title: Detecting disease-associated genes with confounding variable adjustment and the impact on genomic meta-analysis: with application to major depressive disorder.
abstract: BACKGROUND
  Detecting candidate markers in transcriptomic studies often encounters difficulties in complex diseases, particularly when overall signals are weak and sample size is small. Covariates including demographic, clinical and technical variables are often confounded with the underlying disease effects, which further hampers accurate biomarker detection. Our motivating example came from an analysis of five microarray studies in major depressive disorder (MDD), a heterogeneous psychiatric illness with mostly uncharacterized genetic mechanisms.
  
  
  RESULTS
  We applied a random intercept model to account for confounding variables and case-control paired design. A variable selection scheme was developed to determine the effective confounders in each gene. Meta-analysis methods were used to integrate information from five studies and post hoc analyses enhanced biological interpretations. Simulations and application results showed that the adjustment for confounding variables and meta-analysis improved detection of biomarkers and associated pathways.
  
  
  CONCLUSIONS
  The proposed framework simultaneously considers correction for confounding variables, selection of effective confounders, random effects from paired design and integration by meta-analysis. The approach improved disease-related biomarker and pathway detection, which greatly enhanced understanding of MDD neurobiology. The statistical framework can be applied to similar experimental design encountered in other complex and heterogeneous diseases.
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Xingbin
authors.initials: X
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Chi
authors.initials: C
authors.lastname: Song
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
mesh_terms: D015415:Biomarkers; D016022:Case-Control Studies; D003198:Computer Simulation; D015986:Confounding Factors, Epidemiologic; D003865:Major Depressive Disorder / Q000453:epidemiology / Q000235:genetics*; D023281:Genomics; D006801:Humans; D015201:Meta-Analysis as Topic; D018401:Sample Size
chemical_list: D015415:Biomarkers