edge2vec: Representation learning using edge semantics for biomedical knowledge discovery

Representation learning provides new and powerful graph analytical approaches and tools for the highly valued data science challenge of mining knowledge graphs. Since previous graph analytical methods have mostly focused on homogeneous graphs, an important current challenge is extending this methodology for richly heterogeneous graphs and knowledge domains. The biomedical sciences are such a domain, reflecting the complexity of biology, with entities such as genes, proteins, drugs, diseases, and phenotypes, and relationships such as gene co-expression, biochemical regulation, and biomolecular inhibition or activation. Therefore, the semantics of edges and nodes are critical for representation learning and knowledge discovery in real world biomedical problems. In this paper, we propose the edge2vec model, which represents graphs considering edge semantics. An edge-type transition matrix is trained by an Expectation-Maximization approach, and a stochastic gradient descent model is employed to learn node embedding on a heterogeneous graph via the trained transition matrix. edge2vec is validated on three biomedical domain tasks: biomedical entity classification, compound-gene bioactivity prediction, and biomedical information retrieval. Results show that by considering edge-types into node embedding learning in heterogeneous graphs, \textbf{edge2vec}\ significantly outperforms state-of-the-art models on all three tasks. We propose this method for its added value relative to existing graph analytical methodology, and in the real world context of biomedical knowledge discovery applicability.Comment: 10 page

RANDOM WALK APPLIED TO HETEROGENOUS DRUG-TARGET NETWORKS FOR PREDICTING BIOLOGICAL OUTCOMES

Thesis (Ph.D.) - Indiana University, Informatics and Computing, 2016Prediction of unknown drug target interactions from bioassay data is critical not only for the understanding of various interactions but also crucial for the development of new drugs and repurposing of old ones. Conventional methods for prediction of such interactions can be divided into 2D based and 3D based methods. 3D methods are more CPU expensive and require more manual interpretation whereas 2D methods are actually fast methods like machine learning and similarity search which use chemical fingerprints. One of the problems of using traditional machine learning based method to predict drug-target pairs is that it requires a labeled information of true and false interactions. One of the major problems of supervised learning methods is selection on negative samples. Unknown drug target interactions are regarded as false interactions, which may influence the predictive accuracy of the model. To overcome this problem network based methods has become an effective tool in predicting the drug target interactions overcoming the negative sampling problem. In this dissertation study, I will describe traditional machine learning methods and 3D methods of pharmacophore modeling for drug target prediction and will show how these methods work in a drug discovery scenario. I will then introduce a new framework for drug target prediction based on bipartite networks of drug target relations known as Random Walk with Restart (RWR). RWR integrates various networks including drug– drug similarity networks, protein-protein similarity networks and drug- target interaction networks into a heterogeneous network that is capable of predicting novel drug-target relations. I will describe how chemical features for measuring drug-drug similarity do not affect performance in predicting interactions and further show the performance of RWR using an external dataset from ChEMBL database. I will describe about further implementations of RWR approach into multilayered networks consisting of biological data like diseases, tissue based gene expression data, protein- complexes and metabolic pathways to predict associations between human diseases and metabolic pathways which are very crucial in drug discovery. I have further developed a software tool package netpredictor in R (standalone and the web) for unipartite and bipartite networks and implemented network-based predictive algorithms and network properties for drug-target prediction. This package will be described

DTi2Vec: Drug-target interaction prediction using network embedding and ensemble learning.

Drug-target interaction (DTI) prediction is a crucial step in drug discovery and repositioning as it reduces experimental validation costs if done right. Thus, developing in-silico methods to predict potential DTI has become a competitive research niche, with one of its main focuses being improving the prediction accuracy. Using machine learning (ML) models for this task, specifically network-based approaches, is effective and has shown great advantages over the other computational methods. However, ML model development involves upstream hand-crafted feature extraction and other processes that impact prediction accuracy. Thus, network-based representation learning techniques that provide automated feature extraction combined with traditional ML classifiers dealing with downstream link prediction tasks may be better-suited paradigms. Here, we present such a method, DTi2Vec, which identifies DTIs using network representation learning and ensemble learning techniques. DTi2Vec constructs the heterogeneous network, and then it automatically generates features for each drug and target using the nodes embedding technique. DTi2Vec demonstrated its ability in drug-target link prediction compared to several state-of-the-art network-based methods, using four benchmark datasets and large-scale data compiled from DrugBank. DTi2Vec showed a statistically significant increase in the prediction performances in terms of AUPR. We verified the novel predicted DTIs using several databases and scientific literature. DTi2Vec is a simple yet effective method that provides high DTI prediction performance while being scalable and efficient in computation, translating into a powerful drug repositioning tool

Network modeling helps to tackle the complexity of drug-disease systems

From the (patho)physiological point of view, diseases can be considered as emergent properties of living systems stemming from the complexity of these systems. Complex systems display some typical features, including the presence of emergent behavior and the organization in successive hierarchic levels. Drug treatments increase this complexity scenario, and from some years the use of network models has been introduced to describe drug-disease systems and to make predictions about them with regard to several aspects related to drug discovery. Here, we review some recent examples thereof with the aim to illustrate how network science tools can be very effective in addressing both tasks. We will examine the use of bipartite networks that lead to the important concept of "disease module", as well as the introduction of more articulated models, like multi-scale and multiplex networks, able to describe disease systems at increasing levels of organization. Examples of predictive models will then be discussed, considering both those that exploit approaches purely based on graph theory and those that integrate machine learning methods. A short account of both kinds of methodological applications will be provided. Finally, the point will be made on the present situation of modeling complex drug-disease systems highlighting some open issues.This article is categorized under:Neurological Diseases > Computational ModelsInfectious Diseases > Computational ModelsCardiovascular Diseases > Computational Model

Scalable Probabilistic Model Selection for Network Representation Learning in Biological Network Inference

A biological system is a complex network of heterogeneous molecular entities and their interactions contributing to various biological characteristics of the system. Although the biological networks not only provide an elegant theoretical framework but also offer a mathematical foundation to analyze, understand, and learn from complex biological systems, the reconstruction of biological networks is an important and unsolved problem. Current biological networks are noisy, sparse and incomplete, limiting the ability to create a holistic view of the biological reconstructions and thus fail to provide a system-level understanding of the biological phenomena. Experimental identification of missing interactions is both time-consuming and expensive. Recent advancements in high-throughput data generation and significant improvement in computational power have led to novel computational methods to predict missing interactions. However, these methods still suffer from several unresolved challenges. It is challenging to extract information about interactions and incorporate that information into the computational model. Furthermore, the biological data are not only heterogeneous but also high-dimensional and sparse presenting the difficulty of modeling from indirect measurements. The heterogeneous nature and sparsity of biological data pose significant challenges to the design of deep neural network structures which use essentially either empirical or heuristic model selection methods. These unscalable methods heavily rely on expertise and experimentation, which is a time-consuming and error-prone process and are prone to overfitting. Furthermore, the complex deep networks tend to be poorly calibrated with high confidence on incorrect predictions. In this dissertation, we describe novel algorithms that address these challenges. In Part I, we design novel neural network structures to learn representation for biological entities and further expand the model to integrate heterogeneous biological data for biological interaction prediction. In part II, we develop a novel Bayesian model selection method to infer the most plausible network structures warranted by data. We demonstrate that our methods achieve the state-of-the-art performance on the tasks across various domains including interaction prediction. Experimental studies on various interaction networks show that our method makes accurate and calibrated predictions. Our novel probabilistic model selection approach enables the network structures to dynamically evolve to accommodate incrementally available data. In conclusion, we discuss the limitations and future directions for proposed works