RADIATION EPIDEMIOLOGY AND LEUKEMIA

RADIATION EPIDEMIOLOGY AND LEUKEMIA B.Ledoshchuk, M.D.,Ph.D. Institute of Epidemiology Research Center for Radiation Medicine of Ukraine Kyiv-2001 EPIDEMIOLOGY OF LEUKAEMIA Results of the 10-year study of leukemia among the Chernobyl accident clean-up workers in Ukraine 1986-96 GENERAL EPIDEMIOLOGY EPIDEMIOLOGY  studies the occurrence and prevalence of diseases among population  identifies disease cases  determines probable relationship between various risk factors UNIVERSITIES AND INSTITUTES OF EPIDEMIOLOGY CANADA 13 ENGLAND 14 WESTERN EUROPE 26 USA 89 UKRAINE 1 AUSTRALIA 12 AFRICA-ASIA 5 GENERAL EPIDEMIOLOGY Types of Epidemiology  medical  pharmaceutical  veterinary  environmental  insurance GENERAL EPIDEMIOLOGY Classification of medical epidemiology • Infection epidemiology • General epidemiology • • • • Environment epidemiology Clinical epidemiology Military epidemiology Epidemiology of insurance Main types of epidemiology research REPRODUCTIVE MOLECULAR SOCIAL ONCOLOGICAL PROFESSIONAL ENDOCRINOLOGICA L ECOLOGICAL CARDIOLOGYCAL GENERAL EPIDEMIOLOGY Methods of analytical epidemiology  Cohort  Case control  Combined GENERAL EPIDEMIOLOGY Methods of analytical epidemiology Cohort study, Follow-up study Investigation for a certain period of time of a group of people defined prior to onset of disease • • • Registration of new disease cases Exposed group (clean-up workers-86 ) Unexposed group(clean-up workers-87, 88-90 ) There is a risk of healthy worker effect in comparison with population (underestimation IR in exposed group) GENERAL EPIDEMIOLOGY Methods of analytical epidemiology Case/control studies • Investigation of groups of people defined by presence or absence of disease • Case - ( patient) exposed and unexposed • Control - (healthy) exposed and unexposed • Only estimation of relative risk is possible RR (relative risk) or OR (odds ratio) EPIDEMIOLOGY OF LEUKAEMIA  Goal of research : Define the dependence of incidence of leukemia among Chernobyl accident clean-up workers (ACW) on the year of participation in emergency works and period of time that passed since exposure to radiation EPIDEMIOLOGY OF LEUKAEMIA Results and discussion • Subject of observation: Chernobyl accident clean-up workers (ACW), males, included in State Chernobyl Registry of Ukraine. • The number of persons under study at the end of the observation period is 179 026 . EPIDEMIOLOGY OF LEUKAEMIA Sources of information • State Registry of victims of Chernobyl accident (CA) • specialized registries and subregistries • primary data from medical clinics • data of official disease registration and death cases registration • special selective registration of cases • data of expert commission for victims of CA EPIDEMIOLOGY OF LEUKAEMIA Main sources of information for case search:  Results of annual medical examination of ACW  Regional hematological clinics data EPIDEMIOLOGY OF LEUKAEMIA Main methods of obtaining of information : • • • • retrospective current passive active EPIDEMIOLOGY OF LEUKAEMIA Period of observation ACW: 1987-1996 Calculation were performed for 5-year intervals 1987-1991, 1992-1996 EPIDEMIOLOGY OF LEUKAEMIA Diagnostic criteria  - under-record of cases due to strong diagnostic criteria  - over-record of cases (including irrelevant to the diagnosis cases) due to insufficient demands to diagnosis Classification of diseases Choice:  Etiology patogeneses Localizations disease ICD-9 or ICD-10 Clinical (FAB) Classification of Leukaemia Reliability of the Diagnoses the Factors influencing the quality of the diagnoses • subjective, objective symptoms; outcomes of laboratory and tool researches • Diagnostic criterions (the majority of diseases has no precise criterions) • Classification of diseases (in case of indeterminacies; vague, not updated cases) • Reliability of the diagnosis - autopsy (types of researches) • interpretation errors of classification Reliability of the Diagnoses Strict selection of cases  Loss of true diseases Soft selection of cases  Deriving cases not have significance Gipo diagnostics Giper diagnostics Sensitivity and specificity Under the sensitivity one understand probability that, the patient canl be classified as the patient Se Number of the patients classified as the patients = Total number of the patients Under the specificity one understand to probability that healthy can be classified as healthy Sp = N umber of Healthy, classified as healthy Total number of healthy MODEL of SENSITIVITY And SPECIFICITY A. Ahlbom, S.Norel 1990 The patients The patients classified as healthy The population Classified cs the patients Healthy classified as the patients (Is false Negative) The patients classified as the patients (Is false Positive) Information flows between institutions and the center •cCITY HOSPITAL •DDISPENSARY OBLAST HOSPITAL OBLAST DISPENSARY INSTITUTIONAL HEMATOLOGICAL DEPARTMENTS CENTER FOR RADIATION MEDICINE Information exchange for quality control EPIDEMIOLOGIST SUPERVISER D/B TECHNICIAN EPIDEMIOLOGY OF LEUKAEMIA LEUKEMIA DIAGNOSIS STRUCTURE There are 48 cases of leukemia among clean-up workers of 1986 • • • • 13 – acute leukemia - AL (27 %), 20 – CLL (42 %), 14 – CML (29 %), 1 – other forms of leukemia (2 %). EPIDEMIOLOGY OF LEUKAEMIA LEUKEMIA DIAGNOSIS STRUCTURE There are 15 cases of leukemia among clean-up workers of 1987 • • • • 8 cases of AL (53 %), 2 cases of CLL (13 %), 4 cases of CML (27 %), 1 case of unspecified leukemia (7 %). EPIDEMIOLOGY OF LEUKAEMIA LEUKEMIA DIAGNOSIS STRUCTURE There are 8 cases of leukemia among clean-up workers of 1988-90 • 1 case of AL , • 4 cases of CLL, • 3 cases of CML. EPIDEMIOLOGY OF LEUKAEMIA LEUKEMIA DIAGNOSIS STRUCTURE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1986 1987 88-90 Total Unspecified leukemia CML CLL AL GENERAL EPIDEMIOLOGY • Crude measure – calculated for population as a whole • Specific measure – calculated for specific groups of population • Standardized measure – for completion of summary comparison between two or more groups diversified according to age or other criteria GENERAL EPIDEMIOLOGY Generate rate • Absolute rate (number) • Popularity • Morbidity • Mortality • Expressed as cases from 106 to 103 in investigated cohort (case/control) GENERAL EPIDEMIOLOGY Popularity prevalence rate, ratio - PR • It is a quota of morbidity among population in certain moment of time PR = A number of existing cases of disease B population during the same of time period GENERAL EPIDEMIOLOGY Morbidity incidence rate - IR Represents rate at which new cases are occurring. • IR = number of new cases of disease over a specified time period person-years, person-time, time at risk GENERAL EPIDEMIOLOGY CUMULATIVE INCIDENCE • cumulative incidence rate - CI • It is a quota of healthy persons that can fall ill during a certain period of time • CI number of new cases over a specified time period = population at the beginning of a specified time period • t x RI  IC , where IR – incidence rate – duration of observation period GENERAL EPIDEMIOLOGY confidence interval Calculation of 95% confidence intervals for • prevalence rate (PR) PR  1,96 PR (1  PR ) N • cumulative incidence rate (CI) CI  1,96 CI (1  CI ) N • incidence rate (IR) IR1.96 IR (R- person-years) R GENERAL EPIDEMIOLOGY confidence interval Calculation of 95% confidence intervals for • relative risk e ln(RR)  1,96 var[ln(RR) ] where e - logarithmic base = 2,718 ln - logarithmic function with e base (natural logarithm) ln(RR) - survey number var[ln(RR) ] = square root of dispersion var calculated number GENERAL EPIDEMIOLOGY Calculation of Relative Risk For cumulative incidence RR=(A1/N1)/(A0/N0) where А=number of cases N=number of person year 95% confidence interval for relative risk ln(RR)-dispersion var[ln(RR)] =[(N1-A1)/(N1*A1)]+[(N0-A0)/(N0*A0] GENERAL EPIDEMIOLOGY Calculation of Relative Risk For incidence rate RR=(A1/R1)/(A0/R0) where А=number of cases R=number of person-years 95% confidence interval for relative risk ln(RR)-dispersion var[ln(RR)] =(1/A1)+(1/A0) GENERAL EPIDEMIOLOGY Stratification • Division of the population into subgroups (strata) if there is the base to assume that the incidence is unequal in different groups • strata distribute according to: – age – sex – occupation – radiation dose – other effects GENERAL EPIDEMIOLOGY Standardization - is one of the method of comparison validity • direct method of standardization • indirect method of standardization GENERAL EPIDEMIOLOGY Direct Method of Standardization • within group, intergroup and international standard age is used for comparison of incidence rates in two groups • ratio of standardized incidence rates is presented by formula (R1.1/R1.n)*RR1.1+(R1.2/R1.n)*RR1.2=ASR1 (R2.1/R2.n)*RR2.1+(R2.2/R2.n)*RR2.2=ASR2 GENERAL EPIDEMIOLOGY indirect method of standardization SIR(O/E)*100 (standardized incidence ratio SIR) • ratio of O-observed number of cases at exposed group and E - expected number of cases at control group • standard age of exposed group is used for comparison incidence rates in two groups E= (N1*IR1)+(N2*IR2) EPIDEMIOLOGY OF LEUKAEMIA D istrib u tion p erson -y ears of ob servation b y age grou p s am on g C W A (fu ll p eriod , 1987 -1996 ) A g e g ro u p 2 0 -2 9 3 0 -3 9 4 0 -4 9 5 0 -5 9 6 0 -6 9 TOTAL 1986 128 470 336 877 187 467 74 242 20 021 747 077 Y ear o f clean -u p w o rk 1987 1 9 8 8 -1 9 9 0 1 9 8 6 -1 9 9 0 52 439 4 180 185 089 165 222 111 563 613 662 98 292 93 248 379 007 13 070 4 437 91 749 2 291 568 22 880 331 314 213 996 1 292 387 EPIDEMIOLOGY OF LEUKAEMIA D istrib u tio n o f p erso n -years o f o b serv atio n b y p erio d s P erio d o f o b serv atio n 1 9 8 7 -1 9 9 1 1 9 9 2 -1 9 9 6 1 9 8 7 -1 9 9 6 Y ear o f clean -u p w o rk 1986 1987 198819861990 1990 292 823 127 330 57 020 477 173 454 254 203 984 156 976 815 214 747 077 331 314 213 996 1 292 387 EPIDEMIOLOGY OF LEUKAEMIA . A g e d is tr ib u tio n o f th e le u k e m ia d ia g n o s e d C W A u n d e r s tu d y in 1 9 8 7 -1 9 9 6 A ge group 2 0 -2 9 3 0 -3 9 4 0 -4 9 5 0 -5 9 6 0 -6 9 2 0 -6 9 Y ear of 1986 4 7 15 18 4 48 th e c le a n -u p w o r k 1 9 8 7 1 9 8 8 -1 9 9 0 1 9 8 6 -1 9 9 0 1 1 6 5 3 15 7 3 25 1 1 20 1 0 5 15 8 71 EPIDEMIOLOGY OF LEUKAEMIA Age Standardized Rate (per 100.000) -Number of cases from 20 to 29 years/1000,000 clean-up workers of 1986 - А1 1987г. – B1 -Number of males from 20 to 29 years/100,000 clean-up workers of 1986 - A2 1987г. – B2 Calculation For clean-up workers of 1986 A1*(12,000/A2)=ASR1 For clean-up workers of 1987 B1*(12,000/B2)=ASR2 where 12,000 – world standard in this interval EPIDEMIOLOGY OF LEUKAEMIA D istrib u tio n o f th e leu k em ia d iag n o sed in C W A u n d er stu d y in 1 9 8 7 -1 9 9 6 b y p erio d s o f o b serv atio n P erio d o f o b serv atio n 1 9 8 7 -1 9 9 1 1 9 9 2 -1 9 9 6 1 9 8 7 -1 9 9 6 Y ear o f th e clean -u p w o rk 1986 1987 198819861990 1990 22 6 1 29 26 9 7 42 48 15 8 71 EPIDEMIOLOGY OF LEUKAEMIA R esu lts o f S tan d ard ized L eu k em ia In cid en ce R atio calcu latio n fo r C W A o f 1 9 8 6 v ersu s C W A o f 1 9 8 7 b y p erio d s o f o b serv atio n . P erio d o f o b serv atio n S R R 1 /S R R 2 (9 5 % C I) 1 9 8 7 -1 9 9 1 1 9 9 2 -1 9 9 6 1 9 8 7 -1 9 9 6 3 ,3 2 (1 ,0 8 ; 1 0 ,2 0 ) 0 ,6 9 (0 ,1 5 ; 3 ,0 5 ) 1 ,0 0 (0 ,2 9 ; 3 ,4 2 ) GENERAL EPIDEMIOLOGY Design formulas of relation between exposure and incidence - COHORT data are presented as relation risk estimation RR=IR1 / IR0 where IR1 and IR0 are incidence coefficients A1 and A0 - number of cases R1 и R0 - person-years at risk RR  IR IR 1 0  A /R A /R 1 0 1 0 GENERAL EPIDEMIOLOGY Design formulas of relation between exposure and incidence - CASE-CONTROL relative risk estimation odds ratio (OR) where A1=a, A0=b R1=c, R0=d A1 and A0 - number of cases R1 and R0 - person-years at risk a OR  b c d  ad bc Sources of Radiation Exposure From NCRP Report No: 93 55% 26% 1% Radon Medical X_rays Consumer Products 3% 4% 11% Natural Sources (ex.Radon) Nuclear Medicine Other ATOM PRINCIPLE DIAGRAM (Craig C. Freudenrich,2001, HAW) Electron Nucleus Orbit PENENTRATING RADIATION Radiation Source Alpha Particles Stopped by a sheet of paper Beta Particles Stopped by a layer of clothing or by a few millimeters of a substance Stopped by several feet of concrete organic tissue or a few inches of lead Gamma Rays RADIO-BIOLOGICAL EFFECTS NOT STOCHASTIC EFFECTS • as a result of high irradiation acute radiation sickness and furnaces radiation injuries are developed STOCHASTIC EFFECTS • developed during prolonged irradiation (external, internal, balanced, critical organs etc.) Somatic, genetic, embryo toxic RADIO-BIOLOGICAL EFFECTS STOCHASTIC EFFECTS • Somatic and genetic, embryo toxic effects are developed in casual, probabilistic nature • Only probability of damage appearance depends on dose, but not weight and depth of damage • Frequency of appearance radiationinduced diseases increases with dose increase RADIO-BIOLOGICAL EFFECTS STOCHASTIC EFFECTS • Summary stochastic effects during population irradiation (population group) are defined by collective dose • It is impossible to define an individual effect or additional risk and it is impossible to determine which kind of cancer is typical for additional cases MODELS of EXCESS of RISKS D.Pierce, D.Preston, 1996-1999 Time dependent models of redundant relative risk for solid swellings Limit of models of risk for a cancer = 10 years Absolute risk for leukaemia Limit of models leukaemia = 2 years The limit of models of risk is a concept latent Period - between the beginning of effect of the radiation factor and diagnostics leukaemia MODELS of EXCESS of RISKS D.Pierce, D.Preston, 1996-1999 Execes absolute risk for leukaemia EAR  α(d  θ d )exp β 2 Where  and  - constant:  - depends on categories Age for want of effect and, for each from these categories, categories of time from time of effect and sex D – Doze equivalent red marrow, in Siverts (Sv) MODELS of EXCESS of RISKS D.Pierce, D.Preston, 1996-1999 • Time dependent models of redundant relative risk adapt DOSE dependence As linear for SOLID CANCERS As linearly – quadratic for LEUKAEMIA EPIDEMIOLOGY OF LEUKAEMIA RESUME:  The comparative analysis was done for clean-up workers CWA of 1986 and 1987 by periods of observation of 19871991 and 1992-1996. • The results of the conducted study indicate the increasing of the leukemia risk among CWA of 1986 most vividly during 1987-1991. • Relative risk was defined at the level of 3,32 (1,08; 10,20), and for 20-59 age group it was 3,45 (1,15; 10,36).  No significant differences were defined in leukemia incidence at survey groups in 1992-1996. About author Ledoshchuk Boris Alexandrovich born in 1946 in Russia. In 1970 graduated from Blagoveschensk Medical Institute, where also studied in coordinator and at post-graduate course. In 1975 – 1978 worked in the Institute of clinical and experimental medicine of the Academy of Sciences of USSR in Novosibirsk. Took part in scientific epidemiological studies of Far-East and Siberia regions inhabitants. In 1978 – 1985 possessed various positions in medical institutions of Nikolaev region (Ukraine). In 1986 – 1988 worked in the Ministry for Health Care of Ukraine where was responsible for rehabilitation programmer of the population of Chernobyl contaminated area. Since 1988 heads scientific leukemia epidemiology laboratory of the Radiation Medicine Scientific Center. In 1995 – 2000 headed the Medical Department of the Ministry of Atomic Energy. Since 27 April 1986 was involved in clean-up works in the Chernobyl area. One of the leading specialists in the problems of automatic systems of longterm medical monitoring of people damaged in result of Chernobyl accident (State Registry of Ukraine). Author of more than 100 scientific articles and works on the problems of epidemiology, automatic systems of registration and radiation medicine. Prominent participant of international epidemiology projects: AIFIKA, Chernobyl, Leukemia. B. A. Ledoshchuk M.D.,Ph.D. channels of information Atlas of Cancer Mortality http://www-dceg.ims.nci.nih.gov/atlas/index.htm/ Epidemiologic Research (Books) www.amazon.com/exec/obidos/ Epidemiology index http://home.beseen.com/technology/bcjung/Episites.htm/ Epidemiology statistics – www.geocities.com/vadivale/internet11.htm/ Epidemiology USA http://acepidemiology.org/ATLANTA.htm/ How Atoms, Radon, Nuclear, Work - www.howstuffworks.com International Agency Atomic Energy http://www.iaea.org/ channels of information International Journal of Epidemiology - www.ije.oupjournals.org Ionizing Radiation, Health Effects www.epa.gov/radiation Lessons of Hiroshima and Chernobyl www.whyfiles.org/020radiation/index.html Leukemia Research http://dspase.dial.pipex.com/lif-/diseases/index/htm Nuclear Energy Agency-Radiation Protection http://www.oecdnea.org/html/rp/ Radiation Research http://www.radres.org/ Radiation and Health Physics http://www.umich.edu/~radinfo/ Radiation effects Research Foundation www.rerf.or.jp/ Radiation effects www.eh.doe.gov/ihp/rerf/ channels of information Radiation Protection Program (EPA) www.epa.gov/radiation/ionize.htm Research Sources (Radiation, Effects) www.umich.edu/~radinfo/reas.html Risk assessment of radiation www.radrisk.obninsk.com Statistics on the Web http://www.execpc.com/~helberg/statistics.htm/ Supercourse –Epidemiology www.pitt.edu/~super1/index.htm Uranium and Health www.antenna.nl/~wise/uranium/uhr.html What is epidemiology? www.bmj.comepidem/epid.1.html Ministry of Nuclear of Energy Russia www.minatom.ru Epidemiology, Radiation, Chernobyl, Ukraine (ERCU) www.epidemUA.svitonline.com