Enrichment methodologies for differential gene expression between cases and controls can be broadly classified into two categories: gene permutation and subject permutation109. In gene permutation methods, such as a hypergeometric test, the null distribution of the overlap statistic is derived by (either analytically or empirically) permuting the genes found in the set being tested. In the subject sampling methods, such as GSEA110, case control labels are (either analytically or empirically) permuted to generate the null distribution of the overlap statistic. Since these methods differ in their statistical assumptions and thus appropriateness for a particular dataset and gene set, which subsequently affects their performance, here we used a combination of methods and then merged the results. Note that for these subject permutation tests, only the expression at the level of genes, but not isoforms, was incorporated.
