Molecular Network Analysis in Rabies Pathogenesis Using Cooperative Game Theory

Background: Recently, many researchers from different fields of science have been used networks to analyze complex relational big data. The identification of which nodes are more important than the others, known as centrality analysis, is a key issue in biological network analysis. Although, several centralities have been introduced degree, closeness, and betweenness centralities are the most popular. These centralities are based on the individual position of each node and the cooperation and synergies between nodes have been ignored. Objectives: Since in many cases, the network function is a consequence of cooperation and interaction between nodes, classical centralities were extended to a group of nodes instead of only individual nodes using cooperative game theory concepts. In this study, we analyze the protein interaction network inferred in rabies disease and rank gene products based on group centrality measurements to identify the novel gene candidates. Materials and Methods: For this purpose, we used a game-theoretic approach at three scenarios, where the power of a coalition of genes assessed using different criteria including the neighbors of genes in the network, and predefined importance of the genes in its neighborhood. The Shapley value of such a game was considered as a new centrality. In this study, we analyze the network of gene products implicates rabies. The network has 1059 nodes and 8844 edges and centrality analysis was performed using CINNA package in R software. Results: Based on three scenarios, we selected genes among the highest Shapley value that had low ranking from classical centralities. The enrichment analysis among the selected genes in scenario 1 indicates important pathways in rabies pathogenesis. Pair-wise correlation analysis reveals that changing the weights of nodes at different scenarios can significantly affect the results of ranking genes in the network. Conclusions: A prior knowledge about the disease and the topology of the network, enable us to design an appropriate game and consequently infer some biological important nodes (genes) in the network. Obviously, a single centrality cannot capture all significant features embedded in the network.