Judith A Strachan

Faecal haemoglobin concentrations by gender and age: implications for population-based screening for colorectal cancer

Abstract Background: Faecal immunochemical tests (FIT) are becoming widely used in colorectal cancer screening. Estimation of faecal haemoglobin concentration in a large group prompted an observational study on gender and age. Methods: A single estimate of faecal haemoglobin concentration was made using quantitative automated immunoturbidimetry. Potential reference intervals were calculated for men and women and for age quintiles according to the Clinical and Laboratory Standards Institute Approved Guideline. The percentages of positive results were calculated at a number of concentrations. The percentages of individuals who fell into different risk groups were assessed. Results: The 97.5 percentiles, potential upper reference limits, were 519 ng haemoglobin/mL (90% CI: 468–575) for men and 283 ng haemoglobin/mL (90% CI: 257–316) for women. Concentrations increased with age in both genders. Decision limits have advantages over reference intervals. At any cut-off concentration, more men are declared positive than women and more older people are declared positive than younger people. Future risk of neoplasia is higher in men than in women and in older people. Conclusions: Faecal haemoglobin concentrations vary with gender and age. More tailored strategies are needed in screening programmes. Faecal haemoglobin concentration could be included in individual risk assessment scores. These data should assist in screening programme design.

Clinical outcomes using a faecal immunochemical test for haemoglobin as a first-line test in a national programme constrained by colonoscopy capacity

Introduction Because of their many advantages, faecal immunochemical tests (FIT) are superseding traditional guaiac-based faecal occult blood tests in bowel screening programmes. Methods A quantitative FIT was adopted for use in two evaluation National Health Service (NHS) Boards in Scotland using a cut-off faecal haemoglobin concentration chosen to give a positivity rate equivalent to that achieved in the Scottish Bowel Screening Programme. Uptake and clinical outcomes were compared with results obtained contemporaneously in two other similar NHS Boards and before and after the evaluation in the two evaluation NHS Boards. Results During the evaluation, uptake was 58.5%. This was higher than in the same NHS Boards both before and after the evaluation, higher than in the other two NHS Boards and higher than the 53.7% achieved overall in Scotland. The overall positivity rate was higher in men than in women and increased with age in both genders. Positive predictive values for cancer (4.8%), high-risk adenoma (23.3%), all adenoma (38.2%) and all neoplasia (43.0%) in the two test NHS Boards were similar in all groups. Conclusions In summary, this evaluation of the FIT supports the introduction of FIT as a first-line test, even when colonoscopy capacity is limited.

Faecal haemoglobin and faecal calprotectin as indicators of bowel disease in patients presenting to primary care with bowel symptoms.

Objective In primary care, assessing which patients with bowel symptoms harbour significant disease (cancer, higher-risk adenoma or IBD) is difficult. We studied the diagnostic accuracies of faecal haemoglobin (FHb) and faecal calprotectin (FC) in a cohort of symptomatic patients. Design From October 2013 to March 2014, general practitioners were prompted to request FHb and FC when referring patients with bowel symptoms to secondary care. Faecal samples were analysed for haemoglobin (EIKEN OC-Sensor io) and calprotectin (BÜHLMANN Calprotectin ELISA). Patients triaged to endoscopy were investigated within 6 weeks. All clinicians and endoscopists were blind to the faecal test results. The diagnostic accuracies of FHb and FC for identification of significant bowel disease were assessed. Results 1043 patients returned samples. FHb was detectable in 57.6% (median 0.4 µg/g, 95% CI 0.4 to 0.8; range 0–200). FC at 50 µg/g or above was present in 60.0%. 755 patients (54.6% women, median age 64 years (range 16–90, IQR 52–73)) returned samples and completed colonic investigations. 103 patients had significant bowel disease; the negative predictive values of FHb for colorectal cancer, higher-risk adenoma and IBD were 100%, 97.8% and 98.4%, respectively. Using cut-offs of detectable FHb and/or 200 µg/g FC detected two further cases of IBD, one higher-risk adenoma and no additional cancers. Conclusions In primary care, undetectable FHb is a good ‘rule-out’ test for significant bowel disease and could guide who requires investigation.

Faecal haemoglobin concentration is related to severity of colorectal neoplasia

Aims Guaiac faecal occult blood tests are being replaced by faecal immunochemical tests (FIT). We investigated whether faecal haemoglobin concentration (f-Hb) was related to stage in progression of colorectal neoplasia, studying cancer and adenoma characteristics in an evaluation of quantitative FIT as a first-line screening test. Methods We invited 66 225 individuals aged 50–74 years to provide one sample of faeces. f-Hb was measured on samples from 38 720 responders. Colonoscopy findings and pathology data were collected on the 943 with f-Hb≥400 ng Hb/ml (80 µg Hb/g faeces). Results Of the 814 participants with outcome data (median age: 63 years, range 50–75, 56.4% male), 39 had cancer, 190 high-risk adenoma (HRA, defined as ≥3 or any ≥10 mm) and 119 low-risk adenoma (LRA). 74.4% of those with cancer had f-Hb>1000 ng Hb/ml compared with 58.4% with HRA, and 44.1% with no pathology. Median f-Hb concentration was higher in those with cancer than those with no (p<0.002) or non-neoplastic (p<0.002) pathology, and those with LRA (p=0.0001). Polyp cancers had lower concentrations than more advanced stage cancers (p<0.04). Higher f-Hb was also found in those with HRA than with LRA (p<0.006), large (>10 mm) compared with small adenoma (p<0.0001), and also an adenoma displaying high-grade dysplasia compared with low-grade dysplasia (p<0.009). Conclusions f-Hb is related to severity of colorectal neoplastic disease. This has ramifications for the selection of the appropriate cut-off concentration adopted for bowel screening programmes.

Low faecal haemoglobin concentration potentially rules out significant colorectal disease

The study aimed to determine whether faecal haemoglobin (Hb) concentration can assist in deciding who with lower abdominal symptoms will benefit from endoscopy.

Use of a faecal immunochemical test narrows current gaps in uptake for sex, age and deprivation in a bowel cancer screening programme

Objectives To investigate the characteristics of participants screened for bowel cancer using a faecal immunochemical test for haemoglobin (FIT). Setting Scottish Bowel Screening Programme. Methods 65909 men and women in two NHS Boards, aged 50 to 74, were invited to participate in an evaluation of FIT as a first-line test. Uptake was calculated by sex, age in quintiles, and deprivation in quintiles, and compared with a group who had completed a guaiac faecal occult blood test (gFOBT) and for whom details of sex, age and deprivation were well documented. Results FIT kits from 38672 participants were tested. The overall uptake of 58.7% was significantly higher than the 53.9% for gFOBT (p < 0.0001). Uptakes in the two NHS Boards were 57.6% and 54.4% for men and 63.2% and 59.1% for women, higher than the 49.5% and 58.1% completing gFOBT. Uptake was higher for FIT than gFOBT in all age and deprivation quintiles for both men and women in both NHS Boards. The difference in uptake fell with age for men but rose for women; the increase in uptake was greater for men than women. Uptake fell as deprivation decreased for both sexes, and was similar in both NHS Boards. Conclusions Use of FIT increases uptake over gFOBT, and the greatest increases are seen in men, younger participants, and more deprived individuals, groups for which an increase in uptake is likely to be beneficial. The results support a move to FIT as a first-line screening test for those countries still using gFOBT.

Deprivation and faecal haemoglobin: implications for bowel cancer screening

Objective To investigate the relationship between deprivation and faecal haemoglobin concentration (f-Hb). Setting Scottish Bowel Screening Programme. Methods A total of 66725 men and women, aged 50 to 74, were invited to provide a single sample for a faecal immunochemical test. Deprivation was estimated using the Scottish Index of Multiple Deprivation quintiles: f-Hb was measured (OC-Sensor, Eiken, Japan) on 38439 participants. The relationship between deprivation quintiles and f-Hb was examined. Results Median age was 60 years, 53.6% women, with 14.1%, 19.7%, 17.7%, 25.9% and 22.6% in the lowest to the highest deprivation quintiles respectively. No detectable f-Hb was found in 51.9%, ranging from 45.5% in the most deprived up to 56.5% in the least deprived. As deprivation increased, f-Hb increased (p < 0.0001). This trend remained controlling for sex and age (p < 0.001). Participants in the most deprived quintile were more likely to have a f-Hb above a cut-off of 80 µg Hb/g faeces compared with the least deprived, independent of sex and age (adjusted odds ratio 1.70, 95% confidence interval: 1.37 to 2.11). Conclusions Deprivation and f-Hb are related. This has important implications for selection of cut-off f-Hb for screening programmes, and supports the inclusion of deprivation in risk-scoring systems.

The fecal hemoglobin concentration, age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients

Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f‐Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi‐square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02–1.05), male sex: 1.6 (95% CI: 1.1–2.3) and f‐Hb (0–<20 µg Hb/g feces): 2.0 (95% CI: 0.7–5.5), (20‐<200 µg Hb/g): 16.8 (95% CI: 6.6–42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3–164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85–0.90) in the derivation and 0.91 (95% CI: 0.90–093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value—PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients.

A nicer approach to the use of ‘faecal occult blood tests’ in assessment of the symptomatic

Faecal occult blood tests, better described as tests for the presence of haemoglobin in faeces, are widely used in asymptomatic population-based screening programmes for colorectal cancer (CRC) as the best available non-invasive initial investigation. However, previously published authoritative guidelines did state that there was no role for these tests in assessment of patients presenting with lower abdominal symptoms in primary care. In consequence, the traditional widely used guaiac-based faecal occult blood test (gFOBT) was eliminated from the repertoires of many laboratories and its use in clinical settings other than screening very much discouraged. New significant controversy has been raised by the recently issued referral guidance for suspected CRC from the National Institute for Health and Care Excellence (NICE) which states that, in possible CRC, patients who do not meet criteria for suspected cancer referral should be offered testing for occult blood in faeces. These recommendations have been subject to significant criticism, in part because the evidence-base was largely founded on the use of gFOBT: these have many well-documented disadvantages throughout the pre-analytical, analytical and post-analytical phases of generation of a result. NICE did note that the recommendation to test for occult blood in faeces would necessitate a change in practice, because such tests are not currently available. It was also recognized by NICE that some evidence suggested that quantitative faecal immunochemical tests (FITs) for haemoglobin might have applicability in triaging symptomatic patients presenting to primary care. There is now significant evidence that FITs do have applicability in assessment of symptomatic patients presenting to primary care, including those who warrant urgent referral, as shown in recent peerreviewed publications, particularly from Scotland and Spain. Although much of the evidence was generated during and after the work on the NICE guidelines was done, it is vital that laboratories are not pressurized into again offering gFOBT to satisfy general practitioner requests made ‘to comply with the NICE guidelines’. Rather, the accumulated evidence is that FIT should be used, ideally using quantitative immunoturbidimetry to measure faecal haemoglobin concentration (f-Hb) with good performance characteristics. It has been shown that use of f-Hb measurements performs better than previous high-risk symptom-based strategies for fast-tracking suspected CRC referrals. Every one of the studies on use of f-Hb at low cut-off concentration in assessment of those presenting with lower abdominal symptoms has shown very high clinical sensitivity (often 100%) for CRC, so that a ‘positive’ test result should stimulate rapid referral for colonoscopy. Moreover and, most importantly, f-Hb in this context has very high negative predictive value (often well over 90%) for the detection of significant colorectal diseases well worthy of detection, namely, CRC, higher-risk adenoma, sometimes precursors of CRC, and inflammatory bowel disease (IBD). In consequence, a ‘negative’ test result provides considerable reassurance that colonoscopy is not required urgently or even at all. There is no doubt that f-Hb

Application of NICE guideline NG12 to the initial assessment of patients with lower gastrointestinal symptoms: not FIT for purpose?

Background The National Institute for Health and Care Excellence (NICE) published NG12 in 2015. The referral criteria for suspected colorectal cancer (CRC) caused controversy, because tests for occult blood in faeces were recommended. Faecal immunochemical tests for haemoglobin (FIT), which estimate faecal haemoglobin concentrations (f-Hb), might more than fulfil the intentions. Our aim was to compare the utility of f-Hb as the initial investigation with the NICE NG12 symptom-based guidelines. Methods Data from three studies were included. Patients had sex, age, symptoms, f-Hb and colonoscopy and histology data recorded. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of f-Hb and NG12 were calculated for all significant colorectal disease (SCD: CRC, higher risk adenoma and inflammatory bowel disease). Overall diagnostic accuracy was also estimated by the area under the receiver operating characteristic curve (AUC). Results A total of 1514 patients were included. At a cut-off of ≥10 µg Hb/g faeces, the sensitivity of f-Hb for CRC was 93.3% (95% confidence interval (CI): 80.7–98.3) with NPV of 99.7% (95%CI: 99.2–99.9). The sensitivity and NPV for SCD were 63.2% (95%CI: 56.6–69.4) and 96.0% (95%CI: 91.4–94.4), respectively. The NG12 sensitivity and NPV for SCD were 58.4% (95%CI: 51.8–64.8) and 87.6% (95%CI: 85.0–89.8), respectively. The AUC for CRC was 0.85 (95% CI: 0.87–0.90) for f-Hb versus 0.65 (95%CI: 0.58–0.73) for NG12 (P < 0.005). For SCD, the AUC was 0.73 (95%CI: 0.69–0.77) for f-Hb versus 0.56 (95%CI: 0.52–0.60) for NG12 (P < 0.0005). Conclusion f-Hb provides a good rule-out test for SCD and has significantly higher overall diagnostic accuracy than NG12.