Digby, Jayne

Fraser, Callum G.

Mowat, Craig

Steele, Robert J. C.

Strachan, Judith A.

English

University of Dundee Online Publications

                                                                    University of DundeeLow Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile SerratedAdenomas/Polyps Confirmed Over Clinical Setting, Geography, and FIT SystemMowat, Craig; Digby, Jayne; Strachan, Judith A.; Steele, Robert J. C.; Fraser, Callum G.Published in:Digestive Diseases and SciencesDOI:10.1007/s10620-019-05661-zPublication date:2019Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Mowat, C., Digby, J., Strachan, J. A., Steele, R. J. C., & Fraser, C. G. (2019). Low Sensitivity of FecalImmunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed Over ClinicalSetting, Geography, and FIT System. Digestive Diseases and Sciences, 64(10), 3024-3026.https://doi.org/10.1007/s10620-019-05661-zGeneral rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 17. Aug. 2021CORRESPONDENCE Low Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed over Clinical Setting, Geography, and FIT System Craig Mowat1 · Jayne Digby2 · Judith A Strachan3 · Robert JC Steele2 · Callum G Fraser2  1Department of Gastroenterology, Ninewells Hospital and Medical School Dundee, Scotland, UK 2Centre for Research into Cancer Prevention and Screening, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK 3Department of Blood Sciences and Scottish Bowel Screening Laboratory, NHS Tayside, Ninewells Hospital and Medical School, Dundee, Scotland, UK Correspondence to: Professor Callum G Fraser, Centre for Research into Cancer Prevention and Screening, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK  Email: { HYPERLINK "mailto:callum.fraser@nhs.ne" }t Author Accepted Manuscript: Mowat, C, Digby, J, Strachan, JA, Steele, RJC & Fraser, CG 2019, 'Low Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed Over Clinical Setting, Geography, and FIT System' Digestive Diseases and Sciences. https://doi.org/10.1007/s10620-019-05661-zKeywords:  Adenoma · Biomarkers · Colorectal neoplasms · Fecal hemoglobin · Fecal immunochemical test · Screening To the Editor,  We were interested to read the study of Cock et al [1] on the clinical sensitivity of fecal immunochemical tests (FIT) for the detection of sessile serrated adenomas/polyps (SSA/SSP), and their conclusion that FIT have low sensitivity for their detection.   Participants in their study were aged over 18 years and underwent colonoscopy in South Australia with FIT analyses performed on the OC-Sensor Diana (Eiken Chemical Co., Ltd, Tokyo, Japan).  Indications for colonoscopy were heterogeneous, and were: positive FIT 519 (27.6%), symptoms 561 (29.8%), surveillance 687 (36.5%), screening 18 (1.0%), and other 97 (5.2%).  However, it is known that the performance outcomes using FIT vary in different clinical settings and different fecal hemoglobin concentrations (f-Hb) are used as thresholds. [2,3]  In addition, quantitative FIT systems use polyclonal antibodies to the globin moiety of human haemoglobin and have different analytical specificities, giving different f-Hb results, particularly at low f-Hb. [3,4]  Further, f-Hb varies with sex, being higher in males than females, [5,6], and increases with age [5,6] and deprivation [6,7], but these effects vary from country to country. [8]  In consequence, here we provide information on the value of FIT in the detection of SSA in a more homogeneous population (only those referred from primary care for colonoscopy due to lower bowel symptoms), from a different country (Scotland), and using a different FIT analytical system (HM-JACKarc, Kyowa Medex Co., Ltd, Tokyo, Japan).   Over the first year of our routine use of FIT in primary care (December, 2015 – November, 2016), 1,447 patients with a variety of lower bowel symptoms, but not participating in a surveillance program, completed a single FIT and colonoscopy: the overall prevalence of significant bowel disease was 20.5% (comprising 95 colorectal cancer [CRC] {6.6%}, 133 higher-risk adenoma [HRA: a polyp > 10 mm diam or more than three polyps, and those with villous characteristics and high grade dysplasia] {9.2%}, and 68 inflammatory bowel disease [IBD] {4.7%}). There were 12 SSA (all proximal) and 176 low-risk adenoma [LRA] (< 10 mm diameter, or less than three).  The location, median size, number with f-Hb > 10 µg Hb/g feces, and median f-Hb of the SSA, HRA, and LRA are shown in Table 1.  Table 1. Number, median size (mm) with 95% confidence intervals (CI), number with fecal hemoglobin concentration (f-Hb) > 10 µg Hb/g feces, median f-Hb (with 95% CI) of sessile serrated adenoma, higher-risk adenoma, and low-risk adenoma in 1447 patients with lower bowel symptoms, all referred from primary care. .  n  median size, mm (95 % CI) n with f-Hb ≥ 10 µg Hb/g feces (%) median f-Hb, µg Hb/g feces (95% CI) p-value* Sessile serrated adenoma 12 9 (6.3 - 10.0) 4 (33.3) 0 (0.0 - 30.5)  Higher-risk adenoma      All 127** 15 (12.0 - 15.0) 99 (78.0) 42.0 (26.0 - 75.0) 0.0071 Proximal*** 37 15 (12.1 - 18.0) 27 (73.0) 22.0 (12.2 - 53.5) 0.0657 Distal 90 15 (12.0 - 16.5) 72 (80.0) 48.0 (33.5 - 101.5) 0.0035 Low-risk adenoma      All 176 5 (5.0 - 5.0) 107 (60.8) 17.0 (12.0 - 22.5) 0.1362 Proximal 69 5 (4.0 - 6.0) 37 (53.6) 16.0 (0.0 - 25.1) 0.2725 Distal 107 5 (5.0 - 6.0) 70 (65.4) 17.0 (12.0 - 25.3) 0.0941   * p-value relates to difference in median f-Hb to that of sessile serrated adenomas. ** six SSA had diam > 10 mm and were therefore originally classified in the group of 133 higher-risk adenoma, but investigated separately in this analysis. *** proximal location is proximal to and including the splenic flexure, distal is distal to splenic flexure.  Of the 12 SSA, only four (33.3%) had f-Hb greater than the National Institute for Health and Care Excellence (NICE) recommended f-Hb threshold of 10 µg Hb/g feces. [9]   Of the 127 HRA and 176 LRA, 100 (78.7%) and 107 (60.5%) had f-Hb greater than 10 µg Hb/g feces. Median f-Hb was lower in SSA than HRA and LRA. These findings are unsurprising because f-Hb is related to severity of colorectal disease and higher f-Hb is found in HRA than LRA, large (> 10 mm) compared with small adenoma, and also adenoma displaying high-grade compared with low-grade dysplasia. [10]   Our data would add to the observations that, in comparison to adenomas, SSA are found less frequently at colonoscopy and, for the various reasons elicited by Cock et al., [1] may not be associated with significant f-Hb. Moreover, our data suggest that their findings on SSA/SSP are likely to be transferable between clinical settings, over geography, and with different FIT systems.  Compliance with ethical standards  Conflict of interest   CGF undertakes paid consultancy with Kyowa Medex Co., Ltd, Tokyo, Japan, and has received financial assistance with attendance at conferences from Alpha Labs Ltd. All other authors declare that they have no conflicts of interest.  References  1. Cock C, Anwar S, Byrne SE, et al.  Low sensitivity of fecal immunochemical tests and blood-based markers of DNA hypermethylation for detection of sessile serrated adenomas/polyps.  Dig Dis Sci 2019 Mar 5. doi: 10.1007/s10620-019-05569-8. [Epub ahead of print].  2. Young GP, Symonds EL, Allison JE, et al. Advances in fecal occult blood tests: the FIT revolution. Dig Dis Sci 2015;60:609-622. doi: 10.1007/s10620-014-3445-3.  3. Westwood M, Lang S, Armstrong N, et al.  Faecal immunochemical tests (FIT) can help to rule out colorectal cancer in patients presenting in primary care with lower abdominal symptoms: a systematic review conducted to inform new NICE DG30 diagnostic guidance. BMC Med 2017;15:189. doi: 10.1186/s12916-017-0944-z.  4. Grobbee EJ, van der Vlugt M, van Vuuren AJ, et al.  A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening. Gut 2017;66:1975-1982. doi: 10.1136/gutjnl-2016-311819.  5. McDonald PJ, Strachan JA, Digby J, et al. Faecal haemoglobin concentrations by gender and age: implications for population-based screening for colorectal cancer. Clin Chem Lab Med 2011;50:935-40. doi: 10.1515/CCLM.2011.815.  6. Symonds EL, Osborne JM, Cole SR, et al.  Factors affecting faecal immunochemical test positive rates: demographic, pathological, behavioural and environmental variables. J Med Screen 2015;22:187-193. doi: 10.1177/0969141315584783.  7. Digby J, McDonald PJ, Strachan JA, et al. Deprivation and faecal haemoglobin: implications for bowel cancer screening.  J Med Screen 2014;21:95-7. doi: 10.1177/0969141314535388.  8. Fraser CG, Rubeca T, Rapi S, et al.  Faecal haemoglobin concentrations vary with sex and age, but data are not transferable across geography for colorectal cancer screening. Clin Chem Lab Med 2014;52:1211-1216. doi: 10.1515/cclm-2014-0115.  9. National Institute for Health and Care Excellence. Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care. Diagnostics Guidance [DG30]. July 2017. { HYPERLINK "https://www.nice.org.uk/guidance/dg30" }   10. Digby J, Fraser CG, Carey FA, et al. Faecal haemoglobin concentration is related to severity of colorectal neoplasia. J Clin Pathol 2013;66:415-419. doi: 10.1136/jclinpath-2013-201445. 

Low Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed Over Clinical Setting, Geography, and FIT System

                                                                    University of DundeeLow Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile SerratedAdenomas/Polyps Confirmed Over Clinical Setting, Geography, and FIT SystemMowat, Craig; Digby, Jayne; Strachan, Judith A.; Steele, Robert J. C.; Fraser, Callum G.Published in:Digestive Diseases and SciencesDOI:10.1007/s10620-019-05661-zPublication date:2019Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Mowat, C., Digby, J., Strachan, J. A., Steele, R. J. C., & Fraser, C. G. (2019). Low Sensitivity of FecalImmunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed Over ClinicalSetting, Geography, and FIT System. Digestive Diseases and Sciences, 64(10), 3024-3026.https://doi.org/10.1007/s10620-019-05661-zGeneral rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 19. Apr. 2023CORRESPONDENCE Low Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed over Clinical Setting, Geography, and FIT System Craig Mowat1 · Jayne Digby2 · Judith A Strachan3 · Robert JC Steele2 · Callum G Fraser2  1Department of Gastroenterology, Ninewells Hospital and Medical School Dundee, Scotland, UK 2Centre for Research into Cancer Prevention and Screening, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK 3Department of Blood Sciences and Scottish Bowel Screening Laboratory, NHS Tayside, Ninewells Hospital and Medical School, Dundee, Scotland, UK Correspondence to: Professor Callum G Fraser, Centre for Research into Cancer Prevention and Screening, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK  Email: { HYPERLINK "mailto:callum.fraser@nhs.ne" }t Author Accepted Manuscript: Mowat, C, Digby, J, Strachan, JA, Steele, RJC & Fraser, CG 2019, 'Low Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed Over Clinical Setting, Geography, and FIT System' Digestive Diseases and Sciences. https://doi.org/10.1007/s10620-019-05661-zKeywords:  Adenoma · Biomarkers · Colorectal neoplasms · Fecal hemoglobin · Fecal immunochemical test · Screening To the Editor,  We were interested to read the study of Cock et al [1] on the clinical sensitivity of fecal immunochemical tests (FIT) for the detection of sessile serrated adenomas/polyps (SSA/SSP), and their conclusion that FIT have low sensitivity for their detection.   Participants in their study were aged over 18 years and underwent colonoscopy in South Australia with FIT analyses performed on the OC-Sensor Diana (Eiken Chemical Co., Ltd, Tokyo, Japan).  Indications for colonoscopy were heterogeneous, and were: positive FIT 519 (27.6%), symptoms 561 (29.8%), surveillance 687 (36.5%), screening 18 (1.0%), and other 97 (5.2%).  However, it is known that the performance outcomes using FIT vary in different clinical settings and different fecal hemoglobin concentrations (f-Hb) are used as thresholds. [2,3]  In addition, quantitative FIT systems use polyclonal antibodies to the globin moiety of human haemoglobin and have different analytical specificities, giving different f-Hb results, particularly at low f-Hb. [3,4]  Further, f-Hb varies with sex, being higher in males than females, [5,6], and increases with age [5,6] and deprivation [6,7], but these effects vary from country to country. [8]  In consequence, here we provide information on the value of FIT in the detection of SSA in a more homogeneous population (only those referred from primary care for colonoscopy due to lower bowel symptoms), from a different country (Scotland), and using a different FIT analytical system (HM-JACKarc, Kyowa Medex Co., Ltd, Tokyo, Japan).   Over the first year of our routine use of FIT in primary care (December, 2015 – November, 2016), 1,447 patients with a variety of lower bowel symptoms, but not participating in a surveillance program, completed a single FIT and colonoscopy: the overall prevalence of significant bowel disease was 20.5% (comprising 95 colorectal cancer [CRC] {6.6%}, 133 higher-risk adenoma [HRA: a polyp > 10 mm diam or more than three polyps, and those with villous characteristics and high grade dysplasia] {9.2%}, and 68 inflammatory bowel disease [IBD] {4.7%}). There were 12 SSA (all proximal) and 176 low-risk adenoma [LRA] (< 10 mm diameter, or less than three).  The location, median size, number with f-Hb > 10 µg Hb/g feces, and median f-Hb of the SSA, HRA, and LRA are shown in Table 1.  Table 1. Number, median size (mm) with 95% confidence intervals (CI), number with fecal hemoglobin concentration (f-Hb) > 10 µg Hb/g feces, median f-Hb (with 95% CI) of sessile serrated adenoma, higher-risk adenoma, and low-risk adenoma in 1447 patients with lower bowel symptoms, all referred from primary care. .  n  median size, mm (95 % CI) n with f-Hb ≥ 10 µg Hb/g feces (%) median f-Hb, µg Hb/g feces (95% CI) p-value* Sessile serrated adenoma 12 9 (6.3 - 10.0) 4 (33.3) 0 (0.0 - 30.5)  Higher-risk adenoma      All 127** 15 (12.0 - 15.0) 99 (78.0) 42.0 (26.0 - 75.0) 0.0071 Proximal*** 37 15 (12.1 - 18.0) 27 (73.0) 22.0 (12.2 - 53.5) 0.0657 Distal 90 15 (12.0 - 16.5) 72 (80.0) 48.0 (33.5 - 101.5) 0.0035 Low-risk adenoma      All 176 5 (5.0 - 5.0) 107 (60.8) 17.0 (12.0 - 22.5) 0.1362 Proximal 69 5 (4.0 - 6.0) 37 (53.6) 16.0 (0.0 - 25.1) 0.2725 Distal 107 5 (5.0 - 6.0) 70 (65.4) 17.0 (12.0 - 25.3) 0.0941   * p-value relates to difference in median f-Hb to that of sessile serrated adenomas. ** six SSA had diam > 10 mm and were therefore originally classified in the group of 133 higher-risk adenoma, but investigated separately in this analysis. *** proximal location is proximal to and including the splenic flexure, distal is distal to splenic flexure.  Of the 12 SSA, only four (33.3%) had f-Hb greater than the National Institute for Health and Care Excellence (NICE) recommended f-Hb threshold of 10 µg Hb/g feces. [9]   Of the 127 HRA and 176 LRA, 100 (78.7%) and 107 (60.5%) had f-Hb greater than 10 µg Hb/g feces. Median f-Hb was lower in SSA than HRA and LRA. These findings are unsurprising because f-Hb is related to severity of colorectal disease and higher f-Hb is found in HRA than LRA, large (> 10 mm) compared with small adenoma, and also adenoma displaying high-grade compared with low-grade dysplasia. [10]   Our data would add to the observations that, in comparison to adenomas, SSA are found less frequently at colonoscopy and, for the various reasons elicited by Cock et al., [1] may not be associated with significant f-Hb. Moreover, our data suggest that their findings on SSA/SSP are likely to be transferable between clinical settings, over geography, and with different FIT systems.  Compliance with ethical standards  Conflict of interest   CGF undertakes paid consultancy with Kyowa Medex Co., Ltd, Tokyo, Japan, and has received financial assistance with attendance at conferences from Alpha Labs Ltd. All other authors declare that they have no conflicts of interest.  References  1. Cock C, Anwar S, Byrne SE, et al.  Low sensitivity of fecal immunochemical tests and blood-based markers of DNA hypermethylation for detection of sessile serrated adenomas/polyps.  Dig Dis Sci 2019 Mar 5. doi: 10.1007/s10620-019-05569-8. [Epub ahead of print].  2. Young GP, Symonds EL, Allison JE, et al. Advances in fecal occult blood tests: the FIT revolution. Dig Dis Sci 2015;60:609-622. doi: 10.1007/s10620-014-3445-3.  3. Westwood M, Lang S, Armstrong N, et al.  Faecal immunochemical tests (FIT) can help to rule out colorectal cancer in patients presenting in primary care with lower abdominal symptoms: a systematic review conducted to inform new NICE DG30 diagnostic guidance. BMC Med 2017;15:189. doi: 10.1186/s12916-017-0944-z.  4. Grobbee EJ, van der Vlugt M, van Vuuren AJ, et al.  A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening. Gut 2017;66:1975-1982. doi: 10.1136/gutjnl-2016-311819.  5. McDonald PJ, Strachan JA, Digby J, et al. Faecal haemoglobin concentrations by gender and age: implications for population-based screening for colorectal cancer. Clin Chem Lab Med 2011;50:935-40. doi: 10.1515/CCLM.2011.815.  6. Symonds EL, Osborne JM, Cole SR, et al.  Factors affecting faecal immunochemical test positive rates: demographic, pathological, behavioural and environmental variables. J Med Screen 2015;22:187-193. doi: 10.1177/0969141315584783.  7. Digby J, McDonald PJ, Strachan JA, et al. Deprivation and faecal haemoglobin: implications for bowel cancer screening.  J Med Screen 2014;21:95-7. doi: 10.1177/0969141314535388.  8. Fraser CG, Rubeca T, Rapi S, et al.  Faecal haemoglobin concentrations vary with sex and age, but data are not transferable across geography for colorectal cancer screening. Clin Chem Lab Med 2014;52:1211-1216. doi: 10.1515/cclm-2014-0115.  9. National Institute for Health and Care Excellence. Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care. Diagnostics Guidance [DG30]. July 2017. { HYPERLINK "https://www.nice.org.uk/guidance/dg30" }   10. Digby J, Fraser CG, Carey FA, et al. Faecal haemoglobin concentration is related to severity of colorectal neoplasia. J Clin Pathol 2013;66:415-419. doi: 10.1136/jclinpath-2013-201445. 

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Low Sensitivity of Fecal Immunochemical Tests (FIT) for Detection of Sessile Serrated Adenomas/Polyps Confirmed Over Clinical Setting, Geography, and FIT System

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