Article Text

Original research
Multicentre derivation and validation of a colitis-associated colorectal cancer risk prediction web tool
  1. Kit Curtius1,2,
  2. Misha Kabir3,4,
  3. Ibrahim Al Bakir1,4,
  4. Chang Ho Ryan Choi5,
  5. Juanda L Hartono6,7,
  6. Michael Johnson8,9,
  7. James E East8,9,
  8. Oxford IBD Cohort Study Investigators,
  9. James O Lindsay10,11,
  10. Roser Vega12,
  11. Siwan Thomas-Gibson4,13,
  12. Janindra Warusavitarne3,14,
  13. Ana Wilson3,4,
  14. Trevor A Graham1,
  15. Ailsa Hart4,13
    1. 1Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
    2. 2Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, California, USA
    3. 3Department of Surgery and Cancer, Imperial College London, London, UK
    4. 4Department of Gastroenterology, St Mark's Hospital and Academic Institute, London, UK
    5. 5Department of Gastroenterology & Hepatology, St George Hospital, Sydney, New South Wales, Australia
    6. 6Division of Gastroenterology, National University Hospital, Singapore
    7. 7Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    8. 8Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK
    9. 9Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
    10. 10Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK
    11. 11Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK
    12. 12Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
    13. 13Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
    14. 14Colorectal Surgery and Lennard-Jones Intestinal Failure Unit, St Mark’s Hospital and Academic Institute, London, UK
    1. Correspondence to Dr Kit Curtius, Division of Biomedical Informatics, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; kcurtius{at}health.ucsd.edu; Dr Misha Kabir; misha.kabir1{at}nhs.net

    Abstract

    Objective Patients with ulcerative colitis (UC) diagnosed with low-grade dysplasia (LGD) have increased risk of developing advanced neoplasia (AN: high-grade dysplasia or colorectal cancer). We aimed to develop and validate a predictor of AN risk in patients with UC with LGD and create a visual web tool to effectively communicate the risk.

    Design In our retrospective multicentre validated cohort study, adult patients with UC with an index diagnosis of LGD, identified from four UK centres between 2001 and 2019, were followed until progression to AN. In the discovery cohort (n=246), a multivariate risk prediction model was derived from clinicopathological features using Cox regression. Validation used data from three external centres (n=198). The validated model was embedded in a web tool to calculate patient-specific risk.

    Results Four clinicopathological variables were significantly associated with AN progression in the discovery cohort: endoscopically visible LGD >1 cm (HR 2.7; 95% CI 1.2 to 5.9), unresectable or incomplete endoscopic resection (HR 3.4; 95% CI 1.6 to 7.4), moderate/severe histological inflammation within 5 years of LGD diagnosis (HR 3.1; 95% CI 1.5 to 6.7) and multifocality (HR 2.9; 95% CI 1.3 to 6.2). In the validation cohort, this four-variable model accurately predicted future AN cases with overall calibration Observed/Expected=1.01 (95% CI 0.64 to 1.52), and achieved 100% specificity for the lowest risk group over 13 years of available follow-up.

    Conclusion Multicohort validation confirms that patients with large, unresected, multifocal LGD and recent moderate/severe inflammation are at highest risk of developing AN. Personalised risk prediction provided via the Ulcerative Colitis-Cancer Risk Estimator (www.UC-CaRE.uk) can support treatment decision-making.

    • ulcerative colitis
    • colorectal cancer
    • clinical decision making
    • dysplasia

    Data availability statement

    Data are available upon reasonable request. All essential outputs from model construction are included in the main text (table 3) and supplemental materials (baseline hazard and variance-covariance matrix for multivariate model provided, online supplemental table S11) to enable implementation of our analysis using other data. Sharing of individual-level data requires successful completion of a data sharing agreement with St Mark’s Hospital, in accordance with our ethical approval.

    https://creativecommons.org/licenses/by/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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    Data availability statement

    Data are available upon reasonable request. All essential outputs from model construction are included in the main text (table 3) and supplemental materials (baseline hazard and variance-covariance matrix for multivariate model provided, online supplemental table S11) to enable implementation of our analysis using other data. Sharing of individual-level data requires successful completion of a data sharing agreement with St Mark’s Hospital, in accordance with our ethical approval.

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    Footnotes

    • KC and MK are joint first authors.

    • AW, TAG and AH are joint senior authors.

    • Twitter @yosoykit, @trevoragraham

    • Collaborators Oxford IBD Cohort Study Investigators: Philip Allan, Tim Ambrose, Carolina Arancibia-Cárcamo, Adam Bailey, Ellie Barnes, Elizabeth Bird-lieberman, Jan Bornschein, Barbara Braden, Oliver Brain, Jane Collier, Emma Culver, James East, Alessandra Geremia, Bruce George, Lucy Howarth, Kelsey Jones, Paul Klenerman, Simon Leedham, Rebecca Palmer, Fiona Powrie, Astor Rodrigues, Jack Satsangi, Alison Simmons, Simon Travis, Holm Uhlig, Alissa Walsh.

    • Contributors KC: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for intellectual content; statistical analysis; software/web tool development; obtained funding. MK: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for intellectual content; statistical analysis. IAB: acquisition of data; analysis and interpretation of data. CHRC: acquisition of data; investigation of data. JLH, MJ, Oxford IBD Cohort Study Investigators: acquisition of data. JEE: acquisition of data; interpretation of data; drafting of the manuscript; critical revision of the manuscript; obtained funding. JOL: acquisition of data; interpretation of data; drafting of the manuscript; critical revision of the manuscript. RV, JW: acquisition of data; interpretation of data; critical revision of the manuscript. STG: interpretation of data; drafting of the manuscript; critical revision of the manuscript. AW, AH: study concept and design; study supervision; interpretation of data; drafting of the manuscript; critical revision of the manuscript for intellectual content. TAG: study concept and design; study supervision; obtained funding; interpretation of data; drafting of the manuscript; critical revision of the manuscript for intellectual content.

    • Funding KC received funding from the MRC HDR-UK programme (UKRI Rutherford Fund Fellowship). TAG acknowledges funding from Cancer Research UK (A19771 and A25901) and the Barts Charity (472/2300). JEE was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. AH acknowledges infrastructure support for this research provided by the NIHR Imperial Biomedical Research Centre (BRC).

    • Disclaimer The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health.

    • Competing interests JEE: speaker of FALK; consultant/shareholder of Satisfai Health.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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