Objective To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.
Design Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability).
Results The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC.
Conclusion Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.
- colorectal cancer
- colorectal cancer screening
- cancer prevention
- medical statistics
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Contributors TS, DCM, MJG and IT conceived the study. TS, DCM and IT undertook the systematic review. TS, supervised by IT and DCM, undertook the analysis and drafted the initial manuscript. KGMM provided guidance on data interpretation and critical review on the manuscript. AJC, MJ, PF, GF, PHMP, GS, AH, RK, AT, AO, KO, CB, MR-B, JMH, ABG, KEB, AT, CB, PO, DP, VP, PV, BB-d-M, BO, SH, BVG, GS, EW, MJ, NM, ER, MJG and KJA played roles in data acquisition for the EPIC cohort and provided critical review on the manuscript. IT is the guarantor.
Funding TS is supported by a Medical Research Council studentship (MR/M501712/1). DCM is supported by a Cancer Research UK Population Research Fellowship (C57955/A24390). This work was partly supported by the German Research Foundation (DFG) Grant AL 1784/3-1, which has funded the research position of KA for the time of study conduct and analysis. KEB received research grants from Cancer Research UK (C570/A16491) and the Medical Research Council (MR/M012190/1). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK).
Competing interests TS received a studentship from the Medical Research Council (MR/M501712/1). DCM is supported by a Cancer Research UK Population Research Fellowship (C57955/A24390). KJA received a research grant from the German Research Foundation (DFG) (AL 1784/3-1), KEB received research grants from Cancer Research UK (C570/A16491) and the Medical Research Council (MR/M012190/1); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; KGMM is director of Research of a large (around 500 employees) research and teaching institute within his University Medical Center. They perform both investigator-driven and industry-driven research projects with a number of pharmaceutical and diagnostic companies. In addition, some of the members of staff receive unrestricted grants for research projects from a number of companies. It is their explicit policy to work with several companies and not to focus on one or two industrial partners. He receives no personal payment from any industrial partner.
Patient consent Not required.
Ethics approval All study participants provided written informed consent. Ethical approval for the EPIC study was obtained from the review boards of the International Agency for Research on Cancer and local participating centres: National Committee on Health Research Ethics (Denmark); Comité de Protection des Personnes (France); Ethics Committee of the Heidelberg University Medical School (Germany); Ethikkommission der Landesärztekammer Brandenburg Cottbus (Germany); University of Athens Medical School (Greece) Comitato Etico Indipendente, Fondazione IRCCS Istituto Nazionale dei Tumori (Italy); Human Genetics Foundation Torino Ethics Committee (Italy); Medical Ethical Committee (METC) of the University Medical Center Utrecht (The Netherlands); Regional Ethical Committee for Northern Norway and the Norwegian Data Inspectorate (Norway); Comité de Ética de Investigación Clínica (Spain); Ethics Committee of Lund University (Sweden); Umea Regional Ethical Review Board (Sweden); Norwich District Ethics Committee (UK); Scotland A Research Ethics Committee (UK); and the Imperial College Research Ethics Committee (UK). Approval for this research was obtained from the UK Biobank Research Ethics Committee and Human Tissue Authority, and the participants gave informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This research has been conducted using the UK Biobank Resource under Application Number 19266. UK Biobank is an open-access resource. Bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/. For information on how to submit an application for gaining access toEPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php. The EPIC raw data cannot be made freely available because of restrictions imposed by the Ethical Committee, which does not allow open/public sharing of data on individuals. However, aggregated data are available for other researchers on request. Requests should be sent to Dr Ioanna Tzoulaki, email@example.com. For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php
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