复旦大学医学遗传学课件casecontrolTDT分析.ppt

FudanGeneticWorkshop2005GeneticEpidemiologyinPopulations,YinY,GeneticAssociationStudies:StudieswithUnrelatedIndividuals,FudanGeneticWorkshop,Jan042005,Assessingriskfordiseaseduetospecificalleles/genotypesContrastdirect/indirectgeneticassociationstudiesDiscussgeneticmodelsTestsandestimatesofassociationbetweenalleles/genotypesanddiseaseDesignstobeused,LearningObjectivesforThisLecture,ApplicationsforgeneticassociationanalysesDirectversusindirectassociationIndirectassociation:marker-baseddiseaseassociationExploitsLDbetweenmarkersandunobserveddiseasevariantsExamplesofdirectandindirectassociationstudiesStudydesignsfordirectandmarker-based(LD)association,GeneticAssociationStudiesinEpidemiology,Applications:FinemappingCandidategeneeffectsWholegenomescanGeneenvironmenteffectsDrugresponsemodification,GeneticAssociationStudiesinEpidemiology,CommonDesigns:Cross-sectionalCase-controlCohortClinicalTrial(drugresponsehypothesisisreallyacase-control)Case-family(trios,sibs,extendedfamilies)Case-only,LearningObjectivesforThisLecture,ApplicationsforassociationanalysesDirectversusindirectassociationIndirectassociation:marker-basedassociationExploitsLDExamplesofdirectandindirectassociationstudiesStudydesignsfordirectandmarker-based(LD)association,DirectmethodTestingwhetheraparticularalleleisadisease-predisposing(causative)alleleexposurestatusdirectlymeasured,Geneticepidemiologystudiestwodifferentconcepts,2.LDMapping(indirectmethod)exposurestatusnotdirectlymeasuredRelyonmarkerscorrelatedwithtrueexposurestatusThiscorrelationisduetolinkagedisequilibrium,Geneticepidemiologystudiestwodifferentconcepts,.GACTAAGGCCCCCGTTCAAGGACCTG.C/TA/G,APOEgeneonc19,Eg:Genotypeanearbygeneticmarkeramongstudyparticipants,DirectTests,Testforassociationbetweenobservedgenotypesanddiseaseoutcome,CCCCCG,CCCCCG,CCCCCG,CCTCCG,CCTCCG,CCTCCG,Directlymeasurepotentiallypredisposingalleles,IndirectTests,Testforassociationbetweenmarkergenotypesanddiseaseoutcome,CC?CCGCAG,CC?CCGCAG,UsemarkergenotypesassurrogateforfunctionalgenotypebyexploitinganycorrelationbetweenCandA,CC?CCGCAG,CC?CCGCGG,CC?CCGCGG,CC?CCGCGG,DirectMethod:CandidateAlleleTesting,MustknowpotentiallyfunctionalpolymorphismsSNPsmayoffersetofcandidatelociforthismethodEg,lookatnon-synonymouscSNPs(thoseincodingregionsthatarelikelytobefunctional)Note:Assumingdiseaseiscausedby(relatively)commonallelesCommondisease-commonvarianthypothesisThishypothesisiscontroversialIfgenome-wideproject:multiplecomparisons-30,000genes.Evenifonlyonefunctionallocus/genetested,veryhighnumberoffalse+sduetochance,IndirectMethod:LDGeneMapping,Generalidea:Exploitthephenomenonoflinkagedisequilibrium(LD)betweenallelesofcloselylinkedmarkerstoidentifygeneticregionsassociatedwithdiseasestatus.i.e.,ExploitLD-inducedcorrelationbetweenobservedmarkerallelesandpotentiallyunobserveddiseasealleles,.GACTAAGGCCCCCGTTCAAGGACCTG.C/TA/G,IndirectAssociationStudiesinEpidemiology,Applications:Localization(whatisthebestestimateofthediseasegenelocation?)FinemappingWholegenomescanCandidategeneeffectsGeneenvironmenteffectsDrugresponsemodification,Localization,IndirectAssociationStudiesinEpidemiology,Applications:Localization(whatisthebestestimateofthediseasegenelocation?)FinemappingWholegenomescanCandidategeneeffectsGeneenvironmenteffectsDrugresponsemodification,Source:Uhletal,2001.AJHG69:1290-1300.,IndirectAssociationStudiesinEpidemiology,Applications:Localization(whatisthebestestimateofthediseasegenelocation?)FinemappingWholegenomescanCandidategeneeffectsGeneenvironmenteffectsDrugresponsemodification,CandidategeneLDstudies,InstrumentalinidentifyinggeneticriskfactorsfordiseaseHLAType1diabetesRheumatoidarthritisMultiplesclerosisAPOEAlzheimersdiseaseAtherosclerosisAngiotensinConvertingEnzyme(ACE)MyocardialinfarctionAtherosclerosis,CandidategeneLDstudies,Polymorphismincandidategenescanbeusedasamarkerforvariationinthegene.ThehighertheLDbetweenthecausativevariantandthemarkeralleles,thebetterthesurrogateinformationprovidedbythemarker.,CC?CCGCAG,CC?CCGCAG,CC?CCGCAG,CC?CCGCGG,CC?CCGCGG,CandidategeneLDstudies,UsegeneticmarkerstotestforvariationinthatgenethatmaypredisposetodiseaseriskMarkerallelesaresurrogatesforthe(unobserved)diseasealleleduetoLD,(surrogateforunobserveddiseaseallele),A,dx,Genotype-leveltestsfordiseaseassociation,Testforassociationbetweengenotypesanddiseaseoutcome,Ex:AlzheimersdiseaseandAPOESNPs,Single-markerc2testsfordiseaseassociation:,Modelingissues,Ifwedomeasuretheputativevariationofinterest,whatkindsofstatisticalanalysesshouldbeperformed?Mostgeneralgeneticmodelforrisk:assumetoapriorirelationshipbetweenheterozygoteandhomozygoteriskConsidereachgenotypeasaseparateexposurecategory:,Modelingissues,Thisrequires2riskparametersWhatgeneticmodelscouldbeconsideredtoimprovepower(reduce#ofparameterstoestimate)?,Mayhavemorepowerifparticularmodelscancorrectlybeassumed:DominantRRAA=RRA*1=RR*,AdditivealleleeffectsRAA=2*RA*R*=1,MultiplicativealleleeffectsRRAA=(RRA*)2RR*=1,RecessiveRRAA1=RRA*=RR*,Logisticregression,H0:bi=0Geneticmodelinterpretations:Assume“11”genotypecodingrepresentsgenotypewithlowestabsoluterisk(baseline)b1=b2=0noassociationwiththatpolymorphismb1=0,b20(completely)recessiveb1=b20(completely)dominant0Possibleinteraction!,Logisticregressionwithinteraction,Testforinteraction:H0:gi=0ModelingissuesForCleftexample,dominancewasmodeled,sologisticmodelwouldlooklike:,InterpretationsofIndirectAssociationStudies,Apositiveassociationcanmean:ThetargetedalleleiscausalThetargetedalleleisinLDwithacausalalleleThereisconfoundingduetopopulationstratificationThereisconfoundingorbiasforsomeotherreasonTypeIerrorAnegativefindingcanmean:ThegeneorregionunderstudyisnotassociatedwithdiseaseriskThetargetedalleleisnotinLDwiththecausalalleleAppropriatestratificationorotheraccommodationofheterogeneitywasnotidentifiedTypeIIerror(notenoughpower),LearningObjectivesforThisLecture,LinkageversusassociationUsesofassociationanalysesDirectversusindirectassociationIndirectassociation:marker-basedassociationExploitsLDExamplesofdirectandindirectassociationstudiesStudydesignsfordirectandmarker-based(LD)association,ChoiceofDesignandAnalysis,SamplingdesignUnrelatedindividualsFamily-basedsamplingUnitofanalysisSingle-locusHaplotypesStatisticalProceduresChi-squaretestsLikelihood-basedtestsAsymptoticpvaluesEmpiricalsignificancefromresamplingAppropriatesignificancethresholds,ChoiceofDesignandAnalysis,DesignoptionsforassociationstudiesSamplingunrelatedindividualsFamily-baseddesignsThesedifferonhowcontrolsaredefined,StudyDesignsforLDMappingStrategies,UnrelatedSamples(Eg,Casecontrol)UnrelatedcontrolsaresampledfromthesamepopulationasthecasesMatchedorunmatchedonotherfactorsPerformchi-squaredtestforassociationFamily-basedEx:TDT,looksforexcesstransmissionofparticularallelesfromparentstoaffectedchildrenControlsareuntransmittedalleles,Foreachindividual,have2x2tableof0s,1s,or2sUseallsuchtablestogetamatchedchi-squaretestforexcessoccurrenceincellsbandcMcNemarstest,Contrastsbetweenepidemiologicandfamily-basedassociationdesigns,UnrelatedindividualsDonotneedparentalgeneticinformationProvidesestimatesofallelefrequencies(ifappropriatelysampled)MaybemorepowerfulandsimplertocollectforsomephenotypesOpensthepotentialforconfoundingduetopopulationstratificationFamily-baseddesignsNeedparentalgenotypes(oratleastotherfamilymembers)DonotneedunrelatedcontrolsAvoidspopulationstratificationconfounding(analysisismatchedbyfamily),DesignsforLDstudiesofunrelatedindividuals,AllunrelatedsamplingLDmethodslookforassociationbetweenmarkersandtheoutcomeofinterestacrossindividualsTheutilityofthisapproachwillbeafunctionoftheactualLDbetweenthemarkersandthetruediseaseallele(s)Cross-sectionalCase-controlCohortAnalysesaresimilar,interpretationsmaybedifferentbecausesamplingandtemporalrelationshipsaredifferentClinicaltrial?Suchdataareusedtoassesspharmacogeneticresponseoutcomes.However,thisisoftenacase-controldesign(thegenotypesarenotrandomized!),StudyDesignsusedforLDmapping,Case-Controldesign(unrelatedindividuals)Advantages:Commonlyusedtoolinepidemiology-methodologyiswell-knownConvenienttocollect-opportunitytodrawverylargesamplesMoreefficientrecruitmentthanfamily-basedsamplingmethodsPopulation-baseddesignscanallowthesimultaneouscharacterizationofdiseaseallelefrequency,penetrance,andattributableriskUnrelatedcontrolscanprovideincreasedpowerinmanysituations,StudyDesignsusedforLDmapping,Case-Controldesign(unrelatedindividuals)Limitations:DifficulttoestablishphasewhenfocusingonhaplotypesMaybesusceptibletoconfoundingduetostratificationDifficulttomeasureparent-of-origineffectsorotherparent-specificeffectsDifficulttoestimaterecombinationfractions(localization)usingLDinanunrelated-subjectsetting,Case-Control,SusceptibilitytopopulationstratificationTDTandotherfamily-basedassociationmethodscommonlyusedtoguardagainstconfoundingduetopopulationstratificationBut,RequiresrecruitmentofadditionalfamilymembersAddedcostFamilymembersmaynotbeavailableInefficientifmanymembersrequiredormembersareuninformativeProbablynotasprevalentaproblemasoncethoughtCanbedealtwiththroughassessmentandadjustmentofpopulationstratificationwithinacase-controldataset,StudyDesignsusedforLDmapping,Case-ControldesignLimitations:Maybesusceptibletoconfoundingduetostratif