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

GENERAL EPIDEMIOLOGY EPIDEMIOLOGY  studies the occurrence and prevalence of diseases among population  identifies disease cases  determines probable relationship between various risk factors

AUSTRALIA 12 USA 89 CANADA 13 ENGLAND 14 WESTERN EUROPE 26 AFRICA-ASIA 5 UKRAINE 1 UNIVERSITIES AND INSTITUTES OF EPIDEMIOLOGY

Types of Epidemiology  medical  pharmaceutical  veterinary  environmental  insurance GENERAL EPIDEMIOLOGY

Classification of medical epidemiology Infection epidemiologyInfection epidemiology General epidemiologyGeneral epidemiology Environment epidemiologyEnvironment epidemiology Clinical epidemiologyClinical epidemiology Military epidemiologyMilitary epidemiology Epidemiology of insuranceEpidemiology of insurance GENERAL EPIDEMIOLOGY

Main types of epidemiology research

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 casesRegistration of new disease cases Exposed group (clean-up workers-86 )Exposed group (clean-up workers-86 ) Unexposed group(clean-up workers-87, )Unexposed group(clean-up workers-87, ) 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 diseaseInvestigation of groups of people defined by presence or absence of disease Case - ( patient) exposed and unexposedCase - ( patient) exposed and unexposed Control - (healthy) exposed and unexposedControl - (healthy) exposed and unexposed Only estimation of relative risk is possibleOnly estimation of relative risk is possible RR (relative risk) or OR (odds ratio) GENERAL EPIDEMIOLOGY

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

Results and discussion Subject of observation:Subject of observation: Chernobyl accident clean-up workers (ACW), males, included in State Chernobyl Registry of Ukraine. 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 periodThe number of persons under study at the end of the observation period is. is EPIDEMIOLOGY OF LEUKAEMIA

Sources of information State Registry of victims of Chernobyl accident (CA)State Registry of victims of Chernobyl accident (CA) specialized registries and subregistriesspecialized registries and subregistries primary data from medical clinicsprimary data from medical clinics data of official disease registration and death cases registrationdata of official disease registration and death cases registration special selective registration of casesspecial selective registration of cases data of expert commission for victims of CAdata 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: Calculation were performed for 5-year intervals , 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 EPIDEMIOLOGY OF LEUKAEMIA

Classification of diseases Choice: Etiology patogeneses Localizations disease ICD-9 or ICD-10 Clinical (FAB) Classification of Leukaemia

subjective, objective symptoms; outcomes of laboratory and tool researches Diagnostic criterions (the majority of diseases has no precise criterions) Diagnostic criterions (the majority of diseases has no precise criterions) Classification of diseases (in case of indeterminacies; vague, not updated cases) Classification of diseases (in case of indeterminacies; vague, not updated cases) Reliability of the diagnosis - autopsy (types of researches) Reliability of the diagnosis - autopsy (types of researches) interpretation errors of classification interpretation errors of classification Reliability of the Diagnoses the Factors influencing the quality of the diagnoses

Reliability of the Diagnoses Strict selection of cases  Loss of true diseases Soft selection of cases  Deriving cases not have significance Gipo diagnostics diagnostics Giper diagnostics

Sensitivity and specificity Under the sensitivity one understand probability that, the patient canl be classified as the patient Number of the patients classified as the patients Se = Total number of the patients Under the specificity one understand to probability that healthy can be classified as healthy N umber of Healthy, classified as healthy Sp = Total number of healthy

MODEL of SENSITIVITY And SPECIFICITY A. Ahlbom, S.Norel 1990 The population The patients Classified cs the patients cs the patients The patients classified as healthy (Is false Negative) Healthy classified classified as the patients (Is false Positive) The patients classified as the patients as the patients

Information flows between institutions and the center cCITY HOSPITALcCITY HOSPITAL DDISPENSARYDDISPENSARY OBLAST HOSPITAL OBLAST DISPENSARY INSTITUTIONAL HEMATOLOGICAL DEPARTMENTS CENTER FOR RADIATION MEDICINE

Information exchange for quality control TECHNICIAN EPIDEMIOLOGIST D/BD/B SUPERVISER

LEUKEMIA DIAGNOSIS STRUCTURE There are 48 cases of leukemia among clean-up workers of – 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 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 case of AL, 4 cases of CLL, 3 cases of CML. EPIDEMIOLOGY OF LEUKAEMIA

LEUKEMIA DIAGNOSIS STRUCTURE EPIDEMIOLOGY OF LEUKAEMIA

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

Generate rate Absolute rate (number) Popularity Morbidity Mortality Expressed as cases from 10 6 to 10 3 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 = number of existing cases of disease 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 IR = number of new cases of disease over a specified time period person-years, person-time, time at risk 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, where IR – incidence rate – duration of observation period GENERAL EPIDEMIOLOGY

confidence interval Calculation of 95% confidence intervals for prevalence rate (PR)prevalence rate (PR) cumulative incidence rate (CI)cumulative incidence rate (CI) incidence rate (IR)incidence rate (IR) IR  1.96 (R- person-years) IR  1.96 (R- person-years) GENERAL EPIDEMIOLOGY

confidence interval Calculation of 95% confidence intervals for relative risk where e - logarithmic base = 2,718 ln - logarithmic function with e base (natural logarithm) ln(RR) - survey number = square root of dispersion var calculated number = square root of dispersion var calculated number GENERAL EPIDEMIOLOGY

Calculation of Relative Risk For cumulative incidence RR=(A 1 /N 1 )/(A 0 /N 0 ) where А=number of cases N=number of person year 95% confidence interval for relative risk ln(RR)- dispersion var[ln(RR)] =[(N 1 -A 1 )/(N 1 *A 1 )]+[(N 0 -A 0 )/(N 0 *A 0 ] GENERAL EPIDEMIOLOGY

Calculation of Relative Risk For incidence rate RR=(A 1 /R 1 )/(A 0 /R 0 ) where А=number of cases R=number of person-years 95% confidence interval for relative risk ln(RR)- dispersion var[ln(RR)] =(1/A 1 )+(1/A 0 ) GENERAL EPIDEMIOLOGY

Stratification Division of the population into subgroups (strata) if there is the base to assume that the incidence is unequal in different groupsDivision 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: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 groupswithin group, intergroup and international standard age is used for comparison of incidence rates in two groups ratio of standardized incidence rates is presented by formularatio of standardized incidence rates is presented by formula (R1.1/R1.n)*RR1.1+(R1.2/R1.n)*RR1.2=ASR1 (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 (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= (N 1 *IR 1 )+(N 2 *IR 2 ) GENERAL EPIDEMIOLOGY

EPIDEMIOLOGY OF LEUKAEMIA

-Number of cases from 20 to 29 years/1000,000 clean-up workers of А г. – B 1 -Number of males from 20 to 29 years/100,000 clean-up workers of A г. – B 2 Calculation For clean-up workers of 1986 A 1 *(12,000/A 2 )=ASR 1 For clean-up workers of 1987 B 1 *(12,000/B 2 )=ASR 2 where 12,000 – world standard in this interval Age Standardized Rate (per ) EPIDEMIOLOGY OF LEUKAEMIA

- COHORT data are presented as relation risk estimation RR=IR 1 / IR 0 where IR 1 and IR 0 are incidence coefficients A 1 and A 0 - number of cases R 1 и R 0 - person-years at risk Design formulas of relation between exposure and incidence GENERAL EPIDEMIOLOGY

- CASE-CONTROL relative risk estimation - odds ratio (OR) where A 1 =a, A 0 =b R 1 =c, R 0 =d A 1 and A 0 - number of cases R 1 and R 0 - person-years at risk Design formulas of relation between exposure and incidence GENERAL EPIDEMIOLOGY

Sources of Radiation Exposure From NCRP Report No: 93

ATOM PRINCIPLE DIAGRAM (Craig C. Freudenrich,2001, HAW) Electron Nucleus Orbit

PENENTRATING RADIATION Radiation Source Alpha Particles Beta Particles Gamma Rays Stopped by a sheet of paper 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

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

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 radiation- induced 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 RADIO-BIOLOGICAL EFFECTS

MODELS of EXCESS of RISKS D.Pierce, D.Preston, 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

Execes absolute risk for leukaemia 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,

Time dependent models of redundantTime dependent models of redundant relative risk adapt DOSE dependence As linear for SOLID CANCERS As linearly – quadratic for LEUKAEMIA MODELS of EXCESS of RISKS D.Pierce, D.Preston,

EPIDEMIOLOGY OF LEUKAEMIA RESUME:  The comparative analysis was done for clean-up workers CWA of 1986 and 1987 by periods of observation of and The results of the conducted study indicate the increasing of the leukemia risk among CWA of 1986 most vividly during Relative risk was defined at the level of 3,32 (1,08; 10,20), and for age group it was 3,45 (1,15; 10,36).  No significant differences were defined in leukemia incidence at survey groups in

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 long- term 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.

Atlas of Cancer Mortality Epidemiologic Research (Books) Epidemiology index Epidemiology statistics – Epidemiology USA Epidemiology USA How Atoms, Radon, Nuclear, Work International Agency Atomic Energy channels of information

International Journal of Epidemiology - Ionizing Radiation, Health Effects Lessons of Hiroshima and Chernobyl Leukemia Research Nuclear Energy Agency-Radiation Protection Radiation Research Radiation and Health Physics Radiation effects Research Foundation Radiation effects channels of information

Radiation Protection Program (EPA) Research Sources (Radiation, Effects) Risk assessment of radiation Statistics on the Web Supercourse –Epidemiology Uranium and Health What is epidemiology? Ministry of Nuclear of Energy Russia Epidemiology, Radiation, Chernobyl, Ukraine (ERCU) channels of information