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Epidemiologic Study Designs
Lucia HindorffEpidemiologist Office of Population Genomics
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Learning objectives
Course objective #4: To know the various study designs, their assumptions, advantages, and disadvantages that could be applied to identify associations between phenotypes and genomic variantsCourse objective #8: To appreciate use of epidemiologic study designs for a variety of applications of potential practical importance
To read a GWA study and be familiar with data presentations unique to GWA studies
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Outline - overview
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Who you study is as important as whatyou study
Need to measure genotype and phenotype in the appropriate participants for the question you want to answer
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Which study design?
Purpose of the study– Hypothesis-testing versus hypothesis generating– Finding signal versus quantifying the signal
Available resourcesNeed for data collectionChoice of outcomeAbility to draw valid causal inference
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Population-based designs
Relevant to any study designCan you define the source population from which the study sample is drawn?Ability to define the population– Challenge for convenience, volunteer samples
Why is population-based design important?– Validity– Generalizeability
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Types of epidemiologic study designs
From Wikipedia
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Case-control studies: design
Design: identify participants based on their disease/outcome status, compare presence of risk factor
Cases
ControlsExposed
Non-exposed
Exposed
Non-exposed
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Assumptions
Cases representative of all cases of diseaseControls drawn from the same population as cases (and at risk for the outcome)Exposure data collected similarly in cases and controls
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Case selection
Cases are identified on the basis of their disease/phenotype, representative of all individuals who develop diseaseDistinguishing incident from prevalent or recurrent cases importantHigh participant rates important
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Control selection
“Compared to whom?” – Controls are representative of the general
population who do not develop the disease– Selected from population at risk to become case– Families, population registries, neighborhood
Who is the population at risk?How do you know they don’t have the disease?
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Case-control studies: examples
Aspirin and Reye’s syndrome in childrenOral contraceptives and reduced risk of ovarian/endometrial cancerLOXL1 and exfoliation glaucomaTCF7L2 and type 2 diabetes
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Advantages of a case-control study
Suitable for rare outcomesSuitable for outcomes with long induction periodCheaperNeed fewer people in some casesReadily evaluate multiple exposuresConvenientIf assumptions are met, valid estimates of relative risk
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Disadvantages of a case-control study
Doesn’t estimate risk directlySpecial considerations (more later)
– Exposure-relatedRecall bias: Disease status may influence reportingEtiologic time period
– Outcome-relatedAre studying survivors of the disease
Difficult to study rare exposures
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Case-control study designs: variations on a theme
Nested case-control– Within a cohort study, compares all cases to a
subset of persons who did not develop diseaseCase-cohort– Within a cohort study, compares all cases to a
random subsample of the cohort– Subcohort can be used for multiple case groups
Super-cases and super-controls– Extremes of the phenotypes– Maximizes opportunity to detect signal
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Cohort studies
Identify individuals based on their exposure status, follow forward to ascertain disease/outcome status
Exposed
Non-exposedDiseased
Non-diseased
Diseased
Non-diseased
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Cohort studies
Longitudinal: multiple measurements over time
Exposed
Non-exposedDiseased
Non-diseased
Diseased
Non-diseased
Time
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Assumptions
Exposed and non-exposed groups are representative of a well-defined general populationAbsence of exposure well definedOutcome assessment comparable between exposed and non-exposed
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Example: Framingham Heart Study
Original cohort: 5,209 residents of Framingham, MA (1948)Offspring cohort: 5,124 children + spouses (1971)Framingham III: 3,500 grandchildren (ongoing)Identification of major risk factors for heart disease
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Advantages of a cohort study
Able to directly estimate riskOptimal for short induction periodsCan look at multiple outcomes Potential to investigate natural history of diseaseAmenable to both quantitative and binary outcomesRisk factors ascertained prior to disease
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Disadvantages of a cohort study
Not suitable for rare exposures or rare outcomesRequires large populationsMay be more expensive, time consuming
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Randomized designs
Definition: a comparative study in which study subjects are assigned by a formal chance mechanism between two or more intervention strategiesGold standard for inferring causalityAlso called “randomized controlled trials, randomized clinical trials, experimental studies”
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Randomized trials
RecruitmentRandomization
Intervention
Comparison
Diseased
Non-diseased
Diseased
Non-diseased
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Randomized designs
Hallmark: participant assigned to intervention group by a formal chance mechanismAssumptions– Exposure must be potentially modifiable – Primary outcomes are relatively common, occur
relatively soon
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Randomized designs
Methods of randomization– Several choices, from “flipping a coin” to stratified
randomizationBlinding/masking– Participant, study investigator (and anybody else
involved in follow-up)– Ideally, double-blinded
Analysis: intention-to-treat
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Randomized designs: examples
Women’s Health Initiative– Clinical trial component: 68,131 postmenopausal women – Multiple interventions: Dietary, hormone therapy,
calcium/vitamin DPhysician’s Health Study
– PHS-122,071 male physiciansAssess benefits and risks of aspirin and beta carotene
– PHS-2:14,642 male physiciansMultiple interventions: vitamin C, vitamin E, beta carotene, multivitamin
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Advantages of randomized designs
Similar distribution of baseline characteristics in comparison groupsProtection against confounders, both known and unknownAble to directly estimate riskAllows comparison of multiple outcomes
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Disadvantages of randomized designs
Limitations on types of interventionsCostlyNot suitable for rare outcomesNot suitable for outcomes requiring long or extensive follow-upPotential challenges to the generalizeability of findings
– Eligibility: strict inclusion/exclusion – Adherence/withdrawal issues
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Summary of epi study designs
Design Well suited for
Case-control Rare outcomes, long induction periodsMultiple exposures
Cohort Common outcomesMultiple outcomes
Randomized trials Short induction periodsMultiple outcomesExposures prone to confounding
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Progression of genetic epidemiology
Twin studies, family studies candidate SNPs candidate genes genome-wide associationIntersection of developments in biology, technology and statistical methodsEmphasis shifting from hypothesis-driven to agnostic study designsExpanding focus from single gene disorders to common, multigenic diseases
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Identification of T2D loci
Perry and Frayling, Curr Opin Clin Nutr Metab Care, 2008
GWASGWAS
GWASGWAS
GWAS
GWAS
GWAS
GWASGWAS
GWASGWAS
GWAS
GWAS
RegCG
CG
CG
CG
Fam
FamFam
Fam
Fam
Fam
FamFam
Fam
Fam
Fam
FamFam
Fam
FamFam
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Why family studies?
Good route for gene discovery in Mendelian disorders– Strong familial clustering suggests genetic basis– Sentinel families good for studying specific
phenotypes– Less susceptible to population stratification
Estimation of special parameters– Familial relative risk – Risk penetrance
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Early family study designs
The original agnostic approachHeritability analysis
– Objective: quantify the fraction of total phenotypic variance attributed to genetic differences
Linkage analysis– Objective: identify genomic regions where genes associated
with the phenotype might lie
At best, identify large chromosomal regions, not specific genesFurther fine mapping of causal locus required
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Family-based association studies
A twist on a familiar theme: cases + their relatives– Family history, e.g., first-degree relative– Parent-child trios: compare observed to expected
transmission of alleles– Extension to siblings, nuclear families, extended
pedigrees,
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Family studies: example
Hopper, et al., Lancet, 2005
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Family studies: example
Linkage and association data: HDL3C
Cupples, Curr Opin Lipidol, 2008
PLAGL1, 143cM
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Transmission disequilibrium test (TDT)
Null hypothesis: If neither linkage nor association is present between marker and disease locus, then alleles from heterozygous parents will be randomly transmitted to affected offspring
Elston, et al. Annu Rev Genom Hum Genet, 2007
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Advantages of family studies
Less prone to population stratificationRich context for evaluating shared genetic and environmental influences
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Disadvantages of family studies
Difficult to separate shared environmental from genetic influencesReduced power due to exclusion of uninformative familiesChallenging for outcomes of older ageEstimates may not apply to general population
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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Candidate gene studies - biology
Driven by current state of knowledgeAssumptions about genes, SNPsCommon disease, common variant hypothesisOne or a few common (≥5%) SNPs in one or a few genes, associated with outcome
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Candidate gene studies - methods
Started by interrogating known functional regions – promoters, exonsIncreasing knowledge about linkage disequilibrium tagSNPsHapMapConcern for false positives moderateProblems with replication
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Candidate gene studies - examples
• APOE and Alzheimer’s Disease• BRCA and breast cancer• PPARG and type 2 diabetes
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Outline
Learning objectivesStudy designs– Overview– Case-control studies– Cohort studies– Randomized/experimental designs
The road to GWA studies– Overview– Family studies– Candidate genes– Genome-wide association (GWA) studies
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GWA studies - biology
Robust associations not always with functional variantsSuccess of candidate gene approach depended on correct specification of genesEarly GWA studies identified promising regions that were previously unknown“Agnostic” approach
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GWA studies - methods
Genotyping platforms developed to look at hundreds of thousands of genesSame analysis (and relative risks or odds ratios) as before, but repeated hundreds of thousands of timesFalse positive results a major concernStatistical adjustment of p-values, replication
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GWA studies - overview
Selection of large number of individuals with the trait of interest, including a suitable comparison groupDNA isolation, genotyping, data review to ensure high genotyping qualityStatistical tests for associations Replication of associations in independent population(s) or experimental confirmation of functionReports of allele frequencies, p-values, association statistics
Adapted from Pearson and Manolio, JAMA, 2008
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Anatomy of a GWA study – colorectal cancerZanke, et al. Nat Genet 2007
Stage 1: Ontario Familial Colorectal Cancer Registry1,226 cases / 1,239 controls
99,632 SNPs
Stage 2: Seattle and Newfoundland case-control studies1,139 cases / 1,055 controls
1,143 SNPs
Stage 3: Scotland case-control study of early onset disease975 cases / 1,002 controls
76 SNPs
Stage 4: Scotland case-control study of early onset disease1,910 cases / 1,985 controls
9 SNPs
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Anatomy of a GWA study – heightWeedon, et al., Nat Genet, 2007
HMGA2
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Anatomy of a GWA study – lung cancerHung, et al., Nature, 2008
CHRNA3,CHRNA5, CHRNB4
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Anatomy of a GWA study – colorectal cancerZanke, et al., Nat Genet, 2007
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NHGRI GWA study catalogwww.genome.gov/gwastudies
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NHGRI GWA study catalogwww.genome.gov/gwastudies
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NHGRI GWA study catalogwww.genome.gov/gwastudies
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NHGRI GWA study catalogwww.genome.gov/gwastudies
First authorDateJournalStudyDisease/traitInitial sample sizeReplication sample sizeChromosomal region
Gene (author)Strongest SNP/alleleMinor allele frequencyP-valueOR or beta (95% CI)PlatformNumber of SNPs passing QC
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Take-home messages
Design or read each study to make sure assumptions are metIncorporate population-based designs whenever possible Consider: for which study designs are your scientific questions suitable?Appreciate wealth of information available from GWA studies
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Which study design(s) are most suitable for investigating the following associations?
1) Toxic shock syndrome and tampon use?Case control
2) Cigarette smoking during pregnancy and low birthweight? CohortRandomized trial
3) Antidepressants and quality of life? Randomized trial
4) Genetic variants and celiac disease? GWA case control study
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QUESTIONS?
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END
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Cohort studies
Prospective: study initiated before follow-up for outcome occurs
Exposed
Non-exposed
Diseased
Non-diseased
Diseased
Non-diseased
Time
2008
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Cohort studies
Retrospective: study initiated after follow-up for outcome occurs (e.g., atomic bomb survivors)
Exposed
Non-exposed
Diseased
Non-diseased
Diseased
Non-diseased
Time
2008
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Example of TDT
G72/G30 locus on 13q33 associated with bipolar disorder (Hattori, AJHG, 2003)
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Family studies - examples
Cystic fibrosisNeurofibromatosisBipolar disorderFamilial hypercholesterolemia
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Case-control study: control selection
From Grimes and Schulz, Lancet, 2005
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