sPAGM: inferring subpathway activity by integrating gene and miRNA expression-robust functional signature identification for melanoma prognoses.

MicroRNAs (miRNAs) regulate biological pathways by inhibiting gene expression. However, most current analytical methods fail to consider miRNAs, when inferring functional or pathway activities. In this study, we developed a model called sPAGM to infer subpathway activities by integrating gene and miRNA expressions. In this model, we reconstructed subpathway graphs by embedding miRNA components, and characterized subpathway activity (sPA) scores by simultaneously considering the expression levels of miRNAs and genes. The results showed that the sPA scores could distinguish different samples across tumor types, as well as samples between tumor and normal conditions. Moreover, the sPAGM model displayed more specificities than the entire pathway-based analyses. This model was applied to melanoma tumors to perform a prognosis analysis, which identified a robust 55-subpathway signature. By using The Cancer Genome Atlas and independently verified data sets, the subpathway-based signature significantly predicted the patients' prognoses, which were independent of clinical variables. In the prognostic performance comparison, the sPAGM model was superior to the gene-only and miRNA-only methods. Finally, we dissected the functional roles and interactions of components within the subpathway signature. Taken together, the sPAGM model provided a framework for inferring subpathway activities and identifying functional signatures for clinical applications.