Leveraging conformal prediction to annotate enzyme function space with limited false positives

Machine learning (ML) is increasingly being used to guide biological discovery in biomedicine such as prioritizing promising small molecules in drug discovery. In those applications, ML models are used to predict the properties of biological systems, and researchers use these predictions to prioritize candidates as new biological hypotheses for downstream experimental validations. However, when applied to unseen situations, these models can be overconfident and produce a large number of false positives. One solution to address this issue is to quantify the model's prediction uncertainty and provide a set of hypotheses with a controlled false discovery rate (FDR) pre-specified by researchers. We propose CPEC, an ML framework for FDR-controlled biological discovery. We demonstrate its effectiveness using enzyme function annotation as a case study, simulating the discovery process of identifying the functions of less-characterized enzymes. CPEC integrates a deep learning model with a statistical tool known as conformal prediction, providing accurate and FDR-controlled function predictions for a given protein enzyme. Conformal prediction provides rigorous statistical guarantees to the predictive model and ensures that the expected FDR will not exceed a user-specified level with high probability. Evaluation experiments show that CPEC achieves reliable FDR control, better or comparable prediction performance at a lower FDR than existing methods, and accurate predictions for enzymes under-represented in the training data. We expect CPEC to be a useful tool for biological discovery applications where a high yield rate in validation experiments is desired but the experimental budget is limited.