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

arXiv: https://arxiv.org/abs/2608.30472 · HTML: https://mlsanity.com/paper/2608.30472/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 29 of its 105 references that are in the map.
- First posted on arXiv 31 Aug 2026.

## Builds on (most cited first, 29 of 29)

- [A Unified Approach to Interpreting Model Predictions](https://mlsanity.com/paper/1705.07874/) (2017)
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- [How Powerful are Graph Neural Networks?](https://mlsanity.com/paper/1810.00826/) (2018)
- [Simple and Scalable Predictive Uncertainty Estimation using Deep Ensembles](https://mlsanity.com/paper/1612.01474/) (2016)
- [Neural Message Passing for Quantum Chemistry](https://mlsanity.com/paper/1704.01212/) (2017)
- [Axiomatic Attribution for Deep Networks](https://mlsanity.com/paper/1703.01365/) (2017)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Fast Graph Representation Learning with PyTorch Geometric](https://mlsanity.com/paper/1903.02428/) (2019)
- [What Uncertainties Do We Need in Bayesian Deep Learning for Computer Vision?](https://mlsanity.com/paper/1703.04977/) (2017)
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- [MoleculeNet: A Benchmark for Molecular Machine Learning](https://mlsanity.com/paper/1703.00564/) (2017)
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- [Convolutional Networks on Graphs for Learning Molecular Fingerprints](https://mlsanity.com/paper/1509.09292/) (2015)
- [Distribution-Free Predictive Inference For Regression](https://mlsanity.com/paper/1604.04173/) (2016)
- [Captum: A unified and generic model interpretability library for PyTorch](https://mlsanity.com/paper/2009.07896/) (2020)
- [A Benchmark for Interpretability Methods in Deep Neural Networks](https://mlsanity.com/paper/1806.10758/) (2018)
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- [Analyzing Learned Molecular Representations for Property Prediction](https://mlsanity.com/paper/1904.01561/) (2019)
- [Methods for Interpreting and Understanding Deep Neural Networks](https://mlsanity.com/paper/1706.07979/) (2017)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)
- [Molecular Graph Convolutions: Moving Beyond Fingerprints](https://mlsanity.com/paper/1603.00856/) (2016)
- [Large-Scale Chemical Language Representations Capture Molecular Structure and Properties](https://mlsanity.com/paper/2106.09553/) (2021)
- [Translation between Molecules and Natural Language](https://mlsanity.com/paper/2204.11817/) (2022)
- [Drug discovery with explainable artificial intelligence](https://mlsanity.com/paper/2007.00523/) (2020)

## Abstract (arXiv)

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.