A network-based classification model for deriving novel drug-disease associations and assessing their molecular actions

PLoS One. 2014 Oct 30;9(10):e111668. doi: 10.1371/journal.pone.0111668. eCollection 2014.

Abstract

The growing number and variety of genetic network datasets increases the feasibility of understanding how drugs and diseases are associated at the molecular level. Properly selected features of the network representations of existing drug-disease associations can be used to infer novel indications of existing drugs. To find new drug-disease associations, we generated an integrative genetic network using combinations of interactions, including protein-protein interactions and gene regulatory network datasets. Within this network, network adjacencies of drug-drug and disease-disease were quantified using a scored path between target sets of them. Furthermore, the common topological module of drugs or diseases was extracted, and thereby the distance between topological drug-module and disease (or disease-module and drug) was quantified. These quantified scores were used as features for the prediction of novel drug-disease associations. Our classifiers using Random Forest, Multilayer Perceptron and C4.5 showed a high specificity and sensitivity (AUC score of 0.855, 0.828 and 0.797 respectively) in predicting novel drug indications, and displayed a better performance than other methods with limited drug and disease properties. Our predictions and current clinical trials overlap significantly across the different phases of drug development. We also identified and visualized the topological modules of predicted drug indications for certain types of cancers, and for Alzheimer's disease. Within the network, those modules show potential pathways that illustrate the mechanisms of new drug indications, including propranolol as a potential anticancer agent and telmisartan as treatment for Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Area Under Curve
  • Clinical Trials as Topic
  • Databases as Topic
  • Disease / genetics*
  • Gene Regulatory Networks*
  • Models, Biological*
  • Pharmaceutical Preparations / metabolism*
  • Reproducibility of Results
  • Toxicogenetics

Substances

  • Pharmaceutical Preparations

Grants and funding

This research was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (NRF-2010-0008639). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.