Predicting Dose-Range Chemical Toxicity using Novel Hybrid Deep Machine-Learning Method

Abstract

Humans are exposed to thousands of chemicals, including environmental chemicals. Unfortunately, little is known about their potential toxicity, as determining the toxicity remains challenging due to the substantial resources required to assess a chemical in vivo. Here, we present a novel hybrid neural network (HNN) deep learning method, called HNN-Tox, to predict chemical toxicity at different doses. To develop a hybrid HNN-Tox method, we combined two neural network frameworks, the Convolutional Neural Network (CNN) and the multilayer perceptron (MLP)-type feed-forward neural network (FFNN). Combining the CNN and FCNN in the field of environmental chemical toxicity prediction is a novel approach. We developed several binary and multiclass classification models to assess dose-range chemical toxicity that is trained based on thousands of chemicals with known toxicity. The performance of the HNN-Tox was compared with other machine-learning methods, including Random Forest (RF), Bootstrap Aggregation (Bagging), and Adaptive Boosting (AdaBoost). We also analyzed the model performance dependency on varying features, descriptors, dataset size, route of exposure, and toxic dose. The HNN-Tox model, trained on 59,373 chemicals annotated with known LD50 and routes of exposure, maintained its predictive ability with an accuracy of 84.9% and 84.1%, even after reducing the descriptor size from 318 to 51, and the area under the ROC curve (AUC) was 0.89 and 0.88, respectively. Further, we validated the HNN-Tox with several external toxic chemical datasets on a large scale. The HNN-Tox performed optimally or better than the other machine-learning methods for diverse chemicals. This study is the first to report a large-scale prediction of dose-range chemical toxicity with varying features. The HNN-Tox has broad applicability in predicting toxicity for diverse chemicals and could serve as an alternative methodology approach to animal-based toxicity assessment.