Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis 英文参考文献.docVIP

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Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis 英文参考文献.doc

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Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis 英文参考文献

CapturingHeterogeneityinGeneExpression StudiesbySurrogateVariableAnalysis Jeffrey T.Leek1,John D.Storey1,2* 1DepartmentofBiostatistics,UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica,2DepartmentofGenomeSciences,UniversityofWashington,Seattle, Washington,UnitedStatesofAmerica It has unambiguously been shown that genetic, environmental, demographic, and technical factors may have substantialeffectsongeneexpressionlevels.Inadditiontothemeasuredvariable(s)ofinterest,therewilltendtobe sourcesofsignalduetofactorsthatareunknown,unmeasured,ortoocomplicatedtocapturethroughsimplemodels. We show that failing to incorporate these sources of heterogeneity into an analysis can have widespread and detrimentaleffectsonthestudy.Notonlycanthisreducepowerorinduceunwanteddependenceacrossgenes,butit can also introduce sources of spurious signal to many genes. This phenomenon is true even for well-designed, randomized studies. We introduce ‘‘surrogate variable analysis’’ (SVA) to overcome the problems caused by heterogeneityinexpressionstudies.SVAcanbeappliedinconjunctionwithstandardanalysistechniquestoaccurately capturethe relationship betweenexpression and anymodeled variables of interest. We apply SVA to disease class, time course, and genetics of gene expression studies. We show that SVA increases the biological accuracy and reproducibilityofanalysesingenome-wideexpressionstudies. Citation: Leek JT, Storey JD (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3(9): e161. doi:10.1371/journal.pgen. 0030161 the model when identifying differential expression with respect to disease state, we show that this may (a) induce Introduction Large-scalegeneexpressionstudiesallowonetocharacter- ize transcriptional variation with respect to measured variables of interest, such as differing environments, treat- ments, time points, phenotypes, or clinical outcomes. How- ever,anumberofunmeasuredorunmodeledfactorsmayalso in?uence