RADIATION EPIDEMIOLOGY AND LEUKEMIA RADIATION EPIDEMIOLOGY AND LEUKEMIA B.Ledoshchuk, M.D.,Ph.D. Institute of Epidemiology Research Center for Radiation

RADIATIONRADIATIONEPIDEMIOLOGYEPIDEMIOLOGYAND LEUKEMIAAND LEUKEMIA

B.Ledoshchuk, M.D.,Ph.D.

Institute of Epidemiology

Research Center for Radiation Medicine of Ukraine

Kyiv-2001

EPIDEMIOLOGY OF LEUKAEMIAEPIDEMIOLOGY OF LEUKAEMIA

Results of the 10-year study of leukemia among the

Chernobyl accident clean-up workers in Ukraine

1986-96

GENERAL EPIDEMIOLOGYGENERAL EPIDEMIOLOGY

EPIDEMIOLOGY studies the occurrence and prevalence of

diseases among population identifies disease cases determines probable relationship between

various risk factors

AUSTRALIA12

USA89

CANADA13

ENGLAND14

WESTERN EUROPE

26

AFRICA-ASIA5

UKRAINE1

UNIVERSITIES AND INSTITUTES OF EPIDEMIOLOGYUNIVERSITIES AND INSTITUTES OF EPIDEMIOLOGY

Types of Epidemiology medical pharmaceutical veterinary environmental insurance


Classification of medical epidemiology

•Infection epidemiologyInfection epidemiology

•GeneralGeneral epidemiologyepidemiology •Environment epidemiologyEnvironment epidemiology

•Clinical epidemiologyClinical epidemiology

•Military epidemiologyMilitary epidemiology

•Epidemiology of insuranceEpidemiology of insurance


Main types of epidemiology researchMain types of epidemiology research

MOLECULAR

REPRODUCTIVE

ENDOCRINOLOGICAL

PROFESSIONAL

ECOLOGICALCARDIOLOGYCAL

ONCOLOGICALSOCIAL

Methods of analytical epidemiology

Cohort Case control Combined


Methods of analytical epidemiology

Cohort study, Follow-up studyInvestigation for a certain period of time of a Investigation for a certain period of time of a

group of people defined prior to onset of disease 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, 88-90 )Unexposed group(clean-up workers-87, 88-90 )

There is a risk of healthy worker effect in comparison with There is a risk of healthy worker effect in comparison with population (underestimation IR in exposed group)population (underestimation IR in exposed group)


Methods of analytical epidemiologyCase/control studies

•Investigation of groups of people defined by Investigation of groups of people defined by presence or absence of diseasepresence or absence of disease

•CaseCase - ( - ( patientpatient) ) exposed and unexposedexposed and unexposed•ControlControl - ( - (healthyhealthy) ) exposed and unexposedexposed and unexposed•Only estimation of relative risk is possibleOnly estimation of relative risk is possibleRR (relative risk) orRR (relative risk) or OR OR ((odds ratioodds ratio))


EPIDEMIOLOGYEPIDEMIOLOGY OF LEUKAEMIAOF LEUKAEMIA

Goal of research ::Define the dependenceDefine the dependence of incidence of of incidence of leukemia among Chernobyl accident leukemia among Chernobyl accident clean-up workers (ACW) on the year clean-up workers (ACW) on the year of participation in emergency works of participation in emergency works and period of time that passed since and period of time that passed since exposure to radiationexposure to radiation

Results and discussion• Subject of observation: Subject of observation:

Chernobyl accident clean-up workers Chernobyl accident clean-up workers (ACW), males, included in State (ACW), males, included in State Chernobyl Registry of Ukraine. Chernobyl Registry of Ukraine.

• The number of persons under study at The number of persons under study at the end of the observation period the end of the observation period

is is 179 026 . .


Sources of information• State Registry of victims of State Registry of victims of Chernobyl Chernobyl

accident accident (CA)(CA)

• specialized registries and subregistriesspecialized registries and subregistries• primary data from medical clinicsprimary data from medical clinics• data of official disease registration and death data of official disease registration and death

cases registrationcases 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


Main sources of information for case search:

Results of annual medical examination of ACW

Regional hematological clinics data


Main methods of obtaining of information :

•retrospective

•current

•passive

•active


Period of observation ACW:1987-1996

Calculation were performed for 5-year intervals

1987-1991, 1992-1996


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 Classification of diseasesdiseases

Choice: EtiologypatogenesesLocalizations disease ICD-9 or ICD-10Clinical (FAB) Classification of

Leukaemia

• ssubjectiveubjective, o, objective symptoms; outcomes of bjective symptoms; outcomes of laboratory and tool researcheslaboratory and tool researches• Diagnostic criterions (the majority of Diagnostic criterions (the majority of diseasesdiseases has no has no precise criterions)precise criterions)• Classification of Classification of diseases diseases ((in case of in case of indeterminacies; indeterminacies; vague, not updated cases)vague, not updated cases)• Reliability of the diagnosis - Reliability of the diagnosis - autopsyautopsy ( (typestypes of of researches)researches)• interpretation errorinterpretation errorss of classification of classification

Reliability of the DiagnosesReliability of the Diagnoses

the Factors influencing the quality of the diagnoses

Reliability of the DiagnosesReliability of the Diagnoses

Strict selection of cases

Loss of true diseases

Soft selection of cases

Deriving cases not have significance

GipoGipo diagnosticsdiagnostics

GiperGiper diagnosticsdiagnostics

Sensitivity and specificitySensitivity 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 SPECIFICITYMODEL of SENSITIVITY And SPECIFICITY A. Ahlbom, S.Norel 1990A. Ahlbom, S.Norel 1990

The populationThe populationThe patients ClassifiedClassified ccs the patientss the patients

The patients The patients cclassifiedlassifiedaas healthys healthy

(Is falseNegative)

HealthyHealthy cclassified lassified

aas the patientss the patients

(Is false Positive)

The patients The patients cclassifiedlassified aas the patientss the patients

Information flows between institutions Information flows between institutions and the centerand the center

•ccCITY HOSPITALCITY HOSPITAL•DDDDISPENSARYISPENSARY

OBLAST HOSPITAL OBLAST HOSPITAL OBLAST DISPENSARYOBLAST DISPENSARY

INSTITUTIONAL INSTITUTIONAL HEMATOLOGICAL HEMATOLOGICAL DEPARTMENTSDEPARTMENTS

CENTER FOR RADIATION MEDICINE

Information exchange for Information exchange for quality controlquality control

TECHNICIAN

EPIDEMIOLOGIST

D/B

SUPERVISER

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 %).



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 %).



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.


LEUKEMIA DIAGNOSIS

STRUCTURE

0%10%20%30%40%50%60%70%80%90%

100%

1986 1987 88-90 Total

Unspecifiedleukemia

CML

CLL

AL



• 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 106 to 103 in investigated cohort (case/control)


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

B

A


Morbidity

incidence rate - IR Represents rate at which new cases are Represents rate at which new cases are

occurring.occurring.

• IR IR = = number of new cases of disease over a specified time period number of new cases of disease over a specified time period

person-years, person-time, time at riskperson-years, person-time, time at risk


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

tx IR CI


confidence intervalconfidence intervalCalculation of 95% confidence intervals forCalculation 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) IRIR1.96 (R- person-years)1.96 (R- person-years)

R

IR

NPRPR

PR)1(

96,1

NCICI

CI)1(

96,1


confidence intervalCalculation of 95% confidence intervals for

• relative risk

where where e e - logarithmic base = 2,718- logarithmic base = 2,718ln - logarithmic function with e base (ln - logarithmic function with e base (natural natural

logarithm)logarithm)ln(RR) - survey numberln(RR) - survey number = square root of dispersion var = square root of dispersion var

calculated numbercalculated number]var[ln(RR)

e ]var[ln(RR)1,96ln(RR)


Calculation of Relative RiskFor 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]


Calculation of Relative RiskFor 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)


Stratification• Division of the population into subgroups (strata) Division of the population into subgroups (strata)

if there is the base to assume that the incidence is if there is the base to assume that the incidence is unequal in different groupsunequal in different groups

• strata distribute according to:strata distribute according to:– ageage– sexsex– occupationoccupation– radiation doseradiation dose– other effectsother effects


Standardization- is one of the method of comparison validity

• direct method of standardization

• indirect method of standardization


Direct Method of Standardization

• within group, intergroup and international standard within group, intergroup and international standard age is used for comparison of incidence rates in two age is used for comparison of incidence rates in two groupsgroups

• ratio of standardized incidence rates is presented by ratio of standardized incidence rates is presented by formulaformula

(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


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)



Distribution person-years of observation by age groups among CWA(full period, 1987-1996 )

Year of clean-up work Age group

1986 1987 1988-1990 1986-1990 20-29 128 470 52 439 4 180 185 089 30-39 336 877 165 222 111 563 613 662 40-49 187 467 98 292 93 248 379 007 50-59 74 242 13 070 4 437 91 749 60-69 20 021 2 291 568 22 880

TOTAL 747 077 331 314 213 996 1 292 387

Distribution of person-years of observation by periods

Year of clean-up work Period of observation 1986 1987 1988-

1990 1986- 1990

1987-1991 292 823 127 330 57 020 477 173 1992-1996 454 254 203 984 156 976 815 214 1987-1996 747 077 331 314 213 996 1 292 387


.Age distribution of the leukemia diagnosed CWA under study in 1987-1996

Year of the clean-up work Age group 1986 1987 1988-1990 1986-1990

20-29 4 1 1 6 30-39 7 5 3 15 40-49 15 7 3 25 50-59 18 1 1 20 60-69 4 1 0 5 20-69 48 15 8 71


-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

CalculationFor 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

Age Standardized Rate (per 100.000)


Distribution of the leukemia diagnosed in CWA under study in 1987-1996 by periods of

observation

Year of the clean-up work Period of

observation 1986 1987 1988-1990

1986-1990

1987-1991 22 6 1 29 1992-1996 26 9 7 42 1987-1996 48 15 8 71


Results of Standardized Leukemia Incidence Ratio calculation for CWA of 1986 versus CWA of

1987 by periods of observation.

Period of observation SRR1/SRR2 (95 % CI)

1987-1991 3,32 (1,08; 10,20) 1992-1996 0,69 (0,15; 3,05) 1987-1996 1,00 (0,29; 3,42)


- 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

Design formulasof relation between exposure and incidence

RARA

00

11

/

/

IRIR

0

1RR


- 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

Design formulasof relation between exposure and incidence

bc

ad

dc

ba

OR


Sources of Radiation ExposureSources of Radiation ExposureFrom NCRP Report No: 93

3%1% 4% 11%

26%

55%

Radon Natural Sources (ex.Radon)Medical X_rays Nuclear MedicineConsumer Products Other

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

ElectronElectron

NucleusNucleus

OrbitOrbit

PENENTRATING RADIATIONPENENTRATING 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 EFFECTSRADIO-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


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 MODELS of EXCESSEXCESS of of RISKRISKSS

D.Pierce, D.Preston, 1996-1999D.Pierce, D.Preston, 1996-1999

Time dependent models of redundant relative risk for solid swellingsLimit of models of risk for a cancer = 10 years

Absolute risk for leukaemiaLimit 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 Execes absolute risk for absolute risk for leukaemialeukaemia

Where Where and and - constant: - constant: - depends on - depends on categories categories --Age for want of effect and, for each from these Age for want of effect and, for each from these categoriescategories,, categories of time from time of effect categories of time from time of effect and sexand sexD – D – Doze equivalent red marrowDoze equivalent red marrow, , in in SivertsSiverts (Sv)(Sv)

MODELS of EXCESS of RISKS D.Pierce, D.Preston, 1996-1999

)expβdθα(d 2EAR

• TTime dependent models ime dependent models of of redundant redundant

rrelative riskelative risk a adapt dapt DOSEDOSE dependence dependence

As linear for As linear for SOLIDSOLID CANCERSCANCERS

As linearly – quadraticAs linearly – quadratic f for or LEUKAEMIALEUKAEMIA

MODELS of MODELS of EXCESSEXCESS of of RISKRISKSS

D.Pierce, D.Preston, 1996-1999D.Pierce, D.Preston, 1996-1999


RESUME:The comparative analysis was done for clean-up workers

CWA of 1986 and 1987 by periods of observation of 1987-1991 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 authorAbout 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. LedoshchukM.D.,Ph.D.

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RADIATION EPIDEMIOLOGY AND LEUKEMIA RADIATION EPIDEMIOLOGY AND LEUKEMIA B.Ledoshchuk, M.D.,Ph.D. Institute of Epidemiology Research Center for Radiation