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.
BackgroundPredicting 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.ResultsWe 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.ConclusionsIn 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.
Protein-protein interaction (PPI) networks play an important role in studying the functional roles of proteins, including their association with diseases. However, protein interaction networks are not sufficient without the support of additional biological knowledge for proteins such as their molecular functions and biological processes. To complement and enrich PPI networks, we propose to exploit biological properties of individual proteins. More specifically, we integrate keywords describing protein properties into the PPI network, and construct a novel PPI-Keywords (PPIK) network consisting of both proteins and keywords as two different types of nodes. As disease proteins tend to have a similar topological characteristics on the PPIK network, we further propose to represent proteins with metagraphs. Different from a traditional network motif or subgraph, a metagraph can capture a particular topological arrangement involving the interactions/associations between both proteins and keywords. Based on the novel metagraph representations for proteins, we further build classifiers for disease protein classification through supervised learning. Our experiments on three different PPI databases demonstrate that the proposed method consistently improves disease protein prediction across various classifiers, by 15.3% in AUC on average. It outperforms the baselines including the diffusion-based methods (e.g., RWR) and the module-based methods by 13.8-32.9% for overall disease protein prediction. For predicting breast cancer genes, it outperforms RWR, PRINCE and the module-based baselines by 6.6-14.2%. Finally, our predictions also turn out to have better correlations with literature findings from PubMed.
Real-world networks often exist with multiple views, where each view describes one type of interaction among a common set of nodes. For example, on a video-sharing network, while two user nodes are linked, if they have common favorite videos in one view, then they can also be linked in another view if they share common subscribers. Unlike traditional single-view networks, multiple views maintain different semantics to complement each other. In this article, we propose M ulti-view coll A borative N etwork E mbedding (MANE), a multi-view network embedding approach to learn low-dimensional representations. Similar to existing studies, MANE hinges on diversity and collaboration—while diversity enables views to maintain their individual semantics, collaboration enables views to work together. However, we also discover a novel form of second-order collaboration that has not been explored previously, and further unify it into our framework to attain superior node representations. Furthermore, as each view often has varying importance w.r.t. different nodes, we propose MANE , an attention -based extension of MANE, to model node-wise view importance. Finally, we conduct comprehensive experiments on three public, real-world multi-view networks, and the results demonstrate that our models consistently outperform state-of-the-art approaches.
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.
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