PT  - JOURNAL ARTICLE
AU  - Neel S. Madhukar
AU  - Kaitlyn Gayvert
AU  - Coryandar Gilvary
AU  - Olivier Elemento
TI  - A Machine Learning Approach Predicts Tissue-Specific Drug Adverse Events
AID  - 10.1101/288332
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 288332
4099  - http://biorxiv.org/content/early/2018/03/24/288332.short
4100  - http://biorxiv.org/content/early/2018/03/24/288332.full
AB  - One of the main causes for failure in the drug development pipeline or withdrawal post approval is the unexpected occurrence of severe drug adverse events. Even though such events should be detected by in vitro, in vivo, and human trials, they continue to unexpectedly arise at different stages of drug development causing costly clinical trial failures and market withdrawal. Inspired by the “moneyball” approach used in baseball to integrate diverse features to predict player success, we hypothesized that a similar approach could leverage existing adverse event and tissue-specific toxicity data to learn how to predict adverse events. We introduce MAESTER, a data-driven machine learning approach that integrates information on a compound’s structure, targets, and phenotypic effects with tissue-wide genomic profiling and our toxic target database to predict the probability of a compound presenting with different types of tissue-specific adverse events. When tested on 6 different types of adverse events MAESTER maintains a high accuracy, sensitivity, and specificity across both the training data and new test sets. Additionally, MAESTER scores could flag a number of drugs that were approved, but later withdrawn due to unknown adverse events – highlighting its potential to identify events missed by traditional methods. MAESTER can also be used to identify toxic targets for each tissue type. Overall MAESTER provides a broadly applicable framework to identify toxic targets and predict specific adverse events and can accelerate the drug development pipeline and drive the design of new safer compounds.