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Original article
Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies
  1. Todd Smith1,
  2. David C Muller1,
  3. Karel G M Moons2,
  4. Amanda J Cross1,
  5. Mattias Johansson3,
  6. Pietro Ferrari4,
  7. Guy Fagherazzi5,
  8. Petra H M Peeters6,
  9. Gianluca Severi5,
  10. Anika Hüsing7,
  11. Rudolf Kaaks7,
  12. Anne Tjonneland8,
  13. Anja Olsen8,
  14. Kim Overvad9,
  15. Catalina Bonet10,
  16. Miguel Rodriguez-Barranco11,
  17. Jose Maria Huerta12,
  18. Aurelio Barricarte Gurrea13,
  19. Kathryn E Bradbury14,
  20. Antonia Trichopoulou15,
  21. Christina Bamia15,
  22. Philippos Orfanos16,
  23. Domenico Palli17,
  24. Valeria Pala18,
  25. Paolo Vineis19,
  26. Bas Bueno-de-Mesquita20,
  27. Bodil Ohlsson21,
  28. Sophia Harlid22,
  29. Bethany Van Guelpen22,
  30. Guri Skeie23,
  31. Elisabete Weiderpass24,
  32. Mazda Jenab25,
  33. Neil Murphy25,
  34. Elio Riboli1,
  35. Marc J Gunter25,
  36. Krasimira Jekova Aleksandrova26,
  37. Ioanna Tzoulaki1
  1. 1 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  2. 2 Julius Center for Health Sciences and Primary Care, Umc Utrecht, Utrecht University, Utrecht, The Netherlands
  3. 3 International Agency for Research on Cancer (IARC), Genetic Epidemiology Group, Lyon, France
  4. 4 Nutritional Methodology and Biostatistics Group (NMB), International Agency for Research on Cancer, Lyon, France
  5. 5 Inserm U1018, Gustave Roussy, Universite Paris-Sud, Villejuif, France
  6. 6 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  7. 7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  8. 8 Danish Cancer Society Research Center, Copenhagen, Denmark
  9. 9 Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark
  10. 10 Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Barcelona, Spain
  11. 11 CIBER de Epidemiologia y Salud Publica (CIBERESP), Escuela Andaluza de Salud Publica, Madrid, Spain
  12. 12 Murcia Regional Health Council, IMIB-Arrixaca, CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain
  13. 13 Navarra Public Health Institute, CIBER de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain
  14. 14 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  15. 15 Hellenic Health Foundation, Athens, Greece
  16. 16 Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, WHO Collaborating Center for Nutrition and Health, National and Kapodistrian University of Athens, Athens, Greece
  17. 17 Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Florence, Italy
  18. 18 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  19. 19 Italian Institute for Genomic Medicine, Turin, Italy
  20. 20 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  21. 21 Department of Internal Medicine, Lund University, Skane University Hospital, Malmo, Sweden
  22. 22 Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden
  23. 23 Department of Community Medicine, Faculty of Health Sciences, University of Tromso, The Arctic University of Norway, Tromso, Norway
  24. 24 Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
  25. 25 Nutritional Epidemiology Group, International Agency for Research on Cancer, Lyon, France
  26. 26 Nutrition, Immunity and Metabolism Start-up Lab, Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrucke, Germany
  1. Correspondence to Dr Ioanna Tzoulaki, Department of Biostatistics and Epidemiology, School of Public Health, Imperial College London, London W2 1PG, UK; i.tzoulaki{at}


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
  • epidemiology
  • 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 For information on how to submit an application for gaining access toEPIC data and/or biospecimens, please follow the instructions at 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, For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at

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