Capturing the Spectrum of Interaction Effects in Genetic Association Studies by Simulated Evaporative Cooling Network Analysis 英文参考文献.docVIP

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Capturing the Spectrum of Interaction Effects in Genetic Association Studies by Simulated Evaporative Cooling Network Analysis 英文参考文献.doc

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Capturing the Spectrum of Interaction Effects in Genetic Association Studies by Simulated Evaporative Cooling Network Analysis 英文参考文献

CapturingtheSpectrumofInteractionEffectsinGenetic AssociationStudiesbySimulatedEvaporativeCooling NetworkAnalysis BrettA.McKinney1*,JamesE.Crowe,Jr.2,JingyuGuo1,DehuaTian1 1DepartmentofGenetics,UniversityofAlabamaSchoolofMedicine,Birmingham,Alabama,UnitedStatesofAmerica,2DepartmentsofPediatrics,Microbiologyand Immunology,PrograminVaccineSciences,VanderbiltUniversityMedicalCenter,Nashville,Tennessee,UnitedStatesofAmerica Abstract Evidencefromhumangeneticstudiesofseveraldisorderssuggeststhatinteractionsbetweenallelesatmultiplegenesplay animportantroleininfluencingphenotypicexpression.AnalyticalmethodsforidentifyingMendeliandiseasegenesarenot appropriate when applied to common multigenic diseases, because such methods investigate association with the phenotypeonlyonegeneticlocusatatime.Newstrategiesareneededthatcancapturethespectrumofgeneticeffects, fromMendeliantomultifactorialepistasis.RandomForests(RF)andRelief-Faretwopowerfulmachine-learningmethods thathavebeenstudiedasfiltersforgeneticcase-controldataduetotheirabilitytoaccountforthecontextofallelesat multiplegeneswhenscoringtherelevanceofindividualgeneticvariantstothephenotype.However,whenvariantsinteract strongly,theindependenceassumptionofRFinthetreenode-splittingcriterionleadstodiminishedimportancescoresfor relevant variants. Relief-F, on the other hand, was designed to detect strong interactions but is sensitive to large backgroundsofvariantsthatareirrelevanttoclassificationofthephenotype,whichisanacuteproblemingenome-wide associationstudies.Toovercometheweaknessesofthesedataminingapproaches,wedevelopEvaporativeCooling(EC) feature selection, a flexible machine learning method that can integrate multiple importance scores while removing irrelevant genetic variants. To characterize detailed interactions, we construct a genetic-association interaction network (GAIN),whoseedgesquantifythesynergybetweenvariantswithrespecttothephenotype.Weusesimulationanalysisto showthatECisabletoidentifyawiderangeofinteractioneff