FUNNEL-GSEA: FUNctioNal ELastic-net regression in time-course gene set enrichment analysis

MOTIVATION: Gene set enrichment analyses (GSEAs) are widely used in genomic research to identify underlying biological mechanisms (defined by the gene sets), such as Gene Ontology terms and molecular pathways. There are two caveats in the currently available methods: (i) they are typically designed for group comparisons or regression analyses, which do not utilize temporal information efficiently in time-series of transcriptomics measurements; and (ii) genes overlapping in multiple molecular pathways are considered multiple times in hypothesis testing. RESULTS: We propose an inferential framework for GSEA based on functional data analysis, which utilizes the temporal information based on functional principal component analysis, and disentangles the effects of overlapping genes by a functional extension of the elastic-net regression. Furthermore, the hypothesis testing for the gene sets is performed by an extension of Mann-Whitney U test which is based on weighted rank sums computed from correlated observations. By using both simulated datasets and a large-scale time-course gene expression data on human influenza infection, we demonstrate that our method has uniformly better receiver operating characteristic curves, and identifies more pathways relevant to immune-response to human influenza infection than the competing approaches. AVAILABILITY AND IMPLEMENTATION: The methods are implemented in R package FUNNEL, freely and publicly available at: https://github.com/yunzhang813/FUNNEL-GSEA-R-Package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.