Rapid and Accurate Multiple Testing Correction and Power Estimation for Millions of Correlated Markers 英文参考文献.docVIP

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Rapid and Accurate Multiple Testing Correction and Power Estimation for Millions of Correlated Markers 英文参考文献.doc

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Rapid and Accurate Multiple Testing Correction and Power Estimation for Millions of Correlated Markers 英文参考文献

RapidandAccurateMultipleTestingCorrectionand PowerEstimationforMillionsofCorrelatedMarkers BuhmHan1,HyunMinKang1,EleazarEskin2,3* 1DepartmentofComputerScienceandEngineering,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,2DepartmentofComputerScience, UniversityofCaliforniaLosAngeles,LosAngeles,California,UnitedStatesofAmerica,3DepartmentofHumanGenetics,UniversityofCaliforniaLosAngeles,LosAngeles, California,UnitedStatesofAmerica Abstract Withthedevelopmentofhigh-throughputsequencingandgenotypingtechnologies,thenumberofmarkerscollectedin geneticassociationstudiesisgrowingrapidly,increasingtheimportanceofmethodsforcorrectingformultiplehypothesis testing.Thepermutationtestiswidelyconsideredthegoldstandardforaccuratemultipletestingcorrection,butitisoften computationallyimpracticalfortheselargedatasets.Recently,severalstudiesproposedefficientalternativeapproachestothe permutationtestbasedonthemultivariatenormaldistribution(MVN).However,theycannotaccuratelycorrectformultiple testingingenome-wideassociationstudiesfortworeasons.First,thesemethodsrequirepartitioningofthegenomeinto manydisjointblocksandignoreallcorrelationsbetweenmarkersfromdifferentblocks.Second,thetruenulldistributionof theteststatisticoftenfailstofollowtheasymptoticdistributionatthetailsofthedistribution.Weproposeanaccurateand efficientmethod for multipletesting correction in genome-wide association studies—SLIDE. Our method accounts forall correlation within a sliding window and corrects for the departure of the true null distribution of the statistic from the asymptotic distribution. In simulations using the Wellcome Trust Case Control Consortium data, the error rate of SLIDE’s correctedp-valuesismorethan20timessmallerthantheerrorrateofthepreviousMVN-basedmethods’correctedp-values, whileSLIDEisordersofmagnitudefasterthanthepermutationtestandothercompetingmethods.WealsoextendtheMVN frameworktotheproblemofestimatingthestatisticalpowerofanassociationstudywithcorrelatedmarkersandpro