Secondary Care

We designed algorithms for application to primary and secondary care data to establish incident diabetes cases. Our focus was on type 2 diabetes, given the age of UKB participants at recruitment. To assist generalisability to the UKB population, we restricted CPRD data to those on whom we had linked secondary care data, people aged 40–69 years on 1^st January 2006, (to reflect age entry criteria for UKB) Primary care algorithms were derived based on four types of evidence: 1) Diabetes diagnostic codes (considered separately as any diagnostic code and the more specific C10E [type 1 diabetes] or C10F [type 2 diabetes] codes, these are a requirement for the Quality Outcomes Framework [QOF] system[14 (link)]), 2) Diabetes medication, (excluding those on metformin only as this has other prescribing indications e.g. pre-diabetes, polycystic ovarian syndrome and is therefore not wholly diabetes specific), 3) Hyperglycaemia on blood results (defined as HbA_1c≥6.5% or 48 mmol/mol, or fasting/ random/ unspecified glucose≥11.1 mmol/l) and 4) Presence of diabetes process of care codes (restricted to those routinely recorded for QOF monitoring purposes, e.g. retinopathy screening, foot checks etc.). The threshold for glucose was chosen because primary care records frequently do not specify whether glucose is fasting or not, and we wished to avoid false positives from a non-fasting glucose in the 7.0–11.1 mmol/l range. Using CPRD and the linked Welsh UKB sub-cohort, we used an iterative approach, cross-tabulating evidence at each step, to determine the logical steps to include in the algorithm and in what order. We then applied the final incidence algorithm to both databases. For CPRD, we excluded prevalent diabetes according to pre-existing C10 diabetes-specific Read codes, and for the Welsh dataset, we removed all those with prevalent diabetes according to our UKB algorithm.
When developing the incidence algorithms intended for secondary care data, we defined incident diabetes type based on ICD-10 codes (E10 = type 1 diabetes, E11 = type 2 diabetes, E13/E14 = unspecified diabetes). Prevalent diabetes was excluded as above.
For both primary and secondary care incidence algorithms, we derived event dates by taking the mid-point between the last primary care consultation/ hospital admission without diabetes and the date of the first diabetes Read code/ ICD code/ diabetes medication/ hyperglycaemic blood test/ fifth process of care code. If there were no previous consultations or admissions, we used the UK Biobank inception date. The date of the first diabetes Read code/ ICD code/ diabetes medication/ hyperglycaemic blood test/ fifth process of care code will be available to researchers separately if they wish to calculate the event date in an alternative manner.

A multicentre prospective observational study (the qFIT study) was run between April 2017 and March 2019, recruiting patients from 24 hospitals across England and 59 General Practices in London^{17 (link)}. Primary and secondary care sites were invited through the National Institute for Health Research Clinical Research Network (NIHR CRN). National ethical approval was granted was granted by the UK NRES West Midlands—Solihull Research Ethics Committee (ref. 17/WM/0094) and the Health Research Authority (IRAS/213710), and the study was conducted following the STARD 2015 guideline for diagnostic accuracy studies^{21 (link)}. Three patient representatives with previous experience with colorectal cancer were involved in the development of the patient information leaflet and the design of the FIT kit handout. This study is a subanalysis of a previously published paper on the role of FIT in ruling out CRC among patients presenting with ‘high-risk’ symptoms^{17 (link)}.
Any adult (16 years or older) presenting to primary care with abdominal symptoms that merited an urgent referral for suspected CRC investigations were eligible²² ; symptoms in the urgent referral guidance were associated with a 3 per cent positive predictive value for CRC²² . People who were under 16 years of age or were unable to understand instructions (including non-English speakers who did not have an interpreter) were excluded from the study. A FIT kit and a patient information booklet outlining the purpose of the research study were provided to patients by the primary care physician, hospital consultant, research nurse, or clinical nurse specialist.
The patient was asked to take a single sample from their next bowel movement (before completing any bowel preparation for subsequent colonoscopy or other examination) and post it to a central laboratory. By returning the FIT kit, the patient provided implied consent to participate in the study. Participation did not affect the patient’s clinical care. Participants were informed that the FIT result was for research purposes only (and they would not be informed of the result).
The FIT kit included a FIT sample collection device in a sealable plastic pouch (OC-Sensor™; Eiken Chemical Company, Tokyo, Japan) prelabelled with the patient’s name, National Health Service (NHS) number, a unique laboratory number, and a space to write the sample date; a copy of the urgent referral form or patient data sheet (containing information about the patient and the hospital where the examination took place); a patient experience survey consent form; and a prelabelled return envelope. The urgent referral form contained clinical data, such as symptoms, reasons for referral, medical history, and sociodemographic factors.

Samples for FIT were taken into an Eiken specimen collection device using the sampling probe in the lid and posted to the laboratory. The specimen collection devices were stored at 4°C until analysis, which took place within a week of receipt. F-Hb was measured by immunoturbidimetry using a single OC-Sensor (Eiken Chemical Co., Tokyo, Japan).
The coefficients of variation were 2.8 per cent at 14 µg/g and 3.0 per cent at 91 µg/g. External quality assurance was achieved via satisfactory performance in the relevant UK National External Quality Assessment Service schemes. The lower limit of quantification was 4 µg/g and the upper limit of the measuring range 200 µg/g. The laboratory is accredited by the UK Accreditation Service to ISO 15189 standards.
All test results were performed blinded to patient characteristics and outcomes. If a patient returned more than one sample, due to being given a test kit in both primary and secondary care during the same referral, or the patient had been investigated more than once, only the first test result was selected for inclusion in the analysis.