Predicting adverse drug reactions of combined medication from heterogeneous pharmacologic databases

BMC Bioinformatics. 2018 Dec 31;19(Suppl 19):517. doi: 10.1186/s12859-018-2520-8.


Background: Early and accurate identification of potential adverse drug reactions (ADRs) for combined medication is vital for public health. Existing methods either rely on expensive wet-lab experiments or detecting existing associations from related records. Thus, they inevitably suffer under-reporting, delays in reporting, and inability to detect ADRs for new and rare drugs. The current application of machine learning methods is severely impeded by the lack of proper drug representation and credible negative samples. Therefore, a method to represent drugs properly and to select credible negative samples becomes vital in applying machine learning methods to this problem.

Results: In this work, we propose a machine learning method to predict ADRs of combined medication from pharmacologic databases by building up highly-credible negative samples (HCNS-ADR). Specifically, we fuse heterogeneous information from different databases and represent each drug as a multi-dimensional vector according to its chemical substructures, target proteins, substituents, and related pathways first. Then, a drug-pair vector is obtained by appending the vector of one drug to the other. Next, we construct a drug-disease-gene network and devise a scoring method to measure the interaction probability of every drug pair via network analysis. Drug pairs with lower interaction probability are preferentially selected as negative samples. Following that, the validated positive samples and the selected credible negative samples are projected into a lower-dimensional space using the principal component analysis. Finally, a classifier is built for each ADR using its positive and negative samples with reduced dimensions. The performance of the proposed method is evaluated on simulative prediction for 1276 ADRs and 1048 drugs, comparing using four machine learning algorithms and with two baseline approaches. Extensive experiments show that the proposed way to represent drugs characterizes drugs accurately. With highly-credible negative samples selected by HCNS-ADR, the four machine learning algorithms achieve significant performance improvements. HCNS-ADR is also shown to be able to predict both known and novel drug-drug-ADR associations, outperforming two other baseline approaches significantly.

Conclusions: The results demonstrate that integration of different drug properties to represent drugs are valuable for ADR prediction of combined medication and the selection of highly-credible negative samples can significantly improve the prediction performance.

Keywords: Adverse drug reactions; Combined medication; Drug-drug-ADRs association prediction; Negative sample selection; Pharmacologic databases.

MeSH terms

  • Adverse Drug Reaction Reporting Systems / statistics & numerical data*
  • Algorithms
  • Databases, Pharmaceutical*
  • Drug Interactions*
  • Drug-Related Side Effects and Adverse Reactions / metabolism*
  • Gene Regulatory Networks*
  • Humans
  • Models, Statistical
  • Pharmaceutical Preparations / metabolism*
  • Predictive Value of Tests*


  • Pharmaceutical Preparations