When should we trust the annotation? Selective prediction for molecular structure retrieval from mass spectra

Machine learning methods for identifying molecular structures from tandem mass spectra (MS/MS) have advanced rapidly, yet current approaches still exhibit significant error rates. In high-stakes applications such as clinical metabolomics and environmental screening, incorrect annotations can have serious consequences, making it essential to determine when a prediction can be trusted. We introduce a selective prediction framework for molecular structure retrieval from MS/MS spectra, enabling models to abstain from predictions when uncertainty is too high. We formulate the problem within the risk-coverage tradeoff framework and comprehensively evaluate uncertainty quantification strategies at two levels of granularity: fingerprint-level uncertainty over predicted molecular fingerprint bits, and retrieval-level uncertainty over candidate rankings. We compare scoring functions including first-order confidence measures, aleatoric and epistemic uncertainty estimates from second-order distributions, as well as distance-based measures in the latent space. All experiments are conducted on the MassSpecGym benchmark. Our analysis reveals that while fingerprint-level uncertainty scores are poor proxies for retrieval success, computationally inexpensive first-order confidence measures and retrieval-level aleatoric uncertainty achieve strong risk-coverage tradeoffs across evaluation settings. We demonstrate that by applying distribution-free risk control via generalization bounds, practitioners can specify a tolerable error rate and obtain a subset of annotations satisfying that constraint with high probability.

Small molecule retrieval from tandem mass spectrometry: what are we optimizing for?

One of the central challenges in the computational analysis of liquid chromatography-tandem mass spectrometry (LC-MS/MS) data is to identify the compounds underlying the output spectra. In recent years, this problem is increasingly tackled using deep learning methods. A common strategy involves predicting a molecular fingerprint vector from an input mass spectrum, which is then used to search for matches in a chemical compound database. While various loss functions are employed in training these predictive models, their impact on model performance remains poorly understood. In this study, we investigate commonly used loss functions, deriving novel regret bounds that characterize when Bayes-optimal decisions for these objectives must diverge. Our results reveal a fundamental trade-off between the two objectives of (1) fingerprint similarity and (2) molecular retrieval. Optimizing for more accurate fingerprint predictions typically worsens retrieval results, and vice versa. Our theoretical analysis shows this trade-off depends on the similarity structure of candidate sets, providing guidance for loss function and fingerprint selection.