Pathway-directed weighted testing procedures for the integrative analysis of gene expression and metabolomic data

We explore the utility of p-value weighting for enhancing the power to detect differential metabolites in a two-sample setting. Related gene expression information is used to assign an a priori importance level to each metabolite being tested. We map the gene expression to a metabolite through pathways and then gene expression information is summarized per-pathway using gene set enrichment tests. Through simulation we explore four styles of enrichment tests and four weight functions to convert the gene information into a meaningful p-value weight. We implement the p-value weighting on a prostate cancer metabolomic dataset. Gene expression on matched samples is used to construct the weights. Under certain regulatory conditions, the use of weighted p-values does not inflate the type I error above what we see for the un-weighted tests except in high correlation situations. The power to detect differential metabolites is notably increased in situations with disjoint pathways and shows moderate improvement, relative to the proportion of enriched pathways, when pathway membership overlaps.

► P-value weighting works on disparate data types where elements are indirectly mapped.
► The methodology is applicable to data integration across multiple technology types.
► Weighted multiple testing procedures lead to improved power for biomarker discovery.