For pathway analysis, we propose a parameter free enrichment strategy that does not require the specification of a gene score threshold, and thus allows weakly associated genes to contribute to pathway enrichment. The general approach consists of three steps: (1) gene scores are transformed so that they follow a target distribution, (2) a test statistic is computed by summing the transformed scores of pathway member genes and fusion-genes, and (3) analytic or empirical methods are used to evaluate whether the observed test statistic is higher than expected, i.e., the pathway is enriched for trait-associated genes. We considered two variants of this approach for pathway scoring (see overview in S1 Fig). The first variant is termed as the chi-squared method:
