Prediction of drug-induced liver injury and cardiotoxicity using chemical structure and in vitro assay data

Drug-induced liver injury (DILI) and cardiotoxicity (DICT) are major adverse effects triggered by many clinically important drugs. To provide an alternative to in vivo toxicity testing, the U.S. Tox21 consortium has screened a collection of similar to 10K compounds, including drugs in clinical use, against >70 cell-based assays in a quantitative high-throughput screening (qHTS) format. In this study, we compiled reference compound lists for DILI and DICT and compared the potential of Tox21 assay data with chemical structure information in building prediction models for human in vivo hepatotoxicity and cardiotoxicity. Models were built with four different machine learning algorithms (e.g., Random Forest, Naive Bayes, eXtreme Gradient Boosting, and Support Vector Machine) and model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC-ROC). Chemical structure-based models showed reasonable predictive power for DILI (best AUC-ROC = 0.75 +/- 0.03) and DICT (best AUC-ROC = 0.83 +/- 0.03), while Tox21 assay data alone only showed better than random performance. DILI and DICT prediction models built using a combination of assay data and chemical structure information did not have a positive impact on model performance. The suboptimal predictive per-formance of the assay data is likely due to insufficient coverage of an adequately predictive number of toxicity mechanisms. The Tox21 consortium is currently expanding coverage of biological response space with additional assays that probe toxicologically important targets and under-represented pathways that may improve the prediction of in vivo toxicity such as DILI and DICT.

Automated summary

This study compared the predictive power of Tox21 assay data and chemical structure information in building models for drug-induced liver injury (DILI) and cardiotoxicity (DICT). Chemical structure-based models showed reasonable predictive power, while Tox21 assay data alone showed suboptimal performance. The Tox21 consortium is working on expanding coverage of biological response space to improve the prediction of in vivo toxicity.