In silico prediction of drug‐induced liver injury with a complementary integration strategy based on hybrid representation

Abstract Drug‐induced liver injury (DILI) is one of the major causes of drug withdrawals, acute liver injury and blackbox warnings. Clinical diagnosis of DILI is a huge challenge due to the complex pathogenesis and lack of specific biomarkers. In recent years, machine learning methods have been used for DILI risk assessment, but the model generalization does not perform satisfactorily. In this study, we constructed a large DILI data set and proposed an integration strategy based on hybrid representations for DILI prediction (HR‐DILI). Benefited from feature integration, the hybrid graph neural network models outperformed single representation‐based models, among which hybrid‐GraphSAGE showed balanced performance in cross‐validation with AUC (area under the curve) as 0.804±0.019. In the external validation set, HR‐DILI improved the AUC by 6.4 %‐35.9 % compared to the base model with a single representation. Compared with published DILI prediction models, HR‐DILI had better and balanced performance. The performance of local models for natural products and synthetic compounds were also explored. Furthermore, eight key descriptors and six structural alerts associated with DILI were analyzed to increase the interpretability of the models. The improved performance of HR‐DILI indicated that it would provide reliable guidance for DILI risk assessment.