Kar Wai Lim, Bhanushee Sharma, Payel Das, Vijil Chenthamarakshan, Jonathan S. Dordick
Sep 23, 2020·q-bio.QM·PDF Chemical toxicity prediction using machine learning is important in drug development to reduce repeated animal and human testing, thus saving cost and time. It is highly recommended that the predictions of computational toxicology models are mechanistically explainable. Current state of the art machine learning classifiers are based on deep neural networks, which tend to be complex and harder to interpret. In this paper, we apply a recently developed method named contrastive explanations method (CEM) to explain why a chemical or molecule is predicted to be toxic or not. In contrast to popular methods that provide explanations based on what features are present in the molecule, the CEM provides additional explanation on what features are missing from the molecule that is crucial for the prediction, known as the pertinent negative. The CEM does this by optimizing for the minimum perturbation to the model using a projected fast iterative shrinkage-thresholding algorithm (FISTA). We verified that the explanation from CEM matches known toxicophores and findings from other work.
Bhanushee Sharma, Vijil Chenthamarakshan, Amit Dhurandhar, Shiranee Pereira, James A. Hendler, Jonathan S. Dordick, Payel Das
Apr 13, 2022·q-bio.QM·PDF Explainable ML for molecular toxicity prediction is a promising approach for efficient drug development and chemical safety. A predictive ML model of toxicity can reduce experimental cost and time while mitigating ethical concerns by significantly reducing animal and clinical testing. Herein, we use a deep learning framework for simultaneously modeling in vitro, in vivo, and clinical toxicity data. Two different molecular input representations are used: Morgan fingerprints and pre-training SMILES embeddings. A multi-task deep learning model accurately predicts toxicity for all endpoints, including clinical, as indicated by AUROC and balanced accuracy. In particular, SMILES embeddings as input to the multi-task model improved clinical toxicity predictions compared to existing models in MoleculeNet benchmark. Additionally, our multi-task approach is comprehensive in the sense that it is comparable to state-of-the-art approaches for specific endpoints in in vitro, in vivo and clinical platforms. Through both the multi-task model and transfer learning, we were able to indicate the minimal need of in vivo data for clinical toxicity predictions. To provide confidence and explain the model's predictions, we adapt a post-hoc contrastive explanation method that returns pertinent positive and pertinent negative features, which correspond well to known mutagenic and reactive toxicophores, such as unsubstituted bonded heteroatoms, aromatic amines, and Michael receptors. Furthermore, toxicophore recovery by pertinent feature analysis captures more of the in vitro (53%) and in vivo (56%), rather than of the clinical (8%), endpoints, and indeed uncovers a preference in known toxicophore data towards in vitro and in vivo experimental data. To our knowledge, this is the first contrastive explanation, using both present and absent substructures, for predictions of clinical and in vivo molecular toxicity.