XGSEA: CROSS-species gene set enrichment analysis via domain adaptation

Motivation: Gene set enrichment analysis (GSEA) has been widely used to identify gene sets with statistically significant difference between cases and controls against a large gene set. GSEA needs both phenotype labels and expression of genes. However, gene expression are assessed more often for model organisms than minor species. Also, importantly gene expression are not measured well under specific conditions for human, due to high risk of direct experiments, such as non-approved treatment or gene knockout, and then often substituted by mouse. Thus, predicting enrichment significance (on a phenotype) of a given gene set of a species (target, say human), by using gene expression measured under the same phenotype of the other species (source, say mouse) is a vital and challenging problem, which we call CROSS-species gene set enrichment problem (XGSEP). Results: For XGSEP, we propose the CROSS-species gene set enrichment analysis (XGSEA), with three steps of: (1) running GSEA for a source species to obtain enrichment scores and p-values of source gene sets; (2) representing the relation between source and target gene sets by domain adaptation; and (3) using regression to predict p-values of target gene sets, based on the representation in (2). We extensively validated the XGSEA by using five regression and one classification measurements on four real data sets under various settings, proving that the XGSEA significantly outperformed three baseline methods in most cases. A case study of identifying important human pathways for T -cell dysfunction and reprogramming from mouse ATAC-Seq data further confirmed the reliability of the XGSEA. Availability: Source code of the XGSEA is available through https://github.com/LiminLi-xjtu/XGSEA.