Machine learning for population-level risk prediction of future cholangiocarcinoma
EBioMedicine, vol. 131, pp. 106433
Abstract
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.
Authors 22
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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German Cancer Research Center · Universitätsklinikum Aachen · University Hospital Carl Gustav Carus · Else Kröner Fresenius Center for Digital Health · German Cancer Consortium (DKTK) Dresden · Technische Universität Dresden · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Else Kroener Fresenius Centre for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK) partner site Dresden and German Cancer Research Centre (DKFZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Carl Gustav Carus · German Cancer Research Center (DKFZ) Dresden · Else Kröner Fresenius Center for Digital Health · German Cancer Consortium (DKTK) Dresden · Technische Universität Dresden
Affiliation as printed
Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Else Kroener Fresenius Centre for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK) partner site Dresden and German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Affiliation as printed
College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
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University Hospital Carl Gustav Carus · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Centre for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany
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Affiliation as printed
Division of Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Nagano, Japan
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · University of Pennsylvania · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; The Perelman School of Medicine, The Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
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Affiliation as printed
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
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University of Cincinnati · University of Pennsylvania
Affiliation as printed
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA; Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Affiliation as printed
Division of Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Nagano, Japan
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Affiliation as printed
Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Affiliation as printed
Department of Supportive Oncology, Atrium Health Levine Cancer, Charlotte, NC, 28204, USA
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University of the Basque Country · Biogipuzkoa Health Research Institute · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Donostiako Unibertsitate Ospitalea
Affiliation as printed
Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
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University of the Basque Country · Biogipuzkoa Health Research Institute · Donostiako Unibertsitate Ospitalea · Universidad de Navarra
Affiliation as printed
Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Centre for Autoimmune Liver Diseases & Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, ERN RARE LIVER, Monza, Italy
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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Affiliation as printed
The Perelman School of Medicine, The Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
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University of Leeds · Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases · University Hospital Carl Gustav Carus · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Else Kroener Fresenius Centre for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Medical Oncology, National Centre for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany; Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
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Universitätsklinikum Aachen · University Hospital Carl Gustav Carus · Center for Regenerative Therapies Dresden · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Else Kroener Fresenius Centre for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Centre for Regenerative Therapies Dresden (CRTD), Technische Universität (TU), Dresden, Germany
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Universitätsklinikum Aachen · University Hospital Carl Gustav Carus · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany; Else Kroener Fresenius Centre for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany. Electronic address: cschneider@ukaachen.de
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