Recent advances in network-based methods for disease gene prediction.

Disease-gene association through genome-wide association study (GWAS) is an arduous task for researchers. Investigating single nucleotide polymorphisms that correlate with specific diseases needs statistical analysis of associations. Considering the huge number of possible mutations, in addition to its high cost, another important drawback of GWAS analysis is the large number of false positives. Thus, researchers search for more evidence to cross-check their results through different sources. To provide the researchers with alternative and complementary low-cost disease-gene association evidence, computational approaches come into play. Since molecular networks are able to capture complex interplay among molecules in diseases, they become one of the most extensively used data for disease-gene association prediction. In this survey, we aim to provide a comprehensive and up-to-date review of network-based methods for disease gene prediction. We also conduct an empirical analysis on 14 state-of-the-art methods. To summarize, we first elucidate the task definition for disease gene prediction. Secondly, we categorize existing network-based efforts into network diffusion methods, traditional machine learning methods with handcrafted graph features and graph representation learning methods. Thirdly, an empirical analysis is conducted to evaluate the performance of the selected methods across seven diseases. We also provide distinguishing findings about the discussed methods based on our empirical analysis. Finally, we highlight potential research directions for future studies on disease gene prediction.

Disease Gene Classification with Metagraph Representations.

This chapter is based on exploiting the network-based representations of proteins, metagraphs, in protein-protein interaction network to identify candidate disease-causing proteins. Protein-protein interaction (PPI) networks are effective tools in studying the functional roles of proteins in the development of various diseases. However, they are insufficient without the support of additional biological knowledge for proteins such as their molecular functions and biological processes. To enhance PPI networks, we utilize biological properties of individual proteins as well. More specifically, we integrate keywords from UniProt database describing protein properties into the PPI network and construct a novel heterogeneous PPI-Keyword (PPIK) network consisting of both proteins and keywords. As proteins with similar functional duties or involving in the same metabolic pathway tend to have similar topological characteristics, we propose to represent them with metagraphs. Compared to the traditional network motif or subgraph, a metagraph can capture the topological arrangements through not only the protein-protein interactions but also protein-keyword associations. We feed those novel metagraph representations into classifiers for disease protein prediction and conduct our experiments on three different PPI databases. They show that the proposed method consistently increases disease protein prediction performance across various classifiers, by 15.3% in AUC on average. It outperforms the diffusion-based (e.g., RWR) and the module-based baselines by 13.8-32.9% in overall disease protein prediction. Breast cancer protein prediction outperforms RWR, PRINCE, and the module-based baselines by 6.6-14.2%. Finally, our predictions also exhibit better correlations with literature findings from PubMed database.

Integrating node embeddings and biological annotations for genes to predict disease-gene associations.

BACKGROUND: Predicting disease causative genes (or simply, disease genes) has played critical roles in understanding the genetic basis of human diseases and further providing disease treatment guidelines. While various computational methods have been proposed for disease gene prediction, with the recent increasing availability of biological information for genes, it is highly motivated to leverage these valuable data sources and extract useful information for accurately predicting disease genes. RESULTS: We present an integrative framework called N2VKO to predict disease genes. Firstly, we learn the node embeddings from protein-protein interaction (PPI) network for genes by adapting the well-known representation learning method node2vec. Secondly, we combine the learned node embeddings with various biological annotations as rich feature representation for genes, and subsequently build binary classification models for disease gene prediction. Finally, as the data for disease gene prediction is usually imbalanced (i.e. the number of the causative genes for a specific disease is much less than that of its non-causative genes), we further address this serious data imbalance issue by applying oversampling techniques for imbalance data correction to improve the prediction performance. Comprehensive experiments demonstrate that our proposed N2VKO significantly outperforms four state-of-the-art methods for disease gene prediction across seven diseases. CONCLUSIONS: In this study, we show that node embeddings learned from PPI networks work well for disease gene prediction, while integrating node embeddings with other biological annotations further improves the performance of classification models. Moreover, oversampling techniques for imbalance correction further enhances the prediction performance. In addition, the literature search of predicted disease genes also shows the effectiveness of our proposed N2VKO framework for disease gene prediction.