IMPUTATION OF TRUNCATED p-VALUES FOR META-ANALYSIS METHODS AND ITS GENOMIC APPLICATION

• 成果类型: Article
• 署名作者: Tang, Shaowu; Ding, Ying; Sibille, Etienne; Mogil, Jeffrey S.; Lariviere, William R.; Tseng, George C.
• 署名单位: Roche Holding; Roche Holding USA; Pfizer; Pfizer USA; University of Toronto; Centre for Addiction & Mental Health - Canada; McGill University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh
• 刊物名称: ANNALS OF APPLIED STATISTICS
• ISSN/ISSBN: 1932-6157
• DOI: 10.1214/14-AOAS747
• 发表日期: 2014
• 页码: 2150-2174
• 关键词: false discovery rate; gene-expression; colorectal-cancer; statistical considerations; publication bias; microarray; tissues; tests; fill; trim

摘要

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 transformed p-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 and p-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 certain p-value threshold (e.g., DE genes with p-value < 0.001) are reported in journal publications. The truncated p-value information makes the afore-mentioned meta-analysis methods inapplicable and researchers are forced to apply a less efficient vote counting method or naively drop the studies with incomplete information. The purpose of this paper is to develop effective meta-analysis methods for such situations with partially censored p-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 I error, 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 naive approaches. Mean imputation and multiple imputation methods performed the best and are recommended for future applications.