Network Neighbors of Drug Targets Contribute to Drug Side-Effect Similarity

In pharmacology, it is essential to identify the molecular mechanisms of drug action in order to understand adverse side effects. These adverse side effects have been used to infer whether two drugs share a target protein. However, side-effect similarity of drugs could also be caused by their target proteins being close in a molecular network, which as such could cause similar downstream effects. In this study, we investigated the proportion of side-effect similarities that is due to targets that are close in the network compared to shared drug targets. We found that only a minor fraction of side-effect similarities (5.8 %) are caused by drugs targeting proteins close in the network, compared to side-effect similarities caused by overlapping drug targets (64%). Moreover, these targets that cause similar side effects are more often in a linear part of the network, having two or less interactions, than drug targets in general. Based on the examples, we gained novel insight into the molecular mechanisms of side effects associated with several drug targets. Looking forward, such analyses will be extremely useful in the process of drug development to better understand adverse side effects

Computational Advances in Drug Safety: Systematic and Mapping Review of Knowledge Engineering Based Approaches

Drug Safety (DS) is a domain with significant public health and social impact. Knowledge Engineering (KE) is the Computer Science discipline elaborating on methods and tools for developing “knowledge-intensive” systems, depending on a conceptual “knowledge” schema and some kind of “reasoning” process. The present systematic and mapping review aims to investigate KE-based approaches employed for DS and highlight the introduced added value as well as trends and possible gaps in the domain. Journal articles published between 2006 and 2017 were retrieved from PubMed/MEDLINE and Web of Science® (873 in total) and filtered based on a comprehensive set of inclusion/exclusion criteria. The 80 finally selected articles were reviewed on full-text, while the mapping process relied on a set of concrete criteria (concerning specific KE and DS core activities, special DS topics, employed data sources, reference ontologies/terminologies, and computational methods, etc.). The analysis results are publicly available as online interactive analytics graphs. The review clearly depicted increased use of KE approaches for DS. The collected data illustrate the use of KE for various DS aspects, such as Adverse Drug Event (ADE) information collection, detection, and assessment. Moreover, the quantified analysis of using KE for the respective DS core activities highlighted room for intensifying research on KE for ADE monitoring, prevention and reporting. Finally, the assessed use of the various data sources for DS special topics demonstrated extensive use of dominant data sources for DS surveillance, i.e., Spontaneous Reporting Systems, but also increasing interest in the use of emerging data sources, e.g., observational healthcare databases, biochemical/genetic databases, and social media. Various exemplar applications were identified with promising results, e.g., improvement in Adverse Drug Reaction (ADR) prediction, detection of drug interactions, and novel ADE profiles related with specific mechanisms of action, etc. Nevertheless, since the reviewed studies mostly concerned proof-of-concept implementations, more intense research is required to increase the maturity level that is necessary for KE approaches to reach routine DS practice. In conclusion, we argue that efficiently addressing DS data analytics and management challenges requires the introduction of high-throughput KE-based methods for effective knowledge discovery and management, resulting ultimately, in the establishment of a continuous learning DS system

Knowledge-based incremental induction of clinical algorithms

The current approaches for the induction of medical procedural knowledge suffer from several drawbacks: the structures produced may not be explicit medical structures, they are only based on statistical measures that do not necessarily respect medical criteria which can be essential to guarantee medical correct structures, or they are not prepared to deal with the incremental arrival of new data. In this thesis we propose a methodology to automatically induce medically correct clinical algorithms (CAs) from hospital databases. These CAs are represented according to the SDA knowledge model. The methodology considers relevant background knowledge and it is able to work in an incremental way. The methodology has been tested in the domains of hypertension, diabetes mellitus and the comborbidity of both diseases. As a result, we propose a repository of background knowledge for these pathologies and provide the SDA diagrams obtained. Later analyses show that the results are medically correct and comprehensible when validated with health care professionals

Using Big Data Analytics and Statistical Methods for Improving Drug Safety

This dissertation includes three studies, all focusing on utilizing Big Data and statistical methods for improving one of the most important aspects of health care, namely drug safety. In these studies we develop data analytics methodologies to inspect, clean, and model data with the aim of fulfilling the three main goals of drug safety; detection, understanding, and prediction of adverse drug effects.In the first study, we develop a methodology by combining both analytics and statistical methods with the aim of detecting associations between drugs and adverse events through historical patients' records. Particularly we show applicability of the developed methodology by focusing on investigating potential confounding role of common diabetes drugs on developing acute renal failure in diabetic patients. While traditional methods of signal detection mostly consider one drug and one adverse event at a time for investigation, our proposed methodology takes into account the effect of drug-drug interactions by identifying groups of drugs frequently prescribed together.In the second study, two independent methodologies are developed to investigate the role of prescription sequence factor on the likelihood of developing adverse events. In fact, this study focuses on using data analytics for understanding drug-event associations. Our analyses on the historical medication records of a group of diabetic patients using the proposed approaches revealed that the sequence in which the drugs are prescribed, and administered, significantly do matter in the development of adverse events associated with those drugs.The third study uses a chronological approach to develop a network of approved drugs and their known adverse events. It then utilizes a set of network metrics, both similarity- and centrality-based, to build and train machine learning predictive models and predict the likely adverse events for the newly discovered drugs before their approval and introduction to the market. For this purpose, data of known drug-event associations from a large biomedical publication database (i.e., PubMed) is employed to construct the network. The results indicate significant improvements in terms of accuracy of prediction of drug-evet associations compared with similar approaches