AbstractMotivationMany studies have successfully used network information to prioritize candidate omics profiles associated with diseases. The metabolome, as the link between genotypes and phenotypes, has accumulated growing attention. Using a ”multi-omics” network constructed with a gene–gene network, a metabolite–metabolite network, and a gene–metabolite network to simultaneously prioritize candidate disease-associated metabolites and gene expressions could further utilize gene–metabolite interactions that are not used when prioritizing them separately. However, the number of metabolites is usually 100 times fewer than that of genes. Without accounting for this imbalance issue, we cannot effectively use gene–metabolite interactions when simultaneously prioritizing disease-associated metabolites and genes.ResultsHere, we developed aMulti-omicsNetworkEnhancementPrioritization (MultiNEP) framework with a weighting scheme to reweight contributions of different sub-networks in a multi-omics network to effectively prioritize candidate disease-associated metabolites and genes simultaneously. In simulation studies, MultiNEP outperforms competing methods that do not address network imbalances and identifies more true signal genes and metabolites simultaneously when we down-weight relative contributions of the gene–gene network and up-weight that of the metabolite–metabolite network to the gene–metabolite network. Applications to two human cancer cohorts show that MultiNEP prioritizes more cancer-related genes by effectively using both within- and between-omics interactions after handling network imbalance.Availability and implementationThe developed MultiNEP framework is implemented in an R package and available at:https://github.com/Karenxzr/MultiNep