Ensemble disease gene prediction by clinical sample-based networks

Disease gene prediction is a critical and challenging task. Many computational methods have been developed to predict disease genes, which can reduce the money and time used in the experimental validation. Since proteins (products of genes) usually work together to achieve a specific function, biomolecular networks, such as the protein-protein interaction (PPI) network and gene co-expression networks, are widely used to predict disease genes by analyzing the relationships between known disease genes and other genes in the networks. However, existing methods commonly use a universal static PPI network, which ignore the fact that PPIs are dynamic, and PPIs in various patients should also be different.

To address these issues, we develop an ensemble algorithm to predict disease genes from clinical sample-based networks (EdgCSN). The algorithm first constructs single sample-based networks for each case sample of the disease under study. Then, these single sample-based networks are merged to several fused networks based on the clustering results of the samples. After that, logistic models are trained with centrality features extracted from the fused networks, and an ensemble strategy is used to predict the finial probability of each gene being disease-associated. EdgCSN is evaluated on breast cancer (BC), thyroid cancer (TC) and Alzheimer's disease (AD) and obtains AUC values of 0.970, 0.971 and 0.966, respectively, which are much better than the competing algorithms. Subsequent de novo validations also demonstrate the ability of EdgCSN in predicting new disease genes.

In this study, we propose EdgCSN, which is an ensemble learning algorithm for predicting disease genes with models trained by centrality features extracted from clinical sample-based networks. Results of the leave-one-out cross validation show that our EdgCSN performs much better than the competing algorithms in predicting BC-associated, TC-associated and AD-associated genes. de novo validations also show that EdgCSN is valuable for identifying new disease genes.