Evidence-Based Evaluation of Screening and Diagnostic Tests

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					Biases in Studies of Screening
          Programs


  Thomas B. Newman, MD, MPH
         June 10, 2011
                   Overview
   Introduction
    – TN Biases
    – Defintions
   Problems with observational studies
    – Volunteer bias
    – Lead time bias
    – Length bias
    – Stage migration bias
    – Pseudodisease
Screening tests: TN Biases
   “When your only tool is a hammer, you
    tend to see every problem as a nail.”
   Clinical care accounts for 95% of
    spending but only 20% of determinants
    of health*
   Biggest threats are public health threats
   Interventions aimed at individuals are
    overemphasized because they are more
    profitable and we know how to do/sell
    them
*Teutsch SM, Fielding JE. Comparative effectiveness:
looking under the lamppost. JAMA 2011; 305:2225-6
Cultural characteristics
  "We live in a wasteful, technology
  driven, individualistic and death-
  denying culture."
     --George Annas, New Engl J Med, 1995
 What is screening?
   Common definition: testing to detect
    asymptomatic disease
   Better definition*: application of a test to
    detect a potential disease or condition in
    people with no known signs or
    symptoms of that disease or condition.
    – Disease vs. condition
    – Asymptomatic vs. no known signs or
      symptoms

*Common screening tests. David M. Eddy, editor. Philadelphia, PA:
American College of Physicians, 1991
Screening tests may be history questions
Screening Spectrum




Risk factor   Presymp-     Unrecognized     Recognized
              tomatic      symptomatic      symptomatic
              disease      disease          disease


    Decreasing numbers labeled and treated
    Decreasing difficulty demonstrating benefit
Examples and overlap
   Unrecognized symptomatic disease: vision
    and hearing problems in young children; iron
    deficiency anemia, depression
   Presymptomatic disease: neonatal
    hypothyroidism, syphilis, HIV
   Risk factor: hypercholesterolemia,
    hypertension
   Somewhere between: prostate cancer,
    ductal carcinoma in situ of the breast, more
    severe hypertension
    Evaluating Studies of Screening
        Ideal Study:
         – Randomize patients to be screened or
           not
         – Compare outcomes in ENTIRE
           screened group to ENTIRE
           unscreened group


                                 Mortality after
      Screened          D+
                                 Randomization
R                       D-
     Not screened       D+        Mortaltiy after
                        D-        Randomization
Observational studies: Patients
are not randomized
   Compare outcomes in screened vs.
    unscreened patients
   Or among patients with disease:
    – Compare outcomes in those diagnosed by
      screening vs. those diagnosed by
      symptoms
    – Compare stage-specific survival with and
      without screening
KEY DIFFERENCE: Mortality vs.
Survival
   Mortality: denominator is a population,
    most of whom never get the disease
   Survival: denominator is patients with
    the disease
   Beware of any studies evaluating
    screening tests using survival
Possible Biases in Observational
Studies of Screening Tests
   Volunteer bias
   Lead time bias
   Length time bias
   Stage migration bias
   Pseudodisease
Volunteer Bias
   People who volunteer for screening
    differ from those who do not
   Examples
    – HIP Mammography study:
       • Women who volunteered for mammography
         had lower heart disease death rates
    – Multicenter Aneurysm Screening Study
      (MASS; Problem 6.3)
       • Men aged 65-74 were randomized to either
         receive an invitation for an abdominal
         ultrasound scan or not.
MASS Within Groups Result in
Invited Group
MASS -- Invited Group Only
                  N     AAA Death    %    Total Death %
Scanned        27,147      43       0.16%    2,590       9.54%
Not Scanned 6,692          22       0.33%    1,160      17.33%
               33,839      65                3,750
Avoiding Volunteer Bias

   Randomize patients to screened and
    unscreened
   Otherwise, try to control for factors
    (confounders) associated with both
    screening and outcome
    – Examples: family history, level of health
      concern, other health behaviors, baseline
      health/illnesses
Lead Time Bias (zero-time bias)

   Screening identifies disease during a
    latent period before it becomes
    symptomatic
   If survival is measured from time of
    diagnosis, screening will always improve
    survival even if treatment is ineffective
 Lead time bias




Source: EDITORIAL: Finding and Redefining Disease. Effective Clinical Practice,
March/April 1999. Available at: ACP- Online
http://www.acponline.org/journals/ecp/marapr99/primer.htm accessed 8/30/02
Avoiding Lead Time Bias
   Only occurs when survival from
    diagnosis is compared between
    diseased persons
    – Screened vs. not screened
    – Diagnosed by screening vs. by symptoms
   Avoiding lead time bias
    – Measure mortality, not survival
    – Count from date of randomization
    – Follow patients for a long time (20 years?)
      and use total, not e.g. 5-year survival
Length Bias (Different natural history
bias)
   Screening picks up prevalent disease
   Prevalence = incidence x duration
   Slowly growing tumors have greater duration
    in presymptomatic phase, therefore greater
    prevalence
   Therefore, cases picked up by screening will
    be disproportionately those that are slow
    growing
  Length bias




Source: EDITORIAL: Finding and Redefining Disease. Effective Clinical Practice, March/April 1999.
Available at: ACP- Online http://www.acponline.org/journals/ecp/marapr99/primer.htm
Length Bias


           Slower growing
           tumor with
           better prognosis


                  ?
Early detection           Higher cure rate
Avoiding Length Bias
   Only present when
    – survival from diagnosis is compared
    – AND disease is heterogeneous
   Lead time bias usually present as well
   Avoiding length bias:
    – Compare mortality in the ENTIRE
      screened group to the ENTIRE
      unscreened group
    – Study disease subgroups with a uniform
      natural history
Stage migration bias
                   Stage 0
   Stage 0
                   Stage 1
   Stage 1
                   Stage 2
   Stage 2
                   Stage 3
   Stage 3

   Stage 4         Stage 4

    Old tests          New tests
Stage migration bias
   Also called the "Will Rogers
    Phenomenon"
    – "When the Okies left Oklahoma and moved
      to California, they raised the average
      intelligence level in both states."
                                   -- Will Rogers
   Documented with colon cancer at Yale
   Other examples abound – the more you
    look for disease, the higher the
    prevalence and the better the prognosis
    Best reference on this topic: Black WC and Welch HG. Advances in
    diagnostic imaging and overestimation of disease prevalence and the
    benefits of therapy. NEJM 1993;328:1237-43.
A more general example of Stage
Migration Bias
   VLBW (< 1500 g), LBW (1500-2499 g) and
    NBW (> 2500 g) newborns exposed to Factor
    X in utero have decreased mortality
    compared with those not exposed
   Is factor X good?
   Maybe not! Factor X could be cigarette
    smoking!
    – Smoking moves babies to lower birthweight strata
    – Compared with other causes of LBW (i.e.,
      prematurity) it is not as bad
           Stage Migration Bias
                                       NBW
NBW




                                       LBW
LBW




                                       VLBW
VLBW



       Unexposed to       Exposed to
          smoke             smoke
Avoiding Stage Migration Bias
   The harder you look for disease, and the
    more advanced the technology
    – the higher the prevalence, the higher the stage,
      and the better the (apparent) outcome for the
      stage
   Beware of stage migration in any stratified
    analysis
    – Check OVERALL survival in screened vs.
      unscreened group
   More generally, do not stratify on factors
    distal in a causal pathway to the factor you
    wish to evaluate!
Pseudodisease
   A condition that looks just like the disease,
    but never would have bothered the patient
    – Type I: Disease which would never cause
      symptoms
    – Type II: Preclinical disease in people who will die
      from another cause before disease presents
   In an individual treated patient it is impossible
    to distinguish pseudodisease from
    successfully treated asymptomatic disease
   The Problem:
    – Treating pseudodisease will always look
      successful
    – Treating pseudodisease will always be harmful
Example: Mayo Lung Project
   RCT of lung cancer screening
   Enrollment 1971-76
   9,211 male smokers randomized to two
    study arms
    – Intervention: chest x-ray and sputum
      cytology every 4 months for 6 years (75%
      compliance)
    – Control: Tests at trial entry, then a
      recommendation to receive the same tests
      annually
     *Marcus et al., JNCI 2000;92:1308-16
Mayo Lung Project Extended Follow-up
Results*
   Among those with lung cancer, intervention group
    had more cancers diagnosed at early stage and
    better survival




         *Marcus et al., JNCI 2000;92:1308-16
MLP Extended Follow-up Results*
   Intervention group: slight increase in lung-
    cancer mortality (P=0.09 by 1996)




         *Marcus et al., JNCI 2000;92:1308-16
What happened?
   After 20 years of follow up, there was a
    significant increase (29%) in the total
    number of lung cancers in the screened
    group
    – Excess of tumors in early stage
    – No decrease in late stage tumors
   Overdiagnosis (pseudodisease)

Black W. Overdiagnosis: an underrecognized cause of
confusion and harm in cancer screening. JNCI
2000;92:1308-16
    Looking for Pseudodisease
   Appreciate the varying natural history of
    disease, and limits of diagnosis
   Impossible to distinguish from successful cure
    of (asymptomatic) disease in individual
    patient
   Few compelling stories of pseudodisease…
   Clues to pseudodisease:
    – Higher cumulative incidence of disease in
      screened group
    – No difference in overall mortality between
      screened and unscreened groups
Each year, 182,000 women are diagnosed with breast
cancer and 43,300 die. One woman in eight either has or
will develop breast cancer in her lifetime...
If detected early, the five-year survival rate exceeds 95%.
Mammograms are among the best early detection methods,
yet 13 million women in the U.S. are 40 years old or older
and have never had a mammogram.




    39,800 Clicks per mammogram (Sept, ’04)
Why is this misleading
   Each year 43,000 die, 182,000 new
    cases suggests mortality is ~24%
   5-year survival > 95% with early
    detection suggests < 5% mortality,
    suggesting about 80% of these deaths
    preventable
   Actual efficacy is closer < 20% for
    breast cancer mortality (lower for total
    mortality)
Questions?

				
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posted:9/11/2012
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