# A Quiet Failure in Calibrated Virtual Screening: Marginal Conformal Prediction Under-Covers the Minority Class, and a Class-Conditional Fix Recovers It

arXiv: https://arxiv.org/abs/2607.06605 · HTML: https://mlsanity.com/paper/2607.06605/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 8 of its 22 references that are in the map.
- First posted on arXiv 7 Jul 2026.

## Builds on (most cited first, 8 of 8)

- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [On Calibration of Modern Neural Networks](https://mlsanity.com/paper/1706.04599/) (2017)
- [Fast Graph Representation Learning with PyTorch Geometric](https://mlsanity.com/paper/1903.02428/) (2019)
- [MoleculeNet: A Benchmark for Molecular Machine Learning](https://mlsanity.com/paper/1703.00564/) (2017)
- [A Gentle Introduction to Conformal Prediction and Distribution-Free Uncertainty Quantification](https://mlsanity.com/paper/2107.07511/) (2021)
- [Classification with Valid and Adaptive Coverage](https://mlsanity.com/paper/2006.02544/) (2020)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)
- [Least Ambiguous Set-Valued Classifiers with Bounded Error Levels](https://mlsanity.com/paper/1609.00451/) (2016)

## Built on by (most cited first, 1 of 1)

- [CHOIR: heterogeneity-aware conformal prediction for crash injury severity across driver safety strata](https://mlsanity.com/paper/2609.11592/) (2026)

## Abstract (arXiv)

Conformal prediction is being adopted in drug discovery to put an honest number on model reliability: pick an error rate alpha, and the method returns prediction sets containing the true label with probability at least 1 - alpha. We show this guarantee can be dangerous on imbalanced datasets. Across four datasets, standard (marginal) conformal prediction hits its global 90% coverage target while leaving the minority class badly exposed: realized minority coverage falls to 64.8% on blood-brain-barrier penetration and to 4.2% on clinical-trial toxicity, where the rare class is nearly abandoned. The failure is not tied to one model: a random forest, a graph network, and a frozen chemical language model all reproduce it (p < 0.001 in every case), with severity tracking baseline calibration on rare labels rather than architecture. A conservation identity explains the effect: the minority's shortfall equals the majority's surplus amplified by the imbalance ratio, predicting the measured gap to within one point and ordering severity across datasets. The failure survives realistic scaffold splits and a second conformal score, while aggregate accuracy and overall coverage stay reassuringly high, which is exactly why it is easy to miss. Class-conditional (Mondrian) conformal prediction closes the gap on every dataset, restoring minority coverage to target for a modest increase in prediction-set size. We localize the failures to generic molecular scaffolds - plain benzene and pyridine cores occurring in both classes - propose a one-number diagnostic, and show with a cost model that abstaining on affected compounds flips a screening campaign from net-negative to net-positive utility. Our contribution is demonstrating on real chemistry how severe and invisible this known conformal-theory gap becomes under imbalance, and laying out a practical protocol restoring per-class reliability.