Drug interaction prediction using ontology-driven hypothetical assertion framework for pathway generation followed by numerical simulation

<p>Abstract</p> <p>Background</p> <p>In accordance with the increasing amount of information concerning individual differences in drug response and molecular interaction, the role of <it>in silico </it>prediction of drug interaction on the pathway level is becoming more and more important. However, in view of the interferences for the identification of new drug interactions, most conventional information models of a biological pathway would have limitations. As a reflection of real world biological events triggered by a stimulus, it is important to facilitate the incorporation of known molecular events for inferring (unknown) possible pathways and hypothetic drug interactions. Here, we propose a new Ontology-Driven Hypothetic Assertion (OHA) framework including pathway generation, drug interaction detection, simulation model generation, numerical simulation, and hypothetic assertion. Potential drug interactions are detected from drug metabolic pathways dynamically generated by molecular events triggered after the administration of certain drugs. Numerical simulation enables to estimate the degree of side effects caused by the predicted drug interactions. New hypothetic assertions of the potential drug interactions and simulation are deduced from the Drug Interaction Ontology (DIO) written in Web Ontology Language (OWL).</p> <p>Results</p> <p>The concept of the Ontology-Driven Hypothetic Assertion (OHA) framework was demonstrated with known interactions between irinotecan (CPT-11) and ketoconazole. Four drug interactions that involved cytochrome p450 (CYP3A4) and albumin as potential drug interaction proteins were automatically detected from Drug Interaction Ontology (DIO). The effect of the two interactions involving CYP3A4 were quantitatively evaluated with numerical simulation. The co-administration of ketoconazole may increase AUC and Cmax of SN-38(active metabolite of irinotecan) to 108% and 105%, respectively. We also estimates the potential effects of genetic variations: the AUC and Cmax of SN-38 may increase to 208% and 165% respectively with the genetic variation UGT1A1*28/*28 which reduces the expression of UGT1A1 down to 30%.</p> <p>Conclusion</p> <p>These results demonstrate that the Ontology-Driven Hypothetic Assertion framework is a promising approach for <it>in silico </it>prediction of drug interactions. The following future researches for the <it>in silico </it>prediction of individual differences in the response to the drug and drug interactions after the administration of multiple drugs: expansion of the Drug Interaction Ontology for other drugs, and incorporation of virtual population model for genetic variation analysis, as well as refinement of the pathway generation rules, the drug interaction detection rules, and the numerical simulation models.</p

Drug-drug interactions: A machine learning approach

Automatic detection of drug-drug interaction (DDI) is a difficult problem in pharmaco-surveillance. Recent practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies have been based on carefully selected drug characteristics such as their pharmacological effects, and on drug-target networks, in order to identify and comprehend anomalies in a drug\u27s biochemical function upon co-administration.;In this work, we present a novel DDI prediction framework that combines several drug-attribute similarity measures to construct a feature space from which we train three machine learning algorithms: Support Vector Machine (SVM), J48 Decision Tree and K-Nearest Neighbor (KNN) using a partially supervised classification algorithm called Positive Unlabeled Learning (PU-Learning) tailored specifically to suit our framework.;In summary, we extracted 1,300 U.S. Food and Drug Administration-approved pharmaceutical drugs and paired them to create 1,688,700 feature vectors. Out of 397 drug-pairs known to interact prior to our experiments, our system was able to correctly identify 80% of them and from the remaining 1,688,303 pairs for which no interaction had been determined, we were able to predict 181 potential DDIs with confidence levels greater than 97%. The latter is a set of DDIs unrecognized by our source of ground truth at the time of study.;Evaluation of the effectiveness of our system involved querying the U.S. Food and Drug Administration\u27s Adverse Effect Reporting System (AERS) database for cases involving drug-pairs used in this study. The results returned from the query listed incidents reported for a number of patients, some of whom had experienced severe adverse reactions leading to outcomes such as prolonged hospitalization, diminished medicinal effect of one or more drugs, and in some cases, death

Safety and Reliability - Safe Societies in a Changing World

The contributions cover a wide range of methodologies and application areas for safety and reliability that contribute to safe societies in a changing world. These methodologies and applications include: - foundations of risk and reliability assessment and management - mathematical methods in reliability and safety - risk assessment - risk management - system reliability - uncertainty analysis - digitalization and big data - prognostics and system health management - occupational safety - accident and incident modeling - maintenance modeling and applications - simulation for safety and reliability analysis - dynamic risk and barrier management - organizational factors and safety culture - human factors and human reliability - resilience engineering - structural reliability - natural hazards - security - economic analysis in risk managemen