Genetics, primary care records and lifestyle factors for short-term dynamic risk prediction of colorectal cancer: prospective study of asymptomatic and symptomatic UK Biobank participants

Objectives To quantify the contributions of polygenic scores, primary care records (presenting symptoms, medical history and common blood tests) and lifestyle factors, for short-term risk prediction of colorectal cancer (CRC) in both all and symptomatic individuals. Design Prospective cohort study. Setting UK Biobank with follow-up until 2018. Participants All participants with linked primary care records (n=160,526), and a subcohort of participants with a presentation of a symptom associated with CRC (n=50,728). Main outcome measures Outcome was the first recorded CRC diagnosis within two years. Dynamic risk models with time-varying predictors were derived in a super-landmark framework. Contributions to model discrimination were quantified using novel inclusion-order-agnostic Shapley values of Harrel’s C-index using cross-validation. Results C-indices [95% CIs] were 0.74 [0.72-0.75] and 0.71 [0.67-0.77] for the models derived in all and symptomatic participants respectively. The Shapley contributions to model discrimination differed between the two groups of participants for different predictors: 31% (32% in the symptomatic participants) for core predictors (e.g., age, sex, smoking), 16% (12%) for polygenic scores, 27% (30%) for primary care blood tests, 14% (14%) for primary care medical history, 8% (0.5%) for additional lifestyle factors and 4% (12%) for symptoms. Conclusions Polygenic scores contribute substantially to short-term risk prediction for CRC in both general and symptomatic populations; however, the contribution of information in primary care records (including presenting symptoms, medical history and common blood tests) is greater. There is, however, only a small contribution by the additional lifestyle risk factors which are not routinely collected in primary care. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding The work was supported by the International Alliance for Cancer Early Detection, a partnership between Cancer Research UK (C18081/A31373), Canary Center at Stanford University, the University of Cambridge, OHSU Knight Cancer Institute, University College London, and the University of Manchester. SI is additionally supported by Cancer Research UK (EDDPMA-May22\100062) and HH and MB by CRUK International Alliance for Cancer Early Detection (ACED) Pathway Awards (EDDAPA-2022/100001 and EDDAPA-2022/100002, respectively). GL was supported by a Cancer Research UK (C18081/A18180) Advanced Clinician Scientist Fellowship. CR acknowledges funding from Cancer Research UK Early Detection and Diagnosis Committee (grant number EDDCPJT\100018). JUS is supported by a National Institute of Health Research Advanced Fellowship (NIHR300861). SI and AW are supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312) [*]. AW and SD are part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074. SD is supported by the BHF Data Science Centre, the NIHR-UKRI CONVALESCENCE study, the Longitudinal Health and Wellbeing COVID-19 National Core Study, the BHF Accelerator Award (AA/18/6/24223) and Health Data Research UK. *The views expressed are those of the author(s) and not necessarily those of CRUK, NIHR, NHSBT or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of North West Multi-Centre Research Ethics Committee gave ethical approval for this UK Biobank study (06/MRE09/65) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This paper uses data from UK Biobank that the authors do not have permission to distribute. Bona-fide researchers can apply for access to this data, including linked primary care records, from UK Biobank Resources developed for this project including codelists and analysis code can be found at [TBC GitHub link].