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Published in: BMC Medicine 1/2023

Open Access 01-12-2023 | Colorectal Cancer | Research article

Faecal haemoglobin concentrations are associated with all-cause mortality and cause of death in colorectal cancer screening

Authors: Lasse Kaalby, Ulrik Deding, Issam Al-Najami, Gabriele Berg-Beckhoff, Thomas Bjørsum-Meyer, Tinne Laurberg, Aasma Shaukat, Robert J. C. Steele, Anastasios Koulaouzidis, Morten Rasmussen, Morten Kobaek-Larsen, Gunnar Baatrup

Published in: BMC Medicine | Issue 1/2023

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Abstract

Background

Colorectal cancer (CRC) screening reduces all-cause and CRC-related mortality. New research demonstrates that the faecal haemoglobin concentration (f-Hb) may indicate the presence of other serious diseases not related to CRC. We investigated the association between f-Hb, measured by a faecal immunochemical test (FIT), and both all-cause mortality and cause of death in a population-wide cohort of screening participants.

Methods

Between 2014 and 2018, 1,262,165 participants submitted a FIT for the Danish CRC screening programme. We followed these participants, using the Danish CRC Screening Database and several other national registers on health and population, until December 31, 2018. We stratified participants by f-Hb and compared them using a Cox proportional hazards regression on all-cause mortality and cause of death reported as adjusted hazard ratios (aHRs). We adjusted for several covariates, including comorbidity, socioeconomic factors, demography and prescription medication.

Results

We observed 21,847 deaths in the study period. Our multivariate analyses indicated an association relationship between increasing f-Hb and the risk of dying in the study period. This risk increased steadily from aHR 1.38 (95% CI: 1.32, 1.44) in those with a f-Hb of 7.1–11.9 μg Hb/g faeces to 2.20 (95% CI: 2.10, 2.30) in those with a f-Hb ≥60.0 μg Hb/g faeces, when compared to those with a f-Hb ≤7.0 μg Hb/g faeces. The pattern remained when excluding CRC from the analysis. Similar patterns were observed between incrementally increasing f-Hb and the risk of dying from respiratory disease, cardiovascular disease and cancers other than CRC. Furthermore, we observed an increased risk of dying from CRC with increasing f-Hb.

Conclusions

Our findings support the hypothesis that f-Hb may indicate an elevated risk of having chronic conditions if causes for the bleeding have not been identified. The mechanisms still need to be established, but f-Hb may be a potential biomarker for several non-CRC diseases.
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Literature
1.
go back to reference Kronborg O, Fenger C, Worm J, Pedersen SA, Hem J, Bertelsen K, et al. Causes of death during the first 5 years of a randomized trial of mass screening for colorectal cancer with fecal occult blood test. Scand J Gastroenterol. 1992;27(1):47–52.CrossRef Kronborg O, Fenger C, Worm J, Pedersen SA, Hem J, Bertelsen K, et al. Causes of death during the first 5 years of a randomized trial of mass screening for colorectal cancer with fecal occult blood test. Scand J Gastroenterol. 1992;27(1):47–52.CrossRef
2.
go back to reference Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet. 1996;348(9040):1472–7.CrossRef Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet. 1996;348(9040):1472–7.CrossRef
3.
go back to reference Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328(19):1365–71.CrossRef Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328(19):1365–71.CrossRef
4.
go back to reference Shaukat A, Mongin SJ, Geisser MS, Lederle FA, Bond JH, Mandel JS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369(12):1106–14.CrossRef Shaukat A, Mongin SJ, Geisser MS, Lederle FA, Bond JH, Mandel JS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369(12):1106–14.CrossRef
5.
go back to reference Scholefield JH, Moss SM, Mangham CM, Whynes DK, Hardcastle JD. Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up. Gut. 2012;61(7):1036–40.CrossRef Scholefield JH, Moss SM, Mangham CM, Whynes DK, Hardcastle JD. Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up. Gut. 2012;61(7):1036–40.CrossRef
6.
go back to reference Shaukat A, Kaalby L, Baatrup G, Kronborg O, Duval S, Shyne M, et al. Effects of screening compliance on long-term reductions in all-cause and colorectal cancer mortality. Clin Gastroenterol Hepatol. 2021;19(5):967–75.e2.CrossRef Shaukat A, Kaalby L, Baatrup G, Kronborg O, Duval S, Shyne M, et al. Effects of screening compliance on long-term reductions in all-cause and colorectal cancer mortality. Clin Gastroenterol Hepatol. 2021;19(5):967–75.e2.CrossRef
7.
go back to reference Cardoso R, Guo F, Heisser T, Hackl M, Ihle P, De Schutter H, et al. Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study. Lancet Oncol. 2021;22(7):1002–13.CrossRef Cardoso R, Guo F, Heisser T, Hackl M, Ihle P, De Schutter H, et al. Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study. Lancet Oncol. 2021;22(7):1002–13.CrossRef
8.
go back to reference Bretthauer M, Løberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, et al. Effect of colonoscopy screening on risks of colorectal cancer and related death. N Engl J Med. 2022;387(17):1547–56.CrossRef Bretthauer M, Løberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, et al. Effect of colonoscopy screening on risks of colorectal cancer and related death. N Engl J Med. 2022;387(17):1547–56.CrossRef
9.
go back to reference Lee MW, Pourmorady JS, Laine L. Use of fecal occult blood testing as a diagnostic tool for clinical indications: a systematic review and meta-analysis. Am J Gastroenterol. 2020;115(5):662–70.CrossRef Lee MW, Pourmorady JS, Laine L. Use of fecal occult blood testing as a diagnostic tool for clinical indications: a systematic review and meta-analysis. Am J Gastroenterol. 2020;115(5):662–70.CrossRef
11.
go back to reference Kaminski MF, Robertson DJ, Senore C, Rex DK. Optimizing the quality of colorectal cancer screening worldwide. Gastroenterology. 2020;158(2):404–17.CrossRef Kaminski MF, Robertson DJ, Senore C, Rex DK. Optimizing the quality of colorectal cancer screening worldwide. Gastroenterology. 2020;158(2):404–17.CrossRef
12.
go back to reference Barnett KN, Clark GRC, Steele RJC, Fraser CG. Faecal haemoglobin estimated by faecal immunochemical tests-an indicator of systemic inflammation with real clinical potential. Diagnostics. 2021;11(11):2093.CrossRef Barnett KN, Clark GRC, Steele RJC, Fraser CG. Faecal haemoglobin estimated by faecal immunochemical tests-an indicator of systemic inflammation with real clinical potential. Diagnostics. 2021;11(11):2093.CrossRef
13.
go back to reference Nakajima K, Suwa K. Association between positive fecal occult blood test and diabetes in a population undergoing health screening. Clin Biochem. 2017;50(1-2):97–100.CrossRef Nakajima K, Suwa K. Association between positive fecal occult blood test and diabetes in a population undergoing health screening. Clin Biochem. 2017;50(1-2):97–100.CrossRef
14.
go back to reference Libby G, Barnett KN, Fraser CG, Steele RJC. Association between faecal occult bleeding and medicines prescribed for chronic disease: a data linkage study. J Clin Pathol. 2021;74(10):664–7.CrossRef Libby G, Barnett KN, Fraser CG, Steele RJC. Association between faecal occult bleeding and medicines prescribed for chronic disease: a data linkage study. J Clin Pathol. 2021;74(10):664–7.CrossRef
15.
go back to reference Kaalby L, Al-Najami I, Deding U, Berg-Beckhoff G, Steele RJC, Kobaek-Larsen M, et al. Cause of death, mortality and occult blood in colorectal cancer screening. Cancers. 2022;14(1):246.CrossRef Kaalby L, Al-Najami I, Deding U, Berg-Beckhoff G, Steele RJC, Kobaek-Larsen M, et al. Cause of death, mortality and occult blood in colorectal cancer screening. Cancers. 2022;14(1):246.CrossRef
16.
go back to reference Libby G, Fraser CG, Carey FA, Brewster DH, Steele RJC. Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality. Gut. 2018;67(12):2116–23.CrossRef Libby G, Fraser CG, Carey FA, Brewster DH, Steele RJC. Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality. Gut. 2018;67(12):2116–23.CrossRef
17.
go back to reference Gies A, Cuk K, Schrotz-King P, Brenner H. Direct comparison of ten quantitative fecal immunochemical tests for hemoglobin stability in colorectal cancer screening. Clin Transl Gastroenterol. 2018;9(7):168.CrossRef Gies A, Cuk K, Schrotz-King P, Brenner H. Direct comparison of ten quantitative fecal immunochemical tests for hemoglobin stability in colorectal cancer screening. Clin Transl Gastroenterol. 2018;9(7):168.CrossRef
19.
go back to reference Plantener E, Deding U, Madsen JB, Kroijer R, Madsen JS, Baatrup G. Using fecal immunochemical test values below conventional cut-off to individualize colorectal cancer screening. Endosc Int Open. 2022;10(4):E413–e9.CrossRef Plantener E, Deding U, Madsen JB, Kroijer R, Madsen JS, Baatrup G. Using fecal immunochemical test values below conventional cut-off to individualize colorectal cancer screening. Endosc Int Open. 2022;10(4):E413–e9.CrossRef
20.
go back to reference Njor SH, Friis-Hansen L, Andersen B, Sondergaard B, Linnemann D, Jorgensen JCR, et al. Three years of colorectal cancer screening in Denmark. Cancer Epidemiol. 2018;57:39–44.CrossRef Njor SH, Friis-Hansen L, Andersen B, Sondergaard B, Linnemann D, Jorgensen JCR, et al. Three years of colorectal cancer screening in Denmark. Cancer Epidemiol. 2018;57:39–44.CrossRef
21.
go back to reference Thomsen MK, Njor SH, Rasmussen M, Linnemann D, Andersen B, Baatrup G, et al. Validity of data in the Danish Colorectal Cancer Screening Database. Clin Epidemiol. 2017;9:105–11.CrossRef Thomsen MK, Njor SH, Rasmussen M, Linnemann D, Andersen B, Baatrup G, et al. Validity of data in the Danish Colorectal Cancer Screening Database. Clin Epidemiol. 2017;9:105–11.CrossRef
22.
go back to reference Lynge E, Sandegaard J, Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39:4.CrossRef Lynge E, Sandegaard J, Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39:4.CrossRef
23.
go back to reference Kildemoes HW, Sørensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health. 2011;39(7 Suppl):38–41.CrossRef Kildemoes HW, Sørensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health. 2011;39(7 Suppl):38–41.CrossRef
24.
go back to reference Helweg-Larsen K. The Danish register of causes of death. Scand J Public Health. 2011;39(7 Suppl):26–9.CrossRef Helweg-Larsen K. The Danish register of causes of death. Scand J Public Health. 2011;39(7 Suppl):26–9.CrossRef
25.
go back to reference Jensen VM, Rasmussen AW. Danish education registers. Scand J Public Health. 2011;39(7 Suppl):91–4.CrossRef Jensen VM, Rasmussen AW. Danish education registers. Scand J Public Health. 2011;39(7 Suppl):91–4.CrossRef
26.
go back to reference Baadsgaard M, Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health. 2011;39(7 Suppl):103–5.CrossRef Baadsgaard M, Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health. 2011;39(7 Suppl):103–5.CrossRef
27.
go back to reference Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676–82.CrossRef Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676–82.CrossRef
28.
go back to reference StataCorp. Stata Statistical Software: release 17. College Station, TX: StataCorp LLC.; 2021. StataCorp. Stata Statistical Software: release 17. College Station, TX: StataCorp LLC.; 2021.
29.
go back to reference Pearson-Stuttard J, Bennett J, Cheng YJ, Vamos EP, Cross AJ, Ezzati M, et al. Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: an epidemiological analysis of linked primary care records. Lancet Diabetes Endocrinol. 2021;9(3):165–73.CrossRef Pearson-Stuttard J, Bennett J, Cheng YJ, Vamos EP, Cross AJ, Ezzati M, et al. Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: an epidemiological analysis of linked primary care records. Lancet Diabetes Endocrinol. 2021;9(3):165–73.CrossRef
30.
go back to reference Jung YS, Lee J, Moon CM. Positive fecal immunochemical test results are associated with non-colorectal cancer mortality. Korean J Intern Med. 2022;37(2):313–21.CrossRef Jung YS, Lee J, Moon CM. Positive fecal immunochemical test results are associated with non-colorectal cancer mortality. Korean J Intern Med. 2022;37(2):313–21.CrossRef
31.
go back to reference Chen L-S, Yen AM-F, Fraser CG, Chiu SY-H, Fann JC-Y, Wang P-E, et al. Impact of faecal haemoglobin concentration on colorectal cancer mortality and all-cause death. BMJ Open. 2013;3(11):e003740.CrossRef Chen L-S, Yen AM-F, Fraser CG, Chiu SY-H, Fann JC-Y, Wang P-E, et al. Impact of faecal haemoglobin concentration on colorectal cancer mortality and all-cause death. BMJ Open. 2013;3(11):e003740.CrossRef
32.
go back to reference Kim KW, Lee HJ, Han K, Moon JM, Hong SW, Kang EA, et al. Risk of diabetes in subjects with positive fecal immunochemical test: a nationwide population-based study. Endocrinol Metab. 2021;36(5):1069–77.CrossRef Kim KW, Lee HJ, Han K, Moon JM, Hong SW, Kang EA, et al. Risk of diabetes in subjects with positive fecal immunochemical test: a nationwide population-based study. Endocrinol Metab. 2021;36(5):1069–77.CrossRef
33.
go back to reference Chien KL, Lin TY, Hsu CY, Chan CC, Chen TH, Chen LS. Association between faecal haemoglobin concentration and the risk of cardiovascular diseases among Taiwanese adults in a community-based screening cohort. BMJ Open. 2020;10(6):e032633.CrossRef Chien KL, Lin TY, Hsu CY, Chan CC, Chen TH, Chen LS. Association between faecal haemoglobin concentration and the risk of cardiovascular diseases among Taiwanese adults in a community-based screening cohort. BMJ Open. 2020;10(6):e032633.CrossRef
34.
go back to reference Moon JM, Lee HJ, Han K, Kim DH, Hong SW, Soh H, et al. Occult blood in feces is associated with an increased risk of ischemic stroke and myocardial infarction: a nationwide population study. J Am Heart Assoc. 2021;10(1):e017783.CrossRef Moon JM, Lee HJ, Han K, Kim DH, Hong SW, Soh H, et al. Occult blood in feces is associated with an increased risk of ischemic stroke and myocardial infarction: a nationwide population study. J Am Heart Assoc. 2021;10(1):e017783.CrossRef
35.
go back to reference Noh C-K, Lee E, Park B, Ahn SS. A positive faecal immunochemical test result and its association with the incidence of rheumatoid arthritis, systemic lupus erythematosus, and psoriatic arthritis: an analysis of one-million national colorectal cancer screening programme results. BMC Med. 2022;20(1):226.CrossRef Noh C-K, Lee E, Park B, Ahn SS. A positive faecal immunochemical test result and its association with the incidence of rheumatoid arthritis, systemic lupus erythematosus, and psoriatic arthritis: an analysis of one-million national colorectal cancer screening programme results. BMC Med. 2022;20(1):226.CrossRef
36.
go back to reference Yen AM, Lai H, Fann JC, Chiu SY, Chen SL. Relationship between community periodontal index and fecal hemoglobin concentration, an indicator for colorectal neoplasm. J Dent Res. 2014;93(8):760–6.CrossRef Yen AM, Lai H, Fann JC, Chiu SY, Chen SL. Relationship between community periodontal index and fecal hemoglobin concentration, an indicator for colorectal neoplasm. J Dent Res. 2014;93(8):760–6.CrossRef
37.
go back to reference Lee HJ, Han K, Soh H, Koh SJ, Im JP, Kim JS, et al. Occult blood in feces is associated with increased risk of psoriasis. Dermatology. 2022;238(3):571–8.CrossRef Lee HJ, Han K, Soh H, Koh SJ, Im JP, Kim JS, et al. Occult blood in feces is associated with increased risk of psoriasis. Dermatology. 2022;238(3):571–8.CrossRef
38.
go back to reference Ku M-S, Fann JC-Y, Chiu SY-H, Chen H-H, Hsu C-Y. Elucidating bidirectional relationship between metabolic syndrome and elevated faecal haemoglobin concentration: a Taiwanese community-based cohort study. BMJ Open. 2019;9(3):e021153.CrossRef Ku M-S, Fann JC-Y, Chiu SY-H, Chen H-H, Hsu C-Y. Elucidating bidirectional relationship between metabolic syndrome and elevated faecal haemoglobin concentration: a Taiwanese community-based cohort study. BMJ Open. 2019;9(3):e021153.CrossRef
39.
go back to reference Ku MS, Liu CY, Hsu CY, Chiu HM, Chen HH, Chan CC. Association of ambient fine particulate matter (PM(2.5)) with elevated fecal hemoglobin concentration and colorectal carcinogenesis: a population-based retrospective cohort study. Cancer Control. 2021;28:10732748211041232.CrossRef Ku MS, Liu CY, Hsu CY, Chiu HM, Chen HH, Chan CC. Association of ambient fine particulate matter (PM(2.5)) with elevated fecal hemoglobin concentration and colorectal carcinogenesis: a population-based retrospective cohort study. Cancer Control. 2021;28:10732748211041232.CrossRef
40.
go back to reference Clark GRC, Strachan JA, McPherson A, Digby J, Mowat C, Steele RJC, et al. Faecal haemoglobin distributions by sex, age, deprivation and geographical region: consequences for colorectal cancer screening strategies. Clin Chem Lab Med. 2020;58(12):2073–80.CrossRef Clark GRC, Strachan JA, McPherson A, Digby J, Mowat C, Steele RJC, et al. Faecal haemoglobin distributions by sex, age, deprivation and geographical region: consequences for colorectal cancer screening strategies. Clin Chem Lab Med. 2020;58(12):2073–80.CrossRef
41.
go back to reference Nieuwenburg SAV, Vuik FER, Kruip M, Kuipers EJ, Spaander MCW. Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis. Gut. 2019;68(5):866–72.CrossRef Nieuwenburg SAV, Vuik FER, Kruip M, Kuipers EJ, Spaander MCW. Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis. Gut. 2019;68(5):866–72.CrossRef
42.
go back to reference Jung YS, Im E, Park CH. Impact of antiplatelet agents and anticoagulants on the performance of fecal immunochemical tests: a systematic review and meta-analysis. Surgical Endoscopy. 2022;36(6):4299–311.CrossRef Jung YS, Im E, Park CH. Impact of antiplatelet agents and anticoagulants on the performance of fecal immunochemical tests: a systematic review and meta-analysis. Surgical Endoscopy. 2022;36(6):4299–311.CrossRef
43.
go back to reference Jung YS, Lee J, Moon CM. Positive fecal immunochemical test results are associated with increased risks of esophageal, stomach, and small intestine cancers. J Clin Med. 2020;9(7):2172.CrossRef Jung YS, Lee J, Moon CM. Positive fecal immunochemical test results are associated with increased risks of esophageal, stomach, and small intestine cancers. J Clin Med. 2020;9(7):2172.CrossRef
44.
go back to reference Kim NH, Yang HJ, Park SK, Park JH, Park DI, Sohn CI, et al. Does low threshold value use improve proximal neoplasia detection by fecal immunochemical test? Dig Dis Sci. 2016;61(9):2685–93.CrossRef Kim NH, Yang HJ, Park SK, Park JH, Park DI, Sohn CI, et al. Does low threshold value use improve proximal neoplasia detection by fecal immunochemical test? Dig Dis Sci. 2016;61(9):2685–93.CrossRef
45.
go back to reference Stegeman I, de Wijkerslooth TR, Stoop EM, van Leerdam M, van Ballegooijen M, Kraaijenhagen RA, et al. Risk factors for false positive and for false negative test results in screening with fecal occult blood testing. Int J Cancer. 2013;133(10):2408–14.CrossRef Stegeman I, de Wijkerslooth TR, Stoop EM, van Leerdam M, van Ballegooijen M, Kraaijenhagen RA, et al. Risk factors for false positive and for false negative test results in screening with fecal occult blood testing. Int J Cancer. 2013;133(10):2408–14.CrossRef
46.
go back to reference Amitay EL, Cuk K, Niedermaier T, Weigl K, Brenner H. Factors associated with false-positive fecal immunochemical tests in a large German colorectal cancer screening study. Int J Cancer. 2019;144(10):2419–27.CrossRef Amitay EL, Cuk K, Niedermaier T, Weigl K, Brenner H. Factors associated with false-positive fecal immunochemical tests in a large German colorectal cancer screening study. Int J Cancer. 2019;144(10):2419–27.CrossRef
47.
go back to reference Lu J, Xu B, Xu Y, Wu Y, Xie J, Wang J, et al. A novel insight into fecal occult blood test for the management of gastric cancer: complication, survival, and chemotherapy benefit after r0 resection. Front Oncol. 2020;10:526746.CrossRef Lu J, Xu B, Xu Y, Wu Y, Xie J, Wang J, et al. A novel insight into fecal occult blood test for the management of gastric cancer: complication, survival, and chemotherapy benefit after r0 resection. Front Oncol. 2020;10:526746.CrossRef
Metadata
Title
Faecal haemoglobin concentrations are associated with all-cause mortality and cause of death in colorectal cancer screening
Authors
Lasse Kaalby
Ulrik Deding
Issam Al-Najami
Gabriele Berg-Beckhoff
Thomas Bjørsum-Meyer
Tinne Laurberg
Aasma Shaukat
Robert J. C. Steele
Anastasios Koulaouzidis
Morten Rasmussen
Morten Kobaek-Larsen
Gunnar Baatrup
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2023
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02724-3

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