To benchmark the performance of the various enrichment analysis methods implemented within Enrichr, namely, the proportion test, the Z-score and the combined score, as well as other similar published methods, for example, the over representation analysis (ORA) method (11), as well as simple methods such as the Jaccard distance or the number of overlapping genes, we processed 489 experiments that genetically perturbed (knockdown, knockout or overexpression) transcript factors (TFs) from 293 studies available from GEO. We identified the differentially expressed genes from these studies using the Characteristic Direction (CD) method (31). We then performed enrichment analysis against the ChIP-X enrichment analysis (ChEA) gene set library, ranking TFs with the different scoring methods (32). The hypothesis behind this benchmarking idea is that genes that are differentially expressed after genetic perturbations of a TF are enriched for the targets of the TF as determined by ChIP-seq regardless of cell type, mammalian organism or microarray platform. We then find the ranks of the perturbed TFs for each enrichment analysis scoring methods and plot their cumulative distributions. Our results demonstrate that the combined score
