title: Imputation of Truncatedp-Values For Meta-Analysis Methods and Its Genomic Application.
abstract: Microarray analysis to monitor expression activities in thousands of genes simultaneously has become routine in biomedical research during the past decade. a tremendous amount of expression profiles are generated and stored in the public domain and information integration by meta-analysis to detect differentially expressed (DE) genes has become popular to obtain increased statistical power and validated findings. Methods that aggregate transformedp-value evidence have been widely used in genomic settings, among which Fisher's and Stouffer's methods are the most popular ones. In practice, raw data andp-values of DE evidence are often not available in genomic studies that are to be combined. Instead, only the detected DE gene lists under a certainp-value threshold (e.g., DE genes withp-value < 0.001) are reported in journal publications. The truncatedp-value information makes the aforementioned meta-analysis methods inapplicable and researchers are forced to apply a less efficient vote counting method or naïvely drop the studies with incomplete information. The purpose of this paper is to develop effective meta-analysis methods for such situations with partially censoredp-values. We developed and compared three imputation methods-mean imputation, single random imputation and multiple imputation-for a general class of evidence aggregation methods of which Fisher's and Stouffer's methods are special examples. The null distribution of each method was analytically derived and subsequent inference and genomic analysis frameworks were established. Simulations were performed to investigate the type Ierror, power and the control of false discovery rate (FDR) for (correlated) gene expression data. The proposed methods were applied to several genomic applications in colorectal cancer, pain and liquid association analysis of major depressive disorder (MDD). The results showed that imputation methods outperformed existing naïve approaches. Mean imputation and multiple imputation methods performed the best and are recommended for future applications.
authors.affiliation: Roche Molecular Systems, Inc.
authors.forename: Shaowu
authors.initials: S
authors.lastname: Tang
authors.affiliation: Pfizer.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: University of Toronto.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
authors.affiliation: McGill University.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Mogil
authors.affiliation: University of Pittsburgh.
authors.forename: William R
authors.initials: WR
authors.lastname: Lariviere
authors.affiliation: University of Pittsburgh.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
keywords: Fisher's method; Microarray analysis; Stouffer's method; meta-analysis; missing value imputation