Fused inverse-normal method for integrated differential expression analysis of RNA-seq data

Use of next-generation sequencing technologies to transcriptomics (RNA-seq) for gene expression profiling has found widespread application in studying different biological conditions including cancers. However, RNA-seq experiments are still small sample size experiments due to the cost. Recently, an increased focus has been on meta-analysis methods for integrated differential expression analysis for exploration of potential biomarkers. In this study, we propose a p-value combination method for meta-analysis of multiple related RNA-seq studies that accounts for sample size of a study and direction of expression of genes in individual studies. In contrast to existing meta-analysis methods for RNA-seq data for differential expression analysis, the proposed method does not pre- or post-hoc filter genes that have conflicting direction of expression in different studies. Thus, our method has better potential for the discovery of differentially expressed genes (DEGs) with potentially conflicting differential signals from multiple studies related to disease. In a real data application, we demonstrate the use of our proposed method to detect biologically relevant DEGs in glioblastoma (GBM), the most aggressive brain cancer. Our approach notably enabled the identification of over-expression in GBM compared to healthy controls of the oncogene RAD51, which has recently been shown to be a target for inhibition to enhance radiosensitivity of GBM cells during treatment. Pathway analysis identified multiple aberrant GBM related pathways as well as novel regulators such as TCF7L2 and MAPT as important upstream regulators in GBM.