Network-based pathway enrichment analysis

Finding out the associations between an input gene set, such as genes associated with a certain phenotype, and annotated gene sets, such as known pathways, are a very important problem in modern molecular biology. The existing approaches mainly focus on the overlap between the two, and may miss important but subtle relationships between genes. In this paper, we propose a method, NetPEA, by combining the known pathways and high-throughput networks. Our method not only considers the shared genes, but also takes the gene interactions into account. It utilizes a protein-protein interaction network and a random walk procedure to identify hidden relationships between gene sets, and uses a randomization strategy to evaluate the significance for pathways to achieve such similarity scores. Compared with the over-representation based method, our method can identify more relationships. Compared with a state of the art network-based method, EnrichNet, our method not only provides a ranked list of pathways, but also provides the statistical significant information. Importantly, through independent tests, we show that our method likely has a higher sensitivity in revealing the true casual pathways, while at the same time achieve a higher specificity. Literature review of selected results indicates that some of the novel pathways reported by our method are biologically relevant and important.