Discriminant models on mitochondrial toxicity improved by consensus modeling and resolving imbalance in training

Humans and animals may be exposed to tens of thousands of natural and synthetic chemicals during their lifespan. It is difficult to assess risk for all the chemicals with experimental toxicity tests. An alternative approach is to use computational toxicology methods such as quantitative structure-activity relationship (QSAR) modeling. Mitochondrial toxicity is involved in many diseases such as cancer, neurodegeneration, type 2 diabetes, cardiovascular diseases and autoimmune diseases. Thus, it is important to rapidly and efficiently identify chemicals with mitochondrial toxicity. In this study, five machine learning algorithms and twelve types of molecular fingerprints were employed to generate QSAR discriminant models for mitochondrial toxicity. A threshold moving method was adopted to resolve the imbalance issue in the training data. Consensus of the models by an averaging probability strategy improved prediction performance. The best model has correct classification rates of 81.8% and 88.3% in ten-fold cross validation and external validation, respectively. Substructures such as phenol, carboxylic acid, nitro and arylchloride were found informative through analysis of information gain and frequency of substructures. The results demonstrate that resolving imbalance in training and building consensus models can improve classification rates for mitochondrial toxicity prediction. (C) 2020 Elsevier Ltd. All rights reserved.