Identification of pathways associated with chemosensitivity through network embedding

Sheng Wang, Edward W. Huang, Junmei Cairns, Jian Peng, Liewei Wang, Saurabh Sinha

Abstract: Author summary Gene expression levels have been used to study the cellular response to drug treatments. However, analysis of gene expression without considering gene interactions cannot fully reveal complex genotype-phenotype relationships. Biological pathways reveal the interactions among genes, thus providing a complementary way of understanding the drug response variation among individuals. In this paper, we aim to identify pathways that mediate the chemical response of each drug. We used the recently generated CTRP pharmacogenomics data and CCLE basal expression data to identify these pathways. We showed that using the prior knowledge encoded in molecular networks substantially improves pathway identification. In particular, we integrate genes and pathways into a large heterogeneous network in which links are protein-protein interactions and gene-pathway affiliations. We then project this heterogeneous network onto a low-dimensional space, which enables more precise similarity measurements between pathways and drug-response-correlated genes. Extensive experiments on two benchmarks show that our method substantially improved the pathway identification performance by using the molecular networks. More importantly, our method represents a novel technique of identifying enriched properties of any gene set of interest while also taking into account networks of known gene-gene relationships and interactions.