Machine learning for population-level risk prediction of future cholangiocarcinoma
Summary Background The poor prognosis of cholangiocarcinoma (CCA) is largely driven by rapid, asymptomatic disease progression, which usually results in a late diagnosis in the absence of established screening strategies. An early, cost-effective, and universally applicable risk assessment strategy would therefore be valuable. Methods We developed machine learning (ML) models on prospective, multimodal data from 487,495 UK Biobank (UKB) participants, of whom 649 developed CCA during follow-up. Data from England (80%) were utilised for ML development via five-fold cross-validation, and then all models were tested on withheld data from Scotland, Wales, and Newcastle (20%). Iterative ablation studies reduced inputs from >150 features across demographic data, lifestyle, health records, blood parameters, genomics, and metabolomics to models built on five and ten routinely available clinical parameters. These were externally validated in the Penn Medicine Biobank (PMBB; n = 2638; 28 CCA), All of Us Research Program (AOU; n = 330,433; 362 CCA), Japan Medical Data Centre Claims Database (JMDC; n = 8,425,522; 723 CCA) and TriNetX (n = 728,886; 1592 CCA). Findings We show that ML models integrating biliary-disease associated health records and Gamma glutamyltransferase can stratify risk of future CCA. Evaluation on the UKB test set as well as three independent cohorts revealed robust performance and generalisability across ethnicities. We achieved AUROCs of 0.71 [95% CI: 0.703–0.711], 0.77 [95% CI: 0.764–0.778 ], 0.796 [95% CI: 0.795–0.798] and 0.8 [95% CI: 0.794–0.805] for UKB, PMBB, AOU, and JMDC respectively, with respective AUPRCs of 0.014 [95% CI: 0.009–0.018], 0.042 [95% CI: 0.037–0.048], 0.038 [95% CI: 0.033–0.042] and 0.001 [95% CI: 0.001–0.001]. In AOU, application of the Youden J-optimised threshold yielded a number needed to screen of 79. Separate models for intra- and extrahepatic CCA did not improve performance. In line with the pathophysiology, performance declined for longer intervals between assessment and event. A group-level analysis in the TriNetX cohort revealed hazard ratios of up to 82.5 [95% CI: 26.4–257.96]. We provide extensive interpretability results and release all source codes used to develop the presented models. Interpretation We provide a comprehensive framework for early CCA risk stratification in the general population, identifying key predictors, and demonstrating the potential of data-driven models in personalised screening for hepatobiliary cancer. Funding German Cancer Aid (grant #70115730), Junior Principal Investigator Fellowship programme of RWTH Aachen Excellence strategy.