Graph-based information diffusion method for prioritizing functionally related genes in protein-protein interaction networks

Shortest path length methods are routinely used to validate whether genes of interest are functionally related to each other based on biological network information. However, the methods are computationally intensive, impeding extensive utilization of network information. In addition, non-weighted shortest path length approach, which is more frequently used, often treat all network connections equally without taking into account of confidence levels of the associations. On the other hand, graph-based information diffusion method, which employs both the presence and confidence weights of network edges, can efficiently explore large networks and has previously detected meaningful biological patterns. Therefore, in this study, we hypothesized that the graph-based information diffusion method could prioritize genes with relevant functions more efficiently and accurately than the shortest path length approaches. We demonstrated that the graph-based information diffusion method substantially differentiated not only genes participating in same biological pathways (p << 0.0001) but also genes associated with specific human drug-induced clinical symptoms (p << 0.0001) from random. Furthermore, the diffusion method prioritized these functionally related genes faster and more accurately than the shortest path length approaches (pathways: p = 2.7e-28, clinical symptoms: p = 0.032). These data show the graph-based information diffusion method can be routinely used for robust prioritization of functionally related genes, facilitating efficient network validation and hypothesis generation, especially for human phenotype-specific genes.