
==== Front
BMJ Open Gastroenterol
BMJ Open Gastroenterol
bmjgast
bmjgast
BMJ Open Gastroenterology
2054-4774
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39284679
10.1136/bmjgast-2024-001372
bmjgast-2024-001372
Original Research
Colorectal Cancer
1506
Diagnostic application of the ColonFlag AI tool in combination with faecal immunochemical test in patients on an urgent lower gastrointestinal cancer pathway
http://orcid.org/0000-0003-4662-2502
Ayling Ruth M ruthayling@clinicalbiochemistry.org.uk
1
Cotter Finbarr f.e.cotter@qmul.ac.uk
23
1 Clinical Biochemistry, Barts Health NHS Trust, London, UK
2 Haemato-oncology, Barts Health NHS Trust, London, UK
3 Queen Mary University of London, London, UK
Dr; ruthayling@clinicalbiochemistry.org.uk
None declared.

2024
16 9 2024
11 1 e00137215 2 2024
26 7 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Objective

Colorectal cancer (CRC) is the fourth most common cancer in the UK. Patients with symptoms suggestive of CRC should be referred for urgent investigation. However, gastrointestinal symptoms are often non-specific and there is a need for suitable triage tools to enable prioritisation of investigations. In this study, the performance of the faecal immunochemical test (FIT), anaemia and the artificial intelligence algorithm ColonFlag were retrospectively examined and evaluated for their potential clinical benefits in patients who had been referred on an urgent lower gastrointestinal cancer pathway.

Design

All patients aged over 40 years referred in a 12-month period were included. After 6 months, clinical outcomes were determined and the performance of the triage tests was evaluated.

Results

A total of 3822 patients completed investigations and received a diagnosis. 143 had CRC, 126 high-risk adenomas (HRA). ColonFlag would have missed 27 CRC and 29 HRA. Faecal haemoglobin (f-Hb) at a cut-off of 10 µg/g would have missed 10 CRC and 26 HRA; f-Hb in combination with anaemia would have missed 2 CRC and 14 HRA. Using f-Hb in combination with ColonFlag would have missed only 1 CRC and 5 HRA and would have reduced the need for urgent referral by over 400 patients.

Conclusion

ColonFlag has potential to assist detection of CRC and HRA, alone where no faecal sample is present and in combination with FIT and to reduce the need for urgent referral.

colorectal cancer
colorectal carcinoma
colorectal adenomas
cancer
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pmcWHAT IS ALREADY KNOWN ON THIS TOPIC

There is a need for suitable triage tools to prioritise colonoscopy for colorectal carcinoma.

Measurement of faecal haemoglobin (f-Hb) using the faecal immunochemical test (FIT) is used extensively for screening and assessment of symptomatic patients; however, it is known that f-Hb will not detect a small number of colorectal cancers (CRCs) and a larger number of adenomatous polyps which are a precursor.

WHAT THIS STUDY ADDS

In this study, ColonFlag, an artificial intelligence learning algorithm based on full blood count parameters, age and sex was shown to have a positive predictive value of 4.5% for detection of CRC, when used alone in symptomatic patients.

When used in combination with f-Hb, at a cut-off of 10 µg/g, it increased detection of both CRC and high-risk adenomas.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

ColonFlag has potential to be used alone, when no faecal sample is available or with FIT to improve detection of CRC.

As it is based on the full blood count, it could readily be embedded into laboratory computer systems to assist case finding.

Introduction

Colorectal cancer (CRC) is the fourth most common cancer in the UK, with approximately 43 000 patients diagnosed each year and remains the second largest cause of cancer death.1 Because of variability in the nature of its presentation, many patients may not be symptomatic until the disease reaches an advanced stage. To facilitate early detection of CRC and reduce related mortality, programmes for screening asymptomatic individuals are in place in multiple countries and many of these are based on the detection of faecal haemoglobin (f-Hb) measured by faecal immunochemical testing (FIT). Screening has been shown to lower CRC mortality and reduce the incidence of CRC, due mainly to detection and removal of adenomatous polyps.2 However, engagement by patients in screening programmes is not universal and is lower in London than in other areas of the country.3 In 2017, the National Institute for Health and Care Excellence (NICE) recommended FIT for use in symptomatic patients with low-risk features of CRC to assist decision to refer on an urgent lower gastrointestinal cancer pathway.4 5 During the COVID-19 pandemic, FIT became a requirement in patients being referred for colonoscopy to assist prioritisation for investigation and this led to the test becoming embedded in primary care for indications broader than those originally recommended. NICE have more recently amended their guidance for use of FIT, but they note the lack of evidence for its use in those aged <40 years.6

In both primary and secondary care, a full blood count (FBC) is a common request to assist in assessment of a wide range of symptoms and clinical conditions. An FBC includes up to 20 different parameters; associations between various components and CRC have been reported for many years.7 ColonFlag (Medial Early Sign, Kfar Lalal, Israel) identifies patients of 40 years or older at risk of CRC using artificial intelligence (AI) learning applied to age, sex and FBC parameters based on an ensemble of decision trees.8 Its rationale is that subtle changes can develop in multiple elements of the FBC in CRC before patients become symptomatic. Although these parameters may remain within their respective reference ranges, an AI algorithm can detect changes across multiple FBC results and flag them as potential indicators of CRC. Data from healthy Israelis and patients with CRC were used to develop the model which was then trained using Israeli databases; validation was performed using additional cohorts within the UK and the USA.8 A score can be produced from a single FBC, but using more than one FBC may contribute to the risk score by indicating trends in the indices. Typically, a minimum of three FBCs over a period of 3–5 years is sufficient to achieve near-optimal performance. A potential advantage over other risk prediction models is that it can be fully automated using existing routinely available laboratory data and, if required, results can be made available to all, or relevant groups of, clinicians, in the same way as other laboratory reports.

We have previously reported its potential for use in triage in small cohorts with anaemia9 and for patients awaiting delayed investigation during the first wave of the COVID-19 pandemic.10 We now report a larger study of its use in patients being referred on an urgent lower gastrointestinal cancer pathway.

Methods

Patients

ColonFlag is validated for patients aged >40 years. The study group consisted of patients who had an FIT requested between 1 October 2021 and 30 September 2022 and were subsequently referred via the urgent lower gastrointestinal pathway with suspected CRC. FIT was freely available for use in primary care when considered an appropriate diagnostic test. Results were used to assist in triaging to the urgent lower gastrointestinal cancer pathway, with referral recommended if f-Hb level was ≥10 µg/g, or if it was <10 µg/g with ongoing concerns about CRC as per NG12 guidance.

Sample analysis

Faecal samples were taken at home into a specimen collection device (Eiken Chemical, Tokyo, Japan) and returned to the Clinical Biochemistry Department at Barts Health NHS Trust. They were stored at 4°C before analysis, which took place within 1 week of receipt and 2 weeks of sampling. The assay is accredited by the UK Accreditation Service to ISO 15189 standards. Analysis was performed using a single OC-SensorPledia (Eiken). Inter-run imprecision was assessed with quality control materials (Eiken) in each run. Co-efficients of variation were 2.8% at 14 µg Hb/g faeces (µg/g) and 3.0% at 91 µg/g. External quality assurance was achieved via satisfactory performance in the relevant UK National External Quality Assurance Scheme. The lower limit of quantification was 2 μg/g. The upper analytical limit was 200 µg/g and samples with a concentration above this were not diluted and re-assayed but reported as ≥200 µg/g. If a patient returned more than one FIT sample, only the first test result was selected for inclusion in the analysis. FBCs were measured on a Sysmex XE 2100 (Sysmex, Milton Keynes, UK).

ColonFlag score was calculated in all patients in whom at least one FBC had been performed in the last 6 months. The score ranged from 0 to 1, with higher scores indicting greater risk of undiagnosed CRC. The parameters from all available FBCs from 2017 onwards were used, as these were easily accessible from current laboratory records. FBC parameters, age and sex were used to assign an individual risk score for each patient indicating their probability of CRC.

Clinical outcomes

Data were reviewed and clinical details obtained from patient notes, radiology reports, endoscopy, histology findings and from the local cancer registry. Patients without a cancer diagnosis were not systematically followed up but the cancer registry was checked at the end of the period of data acquisition, that is, between 9 and 18 months after initial presentation, depending on when in the year the patient initially presented.

Statistical considerations

Data were summarised and tabulated; population characteristics were summarised by appropriate descriptive statistics by data type.

Continuance measures, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were described by average and the exact 95% CI for each measure.

Receiver operating characteristic curves were used to evaluate the performance of the two tests and to determine the optimal cut-offs. Analysis was performed using Analyse-It (Leeds, UK).

Results

Data were obtained from 4092 patients, of these 3822 (1764 male) were included in the final analysis, their median age was 66 (range 41–100). The study flow chart is shown in figure 1.

Figure 1 Study flow chart. FBC, full blood count; FIT, faecal immunochemical test; GI, gastrointestinal.

Further investigations

Investigations were performed on clinical grounds and a final diagnosis was obtained in 3822 evaluable patients. Colonoscopy was performed in 2583 patients, abdominopelvic CT in 718 patients (with flexible sigmoidoscopy also performed in 58 of these cases), CT colon in 470 patients (with flexible sigmoidoscopy also performed in 38 of these cases), flexible sigmoidoscopy in 33 patients, colon capsule endoscopy in 8 patients and PET CT in 3 patients. Five patients who had previously been investigated with colonoscopy (3), CT colon (1) and CT scans (1) performed in the past year were further investigated with an MRI scan at the time of this referral. Two patients received a diagnosis at surgery: one while awaiting investigation and one the other while visiting family in India, having declined investigation to go on holiday. 267 patients did not complete investigations—195 declined or did not attend relevant appointments, 5 died from unrelated causes, 38 moved out of area, went overseas or were unable to be contacted and 29 were not investigated because of multiple comorbidities or other medical reasons. Seven additional patients were excluded from final analysis—three who were diagnosed with metastatic disease of unknown primary and four who had sigmoid thickening on radiological imaging but declined further investigation for definitive exclusion of significant pathology.

Final diagnoses

Based on these investigations, 52.2% of patients had no colonic pathology (1702) or only haemorrhoids (292) detected. Serious bowel disease (CRC, inflammatory bowel disease (IBD) or high-risk adenomas (HRA)) was detected in 8.3% of patients. IBD was diagnosed in 47 patients, 6 of whom had a known diagnosis of IBD. HRA were found in 126 patients (3.3%) and CRC was identified in 143 patients (3.7%) out of 3822.

Faecal haemoglobin results

f-Hb results, together with clinical data, are summarised in table 1.

Table 1 Faecal haemoglobin results and demographic data in patients investigated

	Patients number (%)(n=3822)	CRC diagnosis(n=143)	HRA diagnosis(n=126)	
Age (years)	
 41–49	520 (13.6)	13	10	
 50–59	828 (21.7)	25	27	
 60–69	941 (24.6)	33	36	
 70–79	888 (23.2)	43	32	
 80–89	564 (14.7)	24	21	
 ≥90	81 (2.1)	5	0	
Sex	
 Male	1764 (46.1)	66	82	
 Female	2058 (53.9)	77	44	
Faecal haemoglobin (µg/g)	
 <2	769 (20.1)	4	10	
 2–9.9	488 (12.8)	6	17	
 10–99.9	1836 (48.0)	32	62	
 100–199.9	218 (5.7)	12	10	
 ≥200	511 (13.4)	89	27	
CRCcolorectal cancerHRAhigh-risk adenoma

Blood haemoglobin concentration

The median blood haemoglobin concentration in men was 134 g/L (range 59–195) and in women 122 g/L (range 48–198). 814 men (46.1%) were anaemic (Hb concentration <130 g/L) and 967 women (47.0%) were anaemic (Hb concentration <120 g/L).

85 of the 143 patients with CRC (59.4%) were anaemic, 45 of 77 were women and 40 of 66 were men. Of the 1257 patients with f-Hb <10 µg/g, 559 (44.5%) were anaemic.

ColonFlag

The FBC data, age and sex of each patient was used to generate a ColonFlag score. The median number of FBC available was 7 (range 1–137). Of the 143 patients with CRC, scoring was on less than three measurements in 49. The receiver operating characteristic curve for ColonFlag is shown in figure 2.

Figure 2 The receiver operating characteristic curve for (A) CF and (B) faecal immunochemical test. CF, ColonFlag; FIT, faecal immunochemical test; FPF, false positive fraction; TPF, true positive fraction.

For FIT, the area under the curve (AUC) was 0.82 (95% CI 0.79 to 0.86). For ColonFlag, AUC was 0.68 (95% CI 0.63 to 0.72). A cut-off for ColonFlag score of 0.0319 was selected, which fixed its specificity as similar to that of f-Hb at a cut-off of 10 µg/g.

At a cut-off of 10 µg/g, f-Hb failed to detect 10 of 143 tumours (7%). Further details of these patients are shown in table 2. All but one was detected by ColonFlag at a cut-off of 0.0319.

Table 2 Details of patients with colorectal cancer with f-Hb <10 µg/g

Sex	Age (years)	Blood Hb (g/L)	No FBCs	f-Hb (µg/g)	CF score	Tumour	
M	47	154	4	<2	0.0045	Rectum T1N0M0	
F	75	131	1	3	0.0519	Rectum T4N1M0	
M	73	118	14	7	0.0620	Rectum T3N0M0	
M	82	117	6	5	0.0715	Rectum T2N0M0	
F	68	112	1	2	0.0746	Rectum T3N1M0	
M	65	113	1	<2	0.1116	Rectum T3N2M0	
F	85	115	4	<2	0.1958	Caecum T4N1M0	
F	56	97	3	7	0.2242	Hepatic flexure T3N1M1	
F	81	99	2	<2	0.2565	Rectum T4N2M0	
F	87	69	9	7	0.4131	Ascending colon T3N1M1	
Ffemalef-Hbfaecal haemoglobinMmale

The diagnostic performance of f-Hb and ColonFlag alone and in combination, and of f-Hb and anaemia in combination, for patients aged >40 years, referred urgently with suspected colorectal cancer, is shown in table 3.

Table 3 Comparison of the performance of faecal haemoglobin, CF score and anaemia in the detection of colorectal cancer and high-risk adenomas26 (n=3822)

	CF score ≥0.0319	FIT ≥10 µg/g	FIT ≥10 µg/g and FIT <10 µg/g with anaemia*	FIT ≥2 µg/g	FIT ≥10 µg/g and FIT <10 µg/gwith CF score ≥0.0319	
CRC (n=143)						
True positives	116	133	141	139	142	
False negatives	27	10	2	4	1	
True negatives	1220	1247	688	765	437	
False positives	2459	2432	2991	2914	3242	
Sensitivity (%) (95% CI)	81.1 (73.7 to 87.2)	93.0 (87.5 to 96.6)	98.6 (95.0 to 99.8)	97.2 (93.0 to 99.2)	99.3 (96.2 to 100)	
Specificity (%) (95% CI)	33.2 (31.6 to 34.7)	33.9 (32.4 to 35.5)	18.7 (17.5 to 20.0)	20.8 (19.5 to 22.1)	11.9 (10.9 to 13.0)	
PPV (%) (95% CI)	4.5 (3.2 to 4.4)	5.2 (4.9 to 5.4)	4.5 (4.4 to 4.6)	4.6 (4.4 to 4.7)	4.2 (4.1 to 4.3)	
NPV (%) (95% CI)	97.8 (97.0 to 98.5)	99.2 (98.6 to 99.6)	99.7 (98.9 to 99.3)	99.5 (98.6 to 99.8)	99.8 (98.4 to 100)	
CRC+HRA (n=269)						
True positives	213	233	253	255	263	
False negatives	56	36	16	14	6	
True negatives	1191	1221	826	755	432	
False positives	2362	2332	2727	2798	3121	
Sensitivity	79.2 (73.8–83.9)	86.6 (82.0–90.5)	94.1 (90.5–96.6)	94.8 (91.4–97.1)	97.8 (95.2–99.2)	
Specificity	33.5 (32.0–83.9)	34.3 (32.8–36.0)	23.3 (21.9–24.7)	21.3 (19.9–22.6)	12.2 (11.1–13.3)	
PPV (%) (95% CI)	8.3 (7.8 to 8.8)	9.1 (8.7 to 9.5)	8.5 (8.2 to 8.8)	8.4 (8.1 to 8.6)	7.8 (7.6 to 7.9)	
NPV (%) (95% CI)	95.5 (94.4 to 96.4)	97.1 (98.0)	98.1 (97.0 to 98.8)	98.2 (97.0 to 98.9)	98.6 (97.0 to 99.4)	
* Anaemia Hb <130 g/L men, 120 g/L women.

CFColonFlagCRCcolorectal cancerHRAhigh-risk adenomasNPVnegative predictive valuePPVpositive predictive value

Using a cut-off of 20 µg/g for f-Hb, the test had a sensitivity and specificity of 94.1% and 23.3%, respectively, for detecting CRC, and 74.7% and 56.4% for CRC and HRA, with 18 tumours and 50 HRA missed HRA. When combined with anaemia, the sensitivity and specificity were 87.7% and 27.6%, respectively, missing 4 tumours and 29 HRA. When combined with ColonFlag, the sensitivity and specificity were 99.3% and 11.9%, respectively, missing 1 tumour and 5 HRA.

Discussion

In this study, we retrospectively investigated the performance of ColonFlag in patients referred on the urgent lower gastrointestinal cancer pathway, over a 12-month period.

In our population, if a referral criterion of FIT at a cut-off of f-Hb of 10 µg/g had been used, 10 tumours would have been missed. f-Hb, in combination with ColonFlag for those with f-Hb <10 µg/g was found to be more sensitive than f-Hb alone and detected more tumours compared with f-Hb used in combination with anaemia. ColonFlag alone was able to detect 116 of 143 (81%) cases of CRC with a PPV of 4.5%, which is above the 3% threshold for suspected cancer pathway referral recommended by NICE.5

There are limitations to this work likely to affect test performance, but this study was designed to review the actual use of the tests in practice. It is assumed that those patients managed in primary care were highly unlikely to have CRC, and those with CRC were highly likely to have been referred. It is also acknowledged that in the subset of patients who were not investigated with colonoscopy, CT colon or colon capsule, there is an increased probability that CRC or HRA may have been missed. However, the local cancer register was rechecked at the end of data collection and it was found that any missed CRC is likely to present again within 6 months of the initial consultation.11

The specificity of ColonFlag is lower than we have reported previously.9 10 However, specificity of f-Hb is also lower than in many previously published studies. It was noted in the evidence presented to inform the NICE DG30 guidance4 that many of the studies were performed in secondary rather than primary care and included patients with higher risk symptoms than those previously outlined in the guidance on suspected cancer. A recent evaluation of our service showed that in 2021, FIT was requested for indications that were neither low nor high risk for CRC in 28% of patients.12

When using f-Hb to guide referral for CRC, NICE guidance recommends a cut-off of 10 µg/g but a recent meta-analysis of nine UK studies has shown that in symptomatic patients the pooled miss rate for f-Hb for the detection of CRC is 9.7% at a cut-off of 10 µg/g.13 In our study, 32.8% of referrals had f-Hb <10 µg/g and 7% of tumours were found in this group.

Although the incidence of CRC is acknowledged to be higher in males than females,1 in this study it was found to be equal. This may relate to the fact that the population was selected on the basis of having performed a faecal test. It is known that uptake of faecal testing in bowel cancer screening programmes shows lower uptake in men which varies according to ethnicity.14 It is possible that men and women may differ in their willingness to undergo faecal testing, which could explain the sex incidence observed in this study.

The use of blood tests in addition to f-Hb has been examined. A study of 16 604 patients with low-risk symptoms concluded that blood tests, in addition to f-Hb, increased specificity but decreased sensitivity and did not improve discrimination for CRC.15 Other studies have shown that blood tests may be useful in addition to FIT to assist triage, particularly in those with f-Hb <10 µg/g, in whom, in the absence of anaemia, CRC is highly unlikely.16 17

A study of over 33 000 patient indicated that in those who were not anaemic, and had f-Hb between 20 and 40 µg/g, the risk of cancer exceeded the 3% PPV risk threshold set by NICE for urgent referral for CRC, only in those aged >85 years. In patients <40 years, the 3% threshold was an f-Hb of 100 µg/g. In the presence of anaemia, patients with f-Hb >20 µg/g had a risk of CRC >3%, except for those aged <40 years.18

Adenomatous polyps are a precursor of CRC and their early detection and removal is an important preventative intervention. Studies in both symptomatic patients19 20 and asymptomatic screening populations21 have shown that test performance of f-Hb is reduced when the target condition is expanded to include CRC and HRA. The present study supports this, but indicates that f-Hb in combination with ColonFlag may have advantages over f-Hb alone, and f-Hb in combination with anaemia, for detection of HRA. Because ColonFlag is able to use retrospective FBC results, it may have advantages in patients in whom there is no up-to-date FBC result.

ColonFlag has been evaluated in adults non-compliant with other bowel cancer screening approaches. For this purpose, a much higher cut-off (the top 0.87 percentile) was used, identifying 688 individuals from a population of 79 671 who were non-compliant with screening. Of these, 250 agreed to undergo colonoscopy and 19 were diagnosed with CRC.22 The algorithm has also demonstrated the ability to discriminate CRC 18–24 months before the onset of symptoms, although some of this functionality may be influenced by age.23 The cut-off used was significantly higher and would have represented less than the top 1% of patients in this study.

We chose a cut-off for ColonFlag that gave approximately the same specificity as f-Hb at 10 µg/g. When f-Hb is used in the context of bowel cancer screening in asymptomatic people, higher cut-offs may be employed and adjusted based on the health system’s capacity to perform follow-up investigations.24 Further work needs to be done in symptomatic patients to determine the optimal cut-off for ColonFlag according to the exact clinical circumstances in which it is being used.

Colonoscopy can be unpleasant for patients and is not without complications,25 and it is also labour-intensive for hospital staff. Hospital services risk overwhelming their capacity for suspected cancer referrals, which can reduce availability for screening colonoscopies. Therefore, there is a need to appropriately tailor urgent referrals to those who need them most.

However, in our population, using the recommended NICE cut-off of f-Hb ≥10 µg/g would have resulted in 10 tumours and 26 HRA being missed. If a cut-off of f-Hb≥10 µg/g had been used in combination with a raised ColonFlag score below this cut-off, only one tumour and five HRA would have been missed. Despite the reduction in specificity, this approach would still have allowed over 400 patients to be manged without urgent referral.

Conclusion

ColonFlag offers possibilities to assist detection of both CRC and HRA. For instance, it can be useful when a patient has had blood taken previously but has not returned a faecal sample, or when used in combination with FIT to aid in defining clinical pathways or prioritising further investigations. While it has previously been used in the asymptomatic (screening) populations, this study provides further evidence for its effectiveness in symptomatic patients.

Data availability statement

Data are available on reasonable request.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Patient consent for publication: Not applicable.

Ethics approval: ColonFlag was CE marked as a Class 1 device in 2017, hence this work was performed as part of a quality improvement project to establish feasibility of use. Data were gathered during routine patient care, therefore additional ethical approval was not required but the study underwent peer review as part of registration with the Clinical Effectiveness Unit as a quality improvement under Project ID 12402.

Provenance and peer review: Not commissioned; externally peer reviewed.
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