Screening and Replication using the Same Data Set Testing Strategies for Family-Based Studies in which All Probands Are Affected 英文参考文献.docVIP

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Screening and Replication using the Same Data Set Testing Strategies for Family-Based Studies in which All Probands Are Affected 英文参考文献.doc

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Screening and Replication using the Same Data Set Testing Strategies for Family-Based Studies in which All Probands Are Affected 英文参考文献

ScreeningandReplicationusingtheSameDataSet: TestingStrategiesforFamily-BasedStudiesinwhichAll ProbandsAreAffected AmyMurphy1,2,3,ScottT.Weiss1,2,3,ChristophLange2,3,4 * 1ChanningLaboratory,BrighamandWomen’sHospital,Boston,Massachusetts,UnitedStatesofAmerica,2HarvardMedicalSchool,Boston,Massachusetts,UnitedStates of America, 3Center for Genomic Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America, 4Department of Biostatistics, Harvard SchoolofPublicHealth,Boston,Massachusetts,UnitedStatesofAmerica Abstract Forgenome-wideassociationstudiesinfamily-baseddesigns,weproposeapowerfultwo-stagetestingstrategythatcanbe appliedinsituationsinwhichparent-offspringtriodataareavailableandalloffspringareaffectedwiththetraitordisease under study. In the first step of the testing strategy, we construct estimators of genetic effect size in the completely ascertainedsampleofaffectedoffspringandtheirparentsthatarestatisticallyindependentofthefamily-basedassociation/ transmission disequilibrium tests (FBATs/TDTs) that are calculated in the second step of the testing strategy. For each marker, the genetic effect is estimated (without requiring an estimate of the SNP allele frequency) and the conditional power of the corresponding FBAT/TDT is computed. Based on the power estimates, a weighted Bonferroni procedure assignsanindividuallyadjustedsignificanceleveltoeachSNP.Inthesecondstage,theSNPsaretestedwiththeFBAT/TDT statisticattheindividuallyadjustedsignificancelevels.Usingsimulationstudiesforscenarioswithupto1,000,000SNPs, varyingallelefrequenciesandgeneticeffectsizes,thepowerofthestrategyiscomparedwithstandardmethodology(e.g., FBATs/TDTswithBonferronicorrection).Inallconsideredsituations,theproposedtestingstrategydemonstratessubstantial powerincreasesoverthestandardapproach,evenwhenthetruegeneticmodelisunknownandmustbeselectedbasedon theconditionalpowerestimates.Thepracticalrelevanceofourmethodologyisillustratedbyanapplicationtoagenome- wide association