PAND: A Distribution to Identify Functional Linkage from Networks with Preferential Attachment Property

Technology advances have immensely accelerated large-scale mapping of biological networks, which necessitates the development of accurate and powerful network-based algorithms to make functional inferences. A prevailing approach is to leverage functions of neighboring nodes to predict unknown molecular function. However, existing neighbor-based algorithms have ignored the scale-free property hidden in many biological networks. By assuming that neighbor sharing is constrained by the preferential attachment property, we developed a Preferential Attachment based common Neighbor Distribution (PAND) to calculate the probability of the neighbor-sharing event between any two nodes in scale-free networks, which nearly perfectly matched the observed probability in simulations. By applying PAND to a human protein-protein interaction (PPI) network, we showed that smaller probabilities represented closer functional linkages between proteins. With the PAND-derive linkages, we were able to build new networks where the links are more functionally reliable than those of the human PPI network. We then applied simple annotation schemes to a PAND-derived network to make reliable functional predictions for proteins. We also developed an R package called PANDA (PAND-derived functional Associations) to implement the methods proposed in this study. In conclusion, PAND is a useful distribution to calculate the probability of the neighbor-sharing events in scale-free networks. With PAND, we are able to extract reliable functional linkages from real biological networks and builds new networks that are better bases for further functional inference.