Introduction To Principles Of Epidemiology
Introduction to Principles of Epidemiology Applicable toRadiation EpidemiologyMartha Linet, M.D., M.P.H.Senior InvestigatorRadiation Epidemiology BranchDivision of Cancer Epidemiology & Genetics (DCEG)National Cancer Institutelinetm@mail.nih.govDCEG Radiation Epidemiology and Dosimetry Course 2019www.dceg.cancer.gov/RadEpiCourse
ObjectiveProvide a brief overview of epidemiologic concepts,study design, and study components pertinent toradiation epidemiology
Outline Epidemiology: history & definitions Descriptive patterns Disease models and causation Exposures & outcomes: sources and assessment methods Study designs Confounding, effect modification, bias
EpidemiologyA scientific discipline that provides quantitativeinformation about human health risksassociated with specific exposures
History and Definitions
History of s ology:chronic Sophisticatedexposure & outcomeassessment,statistical modeling-Electronic linkages-Genomics, other ‘omics’-Pathology & clinical deep learning al translation
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distributionWho: PopulationsWhat: Risk factors for diseaseWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distributionWho: PopulationsWhat: Risk factors for diseaseWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
Populations Groups of persons that maybe at higher or lower risk ofdeveloping a disease(s) orcondition(s) due to an agentor substance presumed to becausal-Cohorts: exposed vs unexposed/low-level exposure-Cases vs. controlsExamples of radiation-exposed populations
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distributionWho: PopulationsWhat: Risk factors for disease Exposures OutcomesWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
Exposures Agents or substancespresumed to be causal of adisease or event (exposuresurrogate is a factorindicating exposurepotential, e.g., job title)‘Exposures’ include radiation,pesticides, obesity, cigarettes
Outcomes Diseases, conditions,precursors to diseases orconditionsRadiation-related adverse outcomes include most cancers,cataracts, heart disease, and probably leukemiaprecursors such as myelodysplastic syndromes
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distributionWho: PopulationsWhat: Risk factors for disease Risk factor relationships Risk measuresWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
Correlation, Association, Causation Correlation: the degree to which variables change together (nodirection assumed) Association: a disease occurs more (or less) frequently in thepresence of an exposure than in its absence & varies by exposurelevel Causation: in an individual, an exposure caused a given disease;within a population, at least some cases of the disease would nothave occurred in the absence of the exposure
Measures of riskDefinitionsExamples Risk: the probability of diseasedeveloping in a population in aspecified time interval If RR 1.0, then no differencebetween the two groups Relative risk or risk ratio (RR): ameasure of the risk of a certainevent happening in one groupcompared to the risk of the sameevent happening in another group;the incidence/mortality of diseasein an exposed group divided by theincidence/mortality of disease in anon-exposed group If RR 1.0, then being exposed to acertain substance or factorincreases the risk of cancer If RR 1.0, then being exposed to asubstance/factor decreases the riskof cancer
Other measures of risk Attributable risk: the maximum proportion of a diseaseattributable to a given exposures Absolute risk: the observed or calculated probability ofoccurrence of an event in a population related to a specificexposure Example: Among patients treated with a specific agent atages 5-10 and followed up through age 75, four percent willdevelop cardiac insufficiency
Descriptive Patterns & Trendsand Disease Classification
Descriptive epidemiology: Rationale for studyWhy study disease patterns and trends? Explain occurrence (temporal, geographic) and natural history Provide guidance for health services: identify susceptible populations Suggest hypotheses to elucidate causal inferences and mechanisms
What is epidemiology? The study of thedistribution of a disease orconditions in humanpopulations and the factorsthat influence thedistribution* Who:* What:PopulationsRisk factors for diseaseWhen: Temporal aspects* Where:Geographical distributionHow: Methods, mechanisms, biology*Descriptive epidemiology frequently involves factorsin addition to temporal aspects
RatesRate: a measure of change in a quantity per unit time Incidence: the total number of new-onset disease eventsdivided by the total person-time at risk during a given periodof time Mortality: the total number of deaths from a disease dividedby the total person-time at risk during a given period of time
Disease classification: purposeWhat is the purpose of disease classification? Group ill persons into categories to distinguish one categoryfrom another Arrange diseases into groups with common characteristics
Disease classifications internationally usedInternational Classification of Diseases (ICD) Anatomic site Periodically modified to reflect knowledge (currently ICD-10)International Classification of Diseases for Oncology (ICD-O) Two major categories: morphology and topography (anatomic site) Latest revision includes clinical, immunological, treatment-related andmolecular characteristics of some neoplasms (ICD-O-3)Specialty classifications Example: International Classification of Childhood Cancer
International Classification of Childhood iaLymphomas and reticuloendothelial neoplasmsCNS and other intracranial and intraspinal neoplasmsSympathetic nervous system tumorsRetinoblastomaRenal tumorsHepatic tumorsMalignant bone tumorsSoft tissue sarcomasGerm cell, trophoblastic, & other gonadal neoplasmsCarcinomas & other malignant epithelial neoplasmsOther and unspecified malignant neoplasms
Childhood Cancer Statistics - USATotal childhood cancers ages 0-19 15,590 estimated annual incident ca 1,780 estimated annual deaths 5-yr survival 78%Data shown in figure from NCI SEER program:Howlader N, Noone AM, Crapcho M et al. SEERCancer Statistics Review, 1975-2016, NationalCancer Institute, Bethesda, MDhttps://seer.cancer.gov/csr/1975 2016based on November 2018 SEER data submission,Posted to the SEER web site, April 2019
Childhood cancer risks vary by type and subgroupCharacteristicSubgroup Risks by subgroup & cancer type- Ageinfancyneuroblastoma, CNS, leukemia,retinoblastomaadolescenceHodgkin lymphoma, germ cell cancers, CNS,leukemia- Gendermalelymphoma- RaceCaucasianEwing’s sarcoma, acute lymphoblasticleukemiaAfricanAmericanWilms’ tumor, retinoblastomaAfricanendemic Burkitt’s lymphoma
Trends in U.S. Childhood Cancer Incidence Incidence rose about 0.7% per year forall childhood cancers, 1975-2016 Rate of increase was lower (e.g., 0.2%per year) during 1990-2006, but rosemore rapidly after 2006 Mortality steadily declined sincechemotherapy introduced in 1960s,but decrease has leveled offData shown in figure from NCI SEER program:Howlader N, Noone AM, Crapcho M et al. SEERCancer Statistics Review, 1975-2016, NationalCancer Institute, Bethesda, MDhttps://seer.cancer.gov/csr/1975 2016based on November 2018 SEER data submission,Posted to the SEER web site, April 2019
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distribution*Who:PopulationsWhat: Risk factors for diseaseWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
Geographic (and Population) variation in incidence Background disease rates in ageographic area and populationare important for interpretationand extrapolation Japanese atomic bomb survivors:low background rates of femalebreast cancer and chroniclymphocytic leukemia African-Americans: low backgroundrate of childhood leukemiaAge-specific patterns in breast cancer in four countries, 19881992. Hulka BS and Moorman PG. Maturitas 2001;38:103-113.
Endemic (background) vs epidemic Endemic or background rates: usualincidence of a given disease within adefined geographic area “Epidemic:” excess occurrence of agroup of illnesses of a similar naturein a defined area Thyroid cancers in young persons inBelarus after the Chernobyl accident Breast cancer in Hodgkin lymphomasurvivors following radiotherapyEndemic vs. epidemic disease pattern
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distributionWhy: Rationale for methods used Disease models Natural history Association vs. causationWho: PopulationsWhat: Risk factors for diseaseWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
Disease Models
Dynamics of infection and diseaseDynamics ofInfectiousnessTime of infectionsusceptiblelatent periodinfectiousperiodDynamics ofDiseasesusceptibleincubationperiodRothman KJ, Greenland S. Modern Epidemiology, 2nd Edition, 1998symptomaticperiodInfection status-no organism no sequelae sequelae-chronic infectionOutcome-recovered-chronic disease-deceased
Dynamics of exposure and chronic diseaseLung cancer as an exampleSmokingRadiationSpecific ffectmodifiers:SexSESAsbestosLungCancer
Natural history
Steps in Malignant TransformationFigure showing steps ininitiation, promotion, andprogression for DNA-damagingagents such as radiation
Natural History of Chronic Disease Time periods vary among different steps in process Time periods may vary for different exposures and different outcomesRisk factoror Diseaseprogression orregressionCure,chronicity,or deathFigure showing steps from pre-disease state through pre-clinical then clinical manifestations toresolution, chronicity or death
Dynamics of exposure and chronic diseaseLung cancer as an exampleSmokingRadiationSpecific ffectmodifiers:SexSESAsbestosLungCancer
Diseases with Familial Occurrence Familial occurrence‒ Rare diseases that are common within affected families (X-linkedlymphoproliferative syndrome)‒ Rare genetic syndrome with multiple cases of differentphenotypes within affected families (Li-Fraumeni)‒ Small increase in risk within families (sibs with childhoodleukemia) Age at onset sometimes notably younger than for sporadic cases
Genetic vs environmental components of diseaseStudy goal: to identifyStudy typeFamilial clusteringFamily aggregationGenetic vs environmentalTwin/adoption/halfsibling/migrant studiesMode of inheritanceSegregation analysis-single gene-multiple genesDisease susceptibility lociLinkage analysisDisease susceptibilitymarkersAssociation studies-population-based-family-based (trios)Pictures of pedigree (top left),twins (mid-left), comparativemigration (bottom left), and heatmap of genes & other (top right)
Genetic and other molecular population association studies Genetic population-based associationstudies‒ Genotypes: genome-wide associationstudies(Next Generation Sequencing studies) Germline Somatic‒ Other gene-related RNA Gene expression metabolic pathways Epigenetics: DNA, RNA methylation Other molecular studies: O’mics‒ Proteomics‒ MetabolomicsPictures of single nucleotidepolymorphisms (SNPs) (top left),epigenetics (lower left), andglobal gene expression regulatorynetwork (lower right)
Biology and mechanisms: Radiation carcinogenesis Hallmark of radiation damage‒ DNA double strand breaks (DSB)‒ Clustered complex lesions‒ DNA repair processes non-homologous end-joining (NHEJ): errorprone, can lead to chromosome aberrations homologous recombination (HR): error free Non-targeted effects‒ Effects in tissues far from ‘in-field radiation’‒ Genomic instability: manifests after severalgenerations of cell divisionPictures showing direct(targeted) andbystander (nontargeted) effect (top)and DNA double-strandbreak (bottom)
Statistical Association versusDisease Causation
Statistical AssociationDefinition:* Statistical dependence between two or more events,characteristics or other variables. An association is present if theprobability of occurrence of an outcome, depends upon theoccurrence of one or more exposures or characteristics.A statistical association does not imply causation*Modified from Last JM. A Dictionary of Epidemiology, 4th Edition 2001.
Criteria for causationCriteriaDescriptionStrengthLevel of riskConsistencyRepeatedly observed in different populationsSpecificity“If limited to specific workers and to specific types of disease then clearly that is astrong argument in favor of causation”Plausibility“What is biologically plausible depends on the biological knowledge of the day”Coherence“ the cause and effect interpretation should not conflict with the known naturalhistory and biology of the disease”Experiment“Occasionally is it possible to appeal to experimental or semi-experimental evidence?”Analogy“With the effects of thalidomide and rubella before us we would surely be ready toaccept slighter but similar evidence with another drug or another viral disease inpregnancy”Hill AB. The Environment and Diseases. Association or Causation? Proc R Soc Med 1965:58:295-300
Types of causal associationsCommon Cause:RadiationDifferent CausesDifferent outcomesLeukemiaCataractsCommon outcomeUltraviolet radiationCataractsIonizing radiation
Causal model - necessary vs sufficient Necessary: must be present to cause disease(more common with infections: HIV AIDs) Sufficient: can independently cause disease(acute administration of 20 Gray whole body radiation)Necessary ( or -)Sufficient (S )Not sufficient (S-)Necessary (N )N S (necessary & sufficient)N S- (necessary but not sufficient)Not necessary (N-)N-S (sufficient but not necessary)N-S- (neither necessary nor sufficient)Example: smoking is neither a necessary or sufficient cause of lung cancer
Causal model: Types of non-causal associations Chance association Bias may result in spurious associations‒ Selection bias (differential selection or participation of exposed vs.unexposed or controls vs. cases)‒ Recall bias (differential recall by exposed vs. unexposed or controls vs. cases)‒ Confounding (association of disease and an exposure with a third variablemay introduce spurious associations)
Multi-factorial disease causationIndividual-level factors Sex Race/ethnic group Lifestyle, behavioral Environmental Occupational Medical Genetic predispositionSocietal factors Neighborhood Cultural Economic Social Environmental
What is epidemiology? The study of thedistribution of a diseaseor conditions in humanpopulations and thefactors that influencethe distributionWhy: Rationale for methods used Disease models Natural history Association vs. causationWho: PopulationsWhat: Risk factors for diseaseWhen: Temporal aspectsWhere: Geographical distributionHow: Methods, mechanisms, biology
METHODSEpidemiologic Study Designs
Cohort studies Distinguishing features‒ population defined by exposures prior to onset of disease‒ population followed over time to estimate disease/death rate‒ compare rates in exposed vs unexposed groupsor internal comparison (zero or low-level exposure) Retrospective vs prospective follow-up*RetrospectiveProspectiveSelect exposedand non-exposedgroupsTrace & follow up197020112035* Retrospective follow-up is by far the most common method used in cohort studies; if high quality methods areused and care is taken, this approach can be just as methodologically sound as a prospective approach
Follow-up: Multiple axes of timestart king0101950 diesfrom lungcancer20304050Follow-up time (years)01520Age (years)
Case-Control Studies Definition: compare proportion with exposures in diseased cases vscontrols Study base: composed of population at risk of exposure during period ofrisk of exposure; cases and controls should emerge from same study base& have same exposure opportunity Associations identified from case-control studies: smoking and lungcancer; DES and vaginal adenocarcinoma; post-menopausal estrogen andendometrial cancer Nested case-control studies: composed of cases identified from a cohortcompared to a random sample or matched controls from the same cohort:Chronic lymphocytic leukemia compared with leukemia excluding chroniclymphocytic leukemia in Chernobyl clean-up workers
Case-Control Studies Distinguishing features‒ determine exposures prior to diagnosis/referent date using interviews,medical records or other records‒ compare proportion of cases with exposure to proportion of controls withexposure‒ estimate risk using odds ratio a x d/ b x c FrameworkCharacteristicsWith diseaseWithout diseaseTotalWith exposureaba bWithout exposurecdc da cb da b c dTotal
Cross-Sectional Studies Not used much in radiation epidemiology except dosimetrystudies Study types‒ compare exposures of radiation-exposed groups at a given point in time:problematic without considering earlier exposures, age first exposed, sex,age last exposed, and many other factors‒ compare proportion of cases with exposure to proportion of controls withexposure at the time of the study: problematic without considering earlierexposures, age first exposed, sex, age last exposed, and many other factors
METHODSSources of exposure data, strategiesfor exposure assessment, andtypes/sources of associated error
Sources of exposure information Measurements‒ Group: air levels‒ Individual External: badge Internal: blood Questionnaires‒ Medical history‒ Work history Medical records Administrative records‒ birth certificates‒ job recordsPictures of ground radiationmonitor (upper left), CT scanner(lower left), radiation badge (upperright) and questionnaire(immediately above)
Strategies for exposure assessmentStrategies for exposure assessmentDefinition: Process of estimatingmagnitude, frequency, and duration ofexposure to an agentExposure pathwayExposure route‘Direct’ measurementsSurrogate measurementsComponent Who is exposed? Agent location: air, water, skin, other Intensity, frequency, durationSource to receptor Inhalation Ingestion Skin Personal sampling Biological samplingJob title, residence general location
Types and sources of exposure measurement errorTypes/sources of errorDescriptionClassical measurement errorRandom error in dose measurementBerkson measurement errorError when the mean for a group is substituted for the individual doseShared errorError when incorrect group mean is assigned to all individuals in groupDifferential errorDose estimation error that is not independent of case statusNon-differential errorDose estimation error independent of case statusMissing doseDoses of subjects not accounted for
associated with specific exposures. History and Definitions. History of epidemiology. Pre-formal. Epidemiology. . Group ill persons into categories to distinguish one category . and DNA double-strand break (bottom) Statistical Assoc
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