RESEARCH ARTICLE A Comparison of Aggregate P-Value Methods and Multivariate Statistics for Self-Contained Tests of Metabolic Pathway Analysis

For pathway analysis of genomic data, the most common methods involve combining p-val-ues from individual statistical tests. However, there are several multivariate statistical meth-ods that can be used to test whether a pathway has changed. Because of the large number of variables and pathway sizes in genomics data, some of these statistics cannot be com-puted. However, in metabolomics data, the number of variables and pathway sizes are typi-cally much smaller, making such computations feasible. Of particular interest is being able to detect changes in pathways that may not be detected for the individual variables. We compare the performance of both the p-value methods and multivariate statistics for self-contained tests with an extensive simulation study and a human metabolomics study. Per-mutation tests, rather than asymptotic results are used to assess the statistical significance of the pathways. Furthermore, both one and two-sided alternatives hypotheses are exam-ined. From the human metabolomic study, many pathways were statistically significant, al-though the majority of the individual variables in the pathway were not. Overall, the p-value methods perform at least as well as the multivariate statistics for these scenarios