RADIATION EPIDEMIOLOGY AND LEUKEMIA B.Ledoshchuk, M.D.,Ph.D.

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RADIATIONEPIDEMIOLOGYAND LEUKEMIA
B.Ledoshchuk, M.D.,Ph.D.

• Institute of Epidemiology
• Research Center for Radiation Medicine of Ukraine
• Kyiv-2001

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EPIDEMIOLOGY OF LEUKAEMIA

• Results of the 10-year study of leukemia among
  the Chernobyl accident clean-up workers in
  Ukraine
• 1986-96

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GENERAL EPIDEMIOLOGY

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

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

• Types of Epidemiology
• medical
• pharmaceutical
• veterinary
• environmental
• insurance

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GENERAL EPIDEMIOLOGY

• Classification of medical epidemiology
• Infection epidemiology
• General epidemiology
• Environment epidemiology
• Clinical epidemiology
• Military epidemiology
• Epidemiology of insurance

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Main types of epidemiology research

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GENERAL EPIDEMIOLOGY

• Methods of analytical epidemiology
• Cohort
• Case control
• Combined

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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)

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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)

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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

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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 .

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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

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EPIDEMIOLOGY OF LEUKAEMIA

• Main sources of information for case search
• Results of annual medical examination of ACW
• Regional hematological clinics data

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EPIDEMIOLOGY OF LEUKAEMIA

• Main methods of obtaining of information
• retrospective
• current
• passive
• active

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EPIDEMIOLOGY OF LEUKAEMIA

• Period of observation ACW
• 1987-1996
• Calculation were performed for 5-year intervals
• 1987-1991, 1992-1996

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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

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Classification of diseases

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

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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

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Reliability of the Diagnoses
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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

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

• cCITY HOSPITAL
• DDISPENSARY
• OBLAST HOSPITAL OBLAST DISPENSARY
• INSTITUTIONAL HEMATOLOGICAL DEPARTMENTS

CENTER FOR RADIATION MEDICINE
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Information exchange for quality control
EPIDEMIOLOGIST
SUPERVISER
D/B
TECHNICIAN
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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 ).

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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 ).

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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.

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EPIDEMIOLOGY OF LEUKAEMIA

• LEUKEMIA DIAGNOSIS STRUCTURE

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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

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GENERAL EPIDEMIOLOGY

• Generate rate
• Absolute rate (number)
• Popularity
• Morbidity
• Mortality
• Expressed as cases from 106 to 103 in
  investigated cohort (case/control)

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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

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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

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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

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GENERAL EPIDEMIOLOGY

• confidence interval
• Calculation of 95 confidence intervals for
• prevalence rate (PR)
• cumulative incidence rate (CI)
• incidence rate (IR)
• IR?1.96 (R- person-years)

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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

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GENERAL EPIDEMIOLOGY

• Calculation of Relative Risk
• For cumulative incidence RR(A1/N1)/(A0/N0)
• where ?number of cases
• Nnumber of person year
• 95 confidence interval for relative risk
  ln(RR)-dispersion
• varln(RR) (N1-A1)/(N1A1)(N0-A0)/(N0A0

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GENERAL EPIDEMIOLOGY

• Calculation of Relative Risk
• For incidence rate RR(A1/R1)/(A0/R0)
• where ?number of cases
• Rnumber of person-years
• 95 confidence interval for relative risk
• ln(RR)-dispersion
• varln(RR) (1/A1)(1/A0)

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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

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GENERAL EPIDEMIOLOGY

• Standardization
• - is one of the method of comparison validity
• direct method of standardization
• indirect method of standardization

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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)RR1.2ASR1
• (R2.1/R2.n)RR2.1(R2.2/R2.n)RR2.2ASR2

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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 (N1IR1)(N2IR2)
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EPIDEMIOLOGY OF LEUKAEMIA
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EPIDEMIOLOGY OF LEUKAEMIA
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EPIDEMIOLOGY OF LEUKAEMIA
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EPIDEMIOLOGY OF LEUKAEMIA
Age Standardized Rate (per 100.000)
-Number of cases from 20 to 29 years/1000,000
clean-up workers of 1986 - ?1 1987?. B1
-Number of males from 20 to 29 years/100,000
clean-up workers of 1986 - A2 1987?.
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
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EPIDEMIOLOGY OF LEUKAEMIA
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EPIDEMIOLOGY OF LEUKAEMIA
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Design formulasof relation between exposure and
incidence
GENERAL EPIDEMIOLOGY

• - COHORT
• data are presented as relation risk
  estimation
• RRIR1 / IR0
• where IR1 and IR0 are incidence coefficients
• A1 and A0 - number of cases
• R1 ? R0 - person-years at risk

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Design formulasof relation between exposure and
incidence
GENERAL EPIDEMIOLOGY

• - CASE-CONTROL
• relative risk estimation -
• odds ratio (OR)
• where A1a, A0b
• R1c, R0d
• A1 and A0 - number of cases
• R1 and R0 - person-years at risk

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Sources of Radiation Exposure From NCRP Report
No 93
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ATOM PRINCIPLE DIAGRAM (Craig C.
Freudenrich,2001, HAW)
Electron
Nucleus
Orbit
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PENENTRATING RADIATION
Alpha Particles
Radiation Source
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
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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

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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 radiation-induced
  diseases increases with dose increase

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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

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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

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

• 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)

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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

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EPIDEMIOLOGY OF LEUKAEMIA

• 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.

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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.
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channels of information
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nih.gov/atlas/index.htm/ Epidemiologic Research
(Books) www.amazon.com/exec/obidos/ Epidemiology
index http//home.beseen.com/technology/bcjung/Epi
sites.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/
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International Journal of Epidemiology -
www.ije.oupjournals.org Ionizing Radiation,
Health Effects www.epa.gov/radiation Lessons of
Hiroshima and Chernobyl www.whyfiles.org/020radiat
ion/index.html Leukemia Research
http//dspase.dial.pipex.com/lif-/diseases/index/h
tm 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/ Radi
ation effects Research Foundation
www.rerf.or.jp/ Radiation effects
www.eh.doe.gov/ihp/rerf/
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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/ Sup
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htm Uranium and Health www.antenna.nl/wise/uraniu
m/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