayanan et al. Int J    Niger      Niamey.          access clinics via publicity    Thiruvananthpuram were
             Cancer 2004; 112: 341-347        India      Jaipur,          campaigns.                      recruited actively from
             Sankaranarayanan et al. J Med               Kolkata,         Urban populations.              circumscribed communities.
             Screen 2004; 11: 77-84                      Mumbai
             Sankaranarayanan et al.                     Thiruvananthp
             Cancer Det Prev 2004; 8: 345-               uram (India).
             351
Cross-       UZ. Lancet 1999: 353: 869-       Zimbabw    15 1ary care     Women invited to a health       Absence of inclusion criteria.   Pregnancy, history of         Ph I:    25-55 y;
sectional    873                              e          clinics in       education talk on cervical                                       cervical cancer,              8731     mean 32:
Zimbabwe     Blumenthal et al. Int J Gyn Ob              Chitungwiza      cancer.                                                          hysterectomy, missing         Ph II:   (SD: 6.6).
Study        2001; 72: 47-53                             & greater        Urban populations.                                               identifying information.      2203
                                                         Harare area.
Ambilikai    Sankaranarayanan et al.          India      113              Women motivated by local        Apparently healthy women         Absence of uterus.            30577    30-59 y.
RCT          Cancer Det Prev 2003; 27:                   panchayaths,     health workers to               with an intact uterus.                                         &
             457-465                                     Ambilikai        participate in the study        No prior screening.                                            30167
             Sankaranarayanan et al. Int J               area, Dindigul   (study group). Control
             Cancer 2004; 109:461-467                    district.        group was educated on
                                                                          cervical cancer.
                                                                          Rural population.
WKCCPP       No publications yet              Kenya      3 divisions in   Rural population, residing      Not further explained.           Previous history of cancer,   2295     29-40 y.
                                                         the Busia        in one of the 3 target                                           hysterectomy.
                                                         district         divisions.
Thai         Royal Thai College. Lancet       Thailand   4 districts in   Women recruited by              Women consulting at the          Total hysterectomy, history   5999     30-45y:
demonstrat   2003; 361:814-820                           Roi-et           mobile (village health          health services for whatever     of cervical ca, pregnancy              mean: 37y
ion trial                                                Province.        center based) & static          reason or specifically for       (>20W).                                (sd 4.4 y).
                                                                          (hospital-based) teams.         cervical cancer screening
                                                                          Rural populations.              were invited to participate in
                                                                                                          the study.
Ghanaian     Gaffikin et al. JHPIEGO          Ghana      Ridge Hospital   Urban population attending      Women consulting at the          Hysterectomy, pregnancy,      3665     Range: 25-
demonstrat   Report, 2004, 1-42                          (Accra           the family planning clinic,     health services for whatever     history of cervical cancer.            45;
ion trial                                                Metropolitan     after campaigns.                reason or specifically for                                              Median: 34.
                                                         Area).                                           cervical cancer screening
                                                                                                          were invited to participate in
                                                                                                          the study.




                                                                                                                                                                                                222
Table 53. Characteristics of the study population (continued).

Study             Coordinating Agency      Period                      Applied screening tests
Cross-sectional   IARC, Lyon, France       1999-2003.                  VIA, VILI, VIAM, Conventional Pap and HC2
multi-country
Study
Cross-sectional   JHPIEGO, Baltimore, US   October 1995-August         Conventional Pap, VIA, HC2
Zimbabwe                                   1997
Study
Ambilikai         IARC, Lyon, France       Enrolment between March     VIA versus no intervention.
RCT                                        2000-April 2003. Follow-
                                           up until 2007.
WKCCPP            PATH, Seattle, US        November 2002-March         VIA (VILI at the end of the study)
                                           204
Thai              JHPIEGO, Baltimore, US   Enrolment between           VIA
demonstration                              February -November 2000.
trial                                      Follow-up during 1 year
                                           after treatment
Ghanaian          JHPIEGO, Baltimore, US   Women were enrolled         VIA
demonstration                              during an 18-month period
trial                                      (March 2001-August
                                           2002). Follow-up during 1
                                           year after treatment




                                                                                                                   223
Table 54. Main characteristics of the visual inspection tests being evaluated.


Study             Description of the VIA test              Illumination            Qualification/training of "visual               Definition of positive VIA result. Categorization of
                                                                                   inspector"                                      VIA result
Cross-sectional    After the CP, freshly prepared 4%       Halogen focus lamp.     A variety of health workers: auxiliary nurse    Negative:
multi-country      AA was applied to the cervix with a                             midwives, qualified graduated nurses, CTs,      VIA+: faint, translucent, ill defined, irregular AW
Study              cotton swab, inspection after 1                                 high school or university graduates. All        lesions on the cervix. Definite, geographic AW lesions,
                   minute.                                                         received intensive courses using the IARC       far from the SCJ.
                                                                                   manual, photographs & practical exercises;      VIA++: opaque, dense, dull, well-defined AA touching
                                                                                   instructions in cryotherapy. Refresher          the SCJ or close to the external os. Large,
                                                                                   courses of 1-2d during the study.               circumorificial, well-defined, thick, dense AW lesions.
                                                                                                                                   AW growth.
Cross-sectional    After collection of a smear, excess     Handheld flash light.   Nurse-midwife, trained during 3 days in         Normal: smooth,pink,uniform,featureless.
Zimbabwe           mucus was cleansed away with a                                  VIA.                                            Atypical: cervicitis (inflammation,red spots);
Study              saline-soaked swab. AA (4%) was                                                                                    discharge, ectropion, polyp.
                   applied to the cervix with a cotton-                                                                            Abnormal: white plaques, ulcer, AW epithelium.
                   tipped applicator.                                                                                              Cervical cancer: cauliflower-like growths, fungating
                                                                                                                                      mass.
Ambilikai          Application of 4% AA to the cervix      Bright halogen focus    Not documented.                                 Opaque dull well defined confluent AW lesions
RCT                with a cotton swab & excess mucus       lamp.                                                                   touching the SCJ or close to the external os. Large
                   was cleared. VIA findings were                                                                                  Opaque dull well defined AW lesions surrounding the
                   noted after 1’.                                                                                                 os. Warts & leukoplakia turning AW. Dense, opaque
                                                                                                                                   AW visible ulceroproliferative growth
WKCCPP             Use dry cotton swab to wipe away        Flashlight.             Family planning nurses or clinical officers     Negative: No AW lesions; faint patchy lesions without
                   any discharge, blood or mucus.                                  previously trained in both visual cervical      definite margins; polyp; Nabothian follicles; faint line-
                   Application of 5% AA to the cervix                              inspection techniques.                          like AW at SCJ; AW lesions far from TZ; streaky AW;
                   with a cotton swab. After 1’ the                                                                                dot-like AW in endocervix
                   cervix was inspected.                                                                                           VIA+: sharp, distinct, well-defined, dense (opaque) AW
                                                                                                                                   areas, with or without raised margins, close to SCJ;
                                                                                                                                   dense AW lesions in columnar epithelium or near os;
                                                                                                                                   condyloma and leukopakia close to SCJ that turn
                                                                                                                                   intensely AW.
                                                                                                                                   Suspicious for cancer: visible ulcerative-proliferative
                                                                                                                                   growth; oozing and/or bleeding on touch.
                                                                                                                                   Indeterminate: early category based on uncertainty.
                                                                                                                                   Dropped after initial training phase.
Thai               After assessment of presence of         Flash light             12 nurses with some experience in               Positive: raised & thickened AW plaques.
demonstration      gross lesions consistent with cancer,                           reproductive & 4 skilled colposcopists health   Cancer: cauliflower-like growth or ulcer; fungating
trial              5% AA was applied to the cervix.                                were trained in VIA & cryotherapy. The          mass.
                   After 1’ the cervix was inspected                               colposcopists supervised the nurses.
                   Special attention was given to the
                   observation of the entire SCJ.




                                                                                                                                                                                               224
Study           Description of the VIA test           Illumination              Qualification/training of "visual            Definition of positive VIA result. Categorization of
                                                                                inspector"                                   VIA result
Ghanaian         Application 3-5% AA, inspection of   Hand-held flashlight or   Nurse, midwife or other health-worker with   Negative: smooth, pink, uniform, and featureless;
demonstration    the cervix after 1’.                 torch.                    experience in pelvic examinations with       ectropion, polyp, cervicitis, inflammation, Nabothian
trial                                                                           adequate eyesight, trained in VIA &          cysts.
                                                                                cryotherapy. Competency training of 2W, 1    Positive: raised & thickened AW plaques.
                                                                                M pilot with proficiency assessment.         Cancer: cauliflower-like growth or ulcer, fungating
                                                                                Supervision by ObGyn physicians during the   mass.
                                                                                whole study.




                                                                                                                                                                                     225
Table 55. Main characteristics of the other tests being evaluated (continued).
Study            Description of other tests
Cross-           CP: Cervex-Brush in Jaipur, Kolkata & Mumbai; Ayre’s spatula & thin cotton swab. The Cervex or spatula were placed at the os
sectional        and rotated gently over 2x360°. Material was uniformly spread on a slide, which was immediately fixed in 95% ethyl alcohol.
multi-country    Smears were processed in cytopathology labs in India. Interpretation according to the Bethesda System or CIN. CIN was
Study            converted into the Bethesda system. A sample of slides was reviewed in French laboratories.
                 HC2: after collection of the cytology sample, a brush was rotated 3 full turns in the os and place into STM by breaking the tip of
                 the sampler. The specimens were stored at –20°C until processing. Local laboratories were set up and the personnel trained in use
                 of HC2 (prove B for high-risk HPV types). Cutoff at RLU>1 with +control containing 1pg HPV/mL. 300 samples were retested in
                 France.
                 VIAM: following VIA a 2nd health worker applied AA an visualized the cervix with a hand lens (4x) in Mumbai & Kolkata 2; in
                 Kolkata 1 the Aviscope device, including an in-built rechargeable light source.
                 VILI: after VIA and colposcopy, LI was applied to the cervix by an uninformed 2nd health worker. Interpretation using color
                 charts. VILI positivity was defined as: presence of well-defined, dense, yellow non-iodine uptake areas touching the SCJ or
                 circumorificial occupying large portion of the cervix. Growth on the cervix turning yellow.
Cross-            A cytology specimen was obtained with a wooden Ayre spatula. LSIL+ was the cytological cut-off. ASCUS & AGUS were
sectional        considered as cytologically negative. Interpretation by cytologists from the Univ Harare. CTs took part in a review course in
Zimbabwe         cytology. All + slides & 10% of negative slides were reviewed by a cytopathologist of Harare and also by a cytopathologist from J
Study            Hopkins, Baltimore (in phase I). In phase II: review only in J Hopkins.
                 HC2
Ambilikai        No intervention in the control group, where only cancers were detected via the normal existing health care and cancer registration
RCT              system.
WKCCPP           VILI: applied as screening test at the end of the study (137 cases). After VIA was done to identify cervical landmarks, LI was
                 applied to the cervix with cotton swab. Cervix was examined with flashlight. VILI+ was defined as thick bright mustard- or
                 saffron-yellow iodine-nonuptake areas seen touching the SCJ or os; circumferential yellow area surrounds os; or entire cervix
                 appears mustard-yellow. VILI neg was normal mahogany brown or black cervix and columnar epithelium does not change color;
                 patchy areas of no or partial uptake in the TZ; polyps or Nabothian follicles; “leopard skin” appearance; dots or patches far from
                 SCJ. Suspicious for cancer: visible ulcerative-proliferative growth; oozing and/or bleeding on touch; densely yellow irregular
                 surface.

Thai             No other tests.
demonstration
trial




                                                                                                                                                      226
Study           Description of other tests
Ghanaian        No other tests.
demonstration
trial




                                             227
Table 56. Main study characteristics of the applied gold standard used to validate screen test results.
Author, year      Gold standard                                                 Criteria for gold standard application                       Masking of screeners, colposcopists, histologist       Categorization of
                                                                                                                                                                                                    the gold standard
                                                                                                                                                                                                    outcome
Cross-sectional   The colposcopist was unaware of the VIA findings.             Colposcopy was performed on all women.                       Cytology, VIA and VILI were interpreted                CIN1+
multi-country     Colposcopy was done after VIA and completed after VILI.       Punch biopsies were taken from colposcopically abnormal      independently.                                         CIN2/3
Study             A 2nd colposcopy was done after VILI, by the same doctor.     areas. Biopsies were assessed ii national laboratories.      Histologists received colposcopy information.          Cancer
                  Colposcopists were medical staff being trained intensively    Pathologists received colposcopy reports. Special internal
                  during 15d using a IARC manual. Refreshment courses every     and external QA procedures were introduced (not
                  4-6M during 1d.                                               described). A sample of histology samples was reviewed in
                  Biopsies were fixed in formaldehyde and processed &           a reference laboratory. All personal received a training
                  interpreted in the pathology department of RCC. In absence    course. In absence of biopsies, colposcopy was used for
                  of biopsies, colposcopy was accepted as gold standard.        reference diagnosis.
Cross-sectional   Colposcopy at Harare University by faculty members.           Phase I: Abnormal VIA result, cytology LSIL+, and every      Screen tests were interpreted independently, also      CIN1
Zimbabwe          Biopsy if suspect colposcopy. (Treatment according to         10th women with normal/atypical VIA. Potential               colposcopy was done without knowledge of               CIN2
Study             colposcopy/biopsy).                                           verification bias. Phase II: All women. No verification      screen test results. Biopsy interpretation was also
                                                                                bias.                                                        masked to colposcopy.
Ambilikai         Colposcopy with a 9-12x magnification by a nurse under        VIA positive women.                                          The colposcopist knew that she examined women          CIN1
RCT               supervision by a medical officer, who was consulted                                                                        who were VIA+.                                         CIN2-3
                  whenever in doubt. Categories: normal, inflammation,                                                                                                                              Cancer
                  probable CIN1, probable CIN2-3, probable & frank invasive
                  Ca. Punch biopsies from every abnormal area, which were
                  examined in the Inst. Med. Science & Research of
                  Coimbatore.
WKCCPP            Colposcopy targeted punch biopsies, in absence of biopsies    VIA+ cases and VIA indeterminate cases.                      Triage tests (VIAM) were performed by different        CIN1
                  expert colposcopy performed by Dr. E. Kauffman was            At the end of the study (for 137) women: VILI was applied    providers blinded to the results of the other triage   CIN2
                  accepted as gold standard and in absence of expert            as well and the VILI result were determinant for referral.   tests.                                                 CIN3
                  colposcopy, nurse colposcopy was considered as pseudo-gold                                                                                                                        Cancer
                  standard.
Thai              No confirmation of screen negatives. Outcome                  VIA+ cases (not suspicious for cancer, lesions not           Not applicable.                                        Not applicable.
demonstration     (complications, failure) after treatment was observed at 3M   extending onto the vaginal wall, occupying <75% of the
trial             and 12M after treatment.                                      cervix, not extending >2mm beyond the cryoprobe) were
                                                                                treated with cryotherapy immediately.
                                                                                Cryotherapy was delayed: menses, menses expected
                                                                                <7days, known HIV (referred to physician), polyp in
                                                                                cervical os (referred to physician for removal), fibroid
                                                                                tumor (>12W size) (referred to physician).




                                                                                                                                                                                                             228
Author, year    Gold standard                                                  Criteria for gold standard application                        Masking of screeners, colposcopists, histologist   Categorization of
                                                                                                                                                                                                the gold standard
                                                                                                                                                                                                outcome
Ghanaian        Colposcopy and biopsy were offered only to women with          No confirmation of screen negatives. Outcome                  VIA+ cases (not suspicious for cancer, lesions     Not applicable.
demonstration   suspicion of cancer or with AW areas greater than 2/3 of the   (complications, failure) after treatment was observed at 3M   not extending onto the vaginal wall, occupying
trial           cervix or extending to the vaginal wall.                       and 12M after treatment.                                      <75% of the cervix, not extending >2mm beyond
                                                                                                                                             the cryoprobe) were treated with cryotherapy
                                                                                                                                             immediately.
                                                                                                                                             Cryotherapy was delayed: menses, menses
                                                                                                                                             expected <7days, known HIV (referred to
                                                                                                                                             physician), polyp in cervical os (referred to
                                                                                                                                             physician for removal), fibroid tumor (>12W
                                                                                                                                             size) (referred to physician).




                                                                                                                                                                                                       229
Table 57. Study design and remarks.
Study                      Study design                                                                                        Remarks
Cross-sectional multi-     The test accuracy of five cervical cancer screening methods were evaluated in more than 58000       It is not clear how 1st colposcopy after VIA interfered with the 2nd
country study              women from eleven urban settings in India and five African countries. The assessed tests were:      colposcopy. 1st and 2nd colposcopy interpretation was performed by
                           naked eye visual inspection of the uterine cervix after application of acetic acid (VIA) or after   the same colposcopist. Further question: was there a residual VIA
                           application of Lugol’s iodine (VILI), VIA with a low level magnifying loop (VIAM), the              effect on the VILI examination.
                           conventional Papanicolaou smear and the HC2 test. The number of women examined and tests            The contrast in sensitivity between VIA & VILI could be enhanced
                           assessed per center is shown in Table 1.                                                            by the fact that in Kolkata, where sensitivity of VIA was lowest,
                                                                                                                               VILI was not performed.
                           Multiple screening tests were applied independently on the same women by different
                           examiners, who were blinded towards the results of the other tests. All participants were
                           subsequently inspected with colposcopy on the same day and, if a colposcopically suspect or
                           abnormal lesion was identified, punch biopsies were taken. Colposcopists and histologists
                           examining biopsies were masked with respect to the screening test results. The histopatho-
                           logical diagnosis was used as gold standard for women from whom biopsies were taken;
                           otherwise the colposcopic impression was used for determination of the final cervical status.
                           This final outcome was categorized in five classes: normal or non-neoplastic changes, cervical
                           intra-epithelial neoplasia grade 1 (CIN1) including HPV changes, CIN2, CIN3 and invasive
                           cancer.
Cross-sectional Zimbabwe   Phase I: only VIA+ (AW lesions, or worse aspect) and LSIL+ cases and 10% VIA- women                 10% random sample of VIA-/cyto- did not participate at random at
Study                      were referred for colposcopy.                                                                       colposcopy, therefore this sample could not be used to correct for
                           Phase II: all women were referred for colposcopy.                                                   verification bias. Unfortunately this non random participation is not
                                                                                                                               documented. Was it significantly not random?
Ambilikai RCT              Cluster randomized study. 57 panchayaths (villages) with 48,225 women among whom 30,577             Biopsies were taken from colposcopically abnormal areas.
                           participated in the study arm, receiving a single round of VIA versus 56 villages with 30,172       Immediate cryotherapy on low-grade & high-grade lesions if <3/4 of
                           women in the control arm receiving usual care.                                                      the ectocervix, without extension in vagina/endocervix. More
                                                                                                                               extensive lesions were referred for LEEP/conization. Suspect cancer
                                                                                                                               cases were referred to a cancer treatment center.
WKCCPP                     Women were examined with VIA; VIA+ and VIA-indeterminate cases were referred at the                 Attendance at colposcopy referral and follow-up of treated women
                           district hospital for colposcopy. Biopsies were taken from colposcopic suspect areas. VIAM          was limited. The study protocol changed over the period. The gold
                           and cytological examination were performed as well as alternative triage methods. Decision          standard definition was not homogenous.
                           for treatment with cryotherapy was based on the colposcopic impression.
                           Women having received cryotherapy or screen+/colposcopic negative women were followed at
                           1-3M and at 12M.
Thai demonstration trial   Testing of 5999 women with VIA, immediate cryotherapy of VIA+ (referral of cases suspect            This study only provides test-positivity rates for the meta-analysis.
                           for cancer). Observation of complications, failure, satisfaction after treatment.                   Nevertheless, it provides information on safety, acceptability,
                                                                                                                               feasibility of immediate treatment without confirmation of the screen
                                                                                                                               test result.
Ghanaian demonstration     Testing of 3665 women with VIA, immediate cryotherapy of VIA+ (referral of cases suspect            This study only provides test-positivity rates for the meta-analysis.
trial                      for cancer). Observation of complications, failure, satisfaction after treatment.                   Nevertheless, it provides information on safety, acceptability,
                                                                                                                               feasibility of immediate treatment without confirmation of the screen
                                                                                                                               test result.




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