FAM-MDR A Flexible Family-Based Multifactor Dimensionality Reduction Technique to Detect Epistasis Using Related Individuals 英文参考文献.docVIP

FAM-MDR:AFlexibleFamily-BasedMultifactor DimensionalityReductionTechniquetoDetectEpistasis UsingRelatedIndividuals TomCattaert1,2*,V?′ctorUrrea3,AdamC.Naj4,LizzyDeLobel5,VanessaDeWit1,2,MaoFu6,JestinahM. MahachieJohn1,2,HaiqingShen6,M.LuzCalle3,MarylynD.Ritchie7,ToddL.Edwards4,KristelVan Steen1,2 1Montefiore Institute, University of Lie`ge, Lie`ge, Belgium, 2Groupe Interdisciplinaire de Ge′noprote′omique Applique′e- Research, University ofLie`ge, Lie`ge, Belgium, 3Department of Systems Biology, University of Vic, Vic, Spain, 4Miami Institute for Human Genomics, University of Miami, Miami, Florida, United States of America, 5Department of Applied Mathematics and Computer Science, Ghent University, Ghent, Belgium, 6School of Medicine, University of Maryland, Baltimore, Maryland, UnitedStatesofAmerica,7CenterforHumanGeneticsResearch,VanderbiltUniversity,Nashville,Tennessee,UnitedStatesofAmerica Abstract Weproposeanovelmultifactordimensionalityreductionmethodforepistasisdetectioninsmallorextendedpedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR)withModel-BasedMDR(MB-MDR).Wefocusoncontinuoustraits,althoughthemethodisgeneralandcanbe used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based GeneralizedMDR(PGMDR),whichisageneralizationofMultifactorDimensionalityReduction(MDR)tocontinuoustraitsand related individuals, FAM-MDR was foundtooutperform PGMDR in termsof power, in most of the consideredsimulated scenarios.AdditionalsimulationsrevealedthatPGMDRdoesnotappropriatelydealwithmultipletestingandconsequently givesrisetooverlyoptimisticresults.FAM-MDRadequatelydealswithmultipletestinginepistasisscreensandisincontrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmostimportancewhenclaimingepistasis.AsType2DiabetesMellitus(T2DM)isacomplexphenotypelikelyinfluenced by g