title: Positive-Unlabeled Learning for inferring drug interactions based on heterogeneous attributes.
abstract: BACKGROUND
  Investigating and understanding drug-drug interactions (DDIs) is important in improving the effectiveness of clinical care. DDIs can occur when two or more drugs are administered together. Experimentally based DDI detection methods require a large cost and time. Hence, there is a great interest in developing efficient and useful computational methods for inferring potential DDIs. Standard binary classifiers require both positives and negatives for training. In a DDI context, drug pairs that are known to interact can serve as positives for predictive methods. But, the negatives or drug pairs that have been confirmed to have no interaction are scarce. To address this lack of negatives, we introduce a Positive-Unlabeled Learning method for inferring potential DDIs.
  
  
  RESULTS
  The proposed method consists of three steps: i) application of Growing Self Organizing Maps to infer negatives from the unlabeled dataset; ii) using a pairwise similarity function to quantify the overlap between individual features of drugs and iii) using support vector machine classifier for inferring DDIs. We obtained 6036 DDIs from DrugBank database. Using the proposed approach, we inferred 589 drug pairs that are likely to not interact with each other; these drug pairs are used as representative data for the negative class in binary classification for DDI prediction. Moreover, we classify the predicted DDIs as Cytochrome P450 (CYP) enzyme-Dependent and CYP-Independent interactions invoking their locations on the Growing Self Organizing Map, due to the particular importance of these enzymes in clinically significant interaction effects. Further, we provide a case study on three predicted CYP-Dependent DDIs to evaluate the clinical relevance of this study.
  
  
  CONCLUSIONS
  Our proposed approach showed an absolute improvement in F1-score of 14 and 38% in comparison to the method that randomly selects unlabeled data points as likely negatives, depending on the choice of similarity function. We inferred 5300 possible CYP-Dependent DDIs and 592 CYP-Independent DDIs with the highest posterior probabilities. Our discoveries can be used to improve clinical care as well as the research outcomes of drug development.
authors.affiliation: Department of Mechanical Engineering, University of Melbourne, Parkville, Melbourne, 3010, Australia. nusrath@dcs.ruh.ac.lk.|Data61, Victoria Research Lab, West Melbourne, 3003, Australia. nusrath@dcs.ruh.ac.lk.|Department of Computer Science, University of Ruhuna, Matara, 81000, Sri Lanka. nusrath@dcs.ruh.ac.lk.
authors.forename: Pathima Nusrath
authors.identifier: http://orcid.org/0000-0002-8118-9823
authors.initials: PN
authors.lastname: Hameed
authors.affiliation: Department of Computing and Information Systems, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: Verspoor
authors.affiliation: Department of Nursing, University of Melbourne, Parkville, Melbourne, 3010, Australia.|The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Snezana
authors.initials: S
authors.lastname: Kusljic
authors.affiliation: Research School of Engineering, College of Engineering and Computer Science, The Australian National University, Canberra, 2601, ACT, Australia.
authors.forename: Saman
authors.initials: S
authors.lastname: Halgamuge
mesh_terms: D016000:Cluster Analysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016208:Databases, Factual; D004347:Drug Interactions / Q000502:physiology*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D060388:Support Vector Machine
chemical_list: D004364:Pharmaceutical Preparations; D020033:Protein Isoforms; D003577:Cytochrome P-450 Enzyme System
keywords: CYP isoforms; Drug-drug interaction; Growing self organizing map (GSOM); PU learning; Pairwise drug similarity