ToxLens: A Reproducible Graph-Learning Framework for Leakage-Aware, Uncertainty-Calibrated Molecular Toxicity Prediction

Abstract

Molecular toxicity prediction is increasingly used to prioritise compounds before experimental testing, but conventional benchmark performance can overstate practical utility when structurally related molecules occur across training and test folds. We introduce ToxLens, a reproducible multi-task graph-learning framework for 11 toxicity endpoints spanning Ames mutagenicity, acute oral toxicity, hERG inhibition, and Tox21 nuclear-receptor and stress-response assays. The workflow combines conservative chemical curation, sphere-exclusion filtering, a leakage-aware UMAP-HDBSCAN split, parallel graph and global-feature encoders joined by late concatenation, temperature-scaled Monte Carlo dropout with conformal-style prediction sets, applicability-domain analysis, and SHAP-guided toxicophore discovery with occlusion controls. On the leakage-controlled test fold, a five-seed soft-voting ensemble achieved a Matthews correlation coefficient score of 0.44, an area under the receiver operating characteristic curve score of 0.83, and an area under the precision-recall curve score of 0.58. It exceeded four ECFP4-based shallow baselines on all 11 endpoints under the same split and validation-based threshold-selection protocol. Controlled ablations showed that the global pathway was important, whereas late concatenation outperformed the tested gated and feature-wise linear modulation fusion variants. Conformal-style prediction sets revealed substantial endpoint-specific variation in set efficiency, and discrimination and calibration improved with similarity to the training domain. Retraining on fixed published Tox21 Challenge and TDA folds produced competitive, but not uniformly state-of-the-art, performance. SHAP-guided occlusion and consensus subgraph mining yielded model-derived structural hypotheses, 44 of which contained at least one occurrence that passed the predefined counterfactual criteria.