COLOFIT: Development and internal-external validation of models using age, sex, faecal immunochemical and blood tests to optimise diagnosis of colorectal cancer in symptomatic patients

Objective To develop and validate a model using available information at the time of Faecal Immunochemical testing (FIT) in primary care to improve selection of symptomatic patients for colorectal cancer (CRC) investigations. Design Population based cohort study. Setting All adults ≥ 18 years of age referred to Nottingham University Hospitals NHS Trust between 2018 and 2022 with symptoms of suspected CRC who had a FIT. Participants The derivation cohort (Nov/2017-Nov/2021) included 34,435 patients with FIT results who had 533 (1.5%) CRCs at 1-year. The validation analysis included 34,231 patients with first FITs in the derivation cohort with 516 (1.5%) cancers, and 16,735 patients with first FITs in the validation cohort with 206 (1.2%) cancers. Main outcome measures Predicted 1-year CRC diagnosis using Cox proportional hazards modelling with selected multiple fractional polynomial transformations for age, faecal haemoglobin concentration (f-Hb) value, mean corpuscular volume (MCV), platelet count and sex. In the internal-external validation we calculated discrimination and calibration to assess performance and estimated net benefit values across a range of CRC risk thresholds to assess clinical utility. Results In the survival model multiple fractional polynomial transformations were selected for age, f-Hb and platelet count, with MCV included as a linear variable and sex as a binary variable. Haemoglobin was not selected. At a CRC risk threshold of 0.6% (equivalent to f-Hb=10 µgHb/g (µg/g)) overall performance of the validated model across age strata using Harrell’s C index was ≥ 0.91% (overall C-statistic 93%, 95% CI 92%-95%) with acceptable calibration. Using this model would yield similar numbers of detected and missed cancers but require 20% fewer investigations than a f-Hb ≥10 µg/g strategy. For approximately 100,000 people per year with symptoms of suspected CRC, we predict it might save >10,000 colonoscopies with no evidence that more cancers would be missed if we used our model to triage investigations compared to using FIT at the currently recommend level for referral. Conclusions Including age, sex, MCV, platelets and f-Hb in a survival analysis model to predict the risk of CRC yields greater diagnostic utility than a simple binary cut off f-Hb≥10 µg/g. Enacting model-based triage of a symptomatic CRC pathway may decrease the burden on endoscopy whilst maintaining diagnostic accuracy. Further targeted validation of this approach is required in external populations with symptoms of possible CRC. Transparency statement The lead author and manuscript’s guarantor (CJC) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; than no important aspects of the study have been omitted: and that any discrepancies from the study as originally planned have been explained. Role of the funding source This project was funded by the National Institute for Health and Care Research (NIHR) [Health Technology Assessment (HTA) Programme (Project number 133852); awarded to CJR, WH & LS] and will be published in full in the HTA journal. Further information is available at: []. The views expressed are those of the authors and not necessarily those of the NIHR or Department of Health and Social Care and sponsored by Nottingham University Hospitals NHS Trust. The funder and sponsor had no role in the study design, in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. We confirm the independence of researchers from funders and that all authors, external and internal, had full access to all of the statistical reports and tables in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. SERB was supported by an NIHR Advanced Fellowship while undertaking this work (NIHR301666) and received additional support from the Higgins family. BDN was supported by a National Institute of Health Research Academic Clinical Lectureship and a CRUK Research Careers Committee Postdoctoral Fellowship (RCCPDF\100005). Ethics approval statement HRA and Health and Care Research Wales (HCRW) approval was given for this study - IRAS project ID: 312362; Protocol number: 22ON007; REC reference: 22/HRA/2125; Sponsor: Nottingham University Hospitals NHS Trust. ### Competing Interest Statement CJR has received grant funding from ARC medical, Norgine. Medtronic, 3D Matrix solutions and Olympus medical. He was an expert witness for ARC medical and Olympus medical ### Funding Statement This project was funded by the National Institute for Health and Care Research (NIHR) [Health Technology Assessment (HTA) Programme (Project number 133852)) and will be published in full in the HTA journal. Further information is available at: []. The views expressed are those of the authors and not necessarily those of the NIHR or 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: HRA and Health and Care Research Wales (HCRW) approval was given for this study - IRAS project ID: 312362; Protocol number: 22ON007; REC reference: 22/HRA/2125; Sponsor: Nottingham University Hospitals NHS Trust. 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][1]. 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 work uses data that has been provided by patients and collected by the NHS as part of their care and support. Under the Data Protection Impact Assessment approval for this work (DPIA reference: IG0889) we are unable to share the original data outside Nottingham University Hospitals NHS Trust. [1]: http://ClinicalTrials.gov