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

Background Colorectal cancer (CRC) is the 3 rd most common cancer in the United Kingdom and is the 2 nd largest cause of cancer death. Aim 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 CRC investigations. Methods 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. Predicted 1-year CRC diagnosis were calculated, and externally validated, 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. Results 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 yields 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 >4,500 colonoscopies with no evidence that more cancers would be missed if we used our model compared to using FIT f-Hb≥10 µg/g. 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. 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: [ https://fundingawards.nihr.ac.uk/award/NIHR133852 ]. 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.