Testing association of a pathway with survival using gene expression data

Abstract

Motivation: A recent surge of interest in survival as the primary clinical endpoint of microarray studies has called for an extension of the Global Test methodology to survival. Results: We present a score test for association of the expression profile of one or more groups of genes with a (possibly censored) survival time. Groups of genes may be pathways, areas of the genome, clusters from a cluster analysis or all genes on a chip. The test allows one to test hypotheses about the influence of these groups of genes on survival directly, without the intermediary of single gene testing. The test is based on the Cox proportional hazards model and is calculated using martingale residuals. It is possible to adjust the test for the presence of covariates. We also present a diagnostic graph to assist in the interpretation of the test result, visualizing the influence of genes. The test is applied to a tumor dataset, revealing pathways from the gene ontology database that are associated with survival of patients. Availability: The Global Test for survival has been incorporated into the R-package globaltest (version 3.0), available at http://www.bioconductor.org Contact:j.j.goeman@lumc.nl