Accuracy of faecal occult blood test and Helicobacter pylori stool ...

BMJ Open

Accuracy of fecal occult-blood test and Helicobacter pylori stool antigen test for detection of upper gastrointestinal lesions

rp Fo Journal:

Manuscript ID: Article Type:

Date Submitted by the Author:

Complete List of Authors:

BMJ Open bmjopen-2013-003989 Research 10-Sep-2013

w

ie

ev

rr

ee

Lee, Yi-Chia; National Taiwan University Hospital, Internal medicine Chiu, Han-Mo; National Taiwan University Hospital, Internal medicine Chiang, Tsung-Hsien; National Taiwan University Hospital, Internal medicine Yen, Amy Ming-Fang; School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Chiu, Sherry Yueh-Hsia; Department and Graduate Institute of Health Care Management, Chang Gung University, Chen, Li-Sheng; School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Fann, Jean Ching-Yuan; Department and Graduate Institute of Health Care Management, Kainan University, Yeh, Yen-Po; Changhua County Public Health Burea, Liao, Chao-Sheng; Division of Gastroenterology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Hu, Tsung-Hui; Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, Division of Hepatogastroenterology, Department of Internal Medicine, Tu, Chia-Hung; National Taiwan University Hospital, Internal medicine Tseng, Ping-Huei; National Taiwan University Hospital, Internal Medicine Chen, Chien–Chuan; National Taiwan University Hospital, Internal Medicine Chen, Mei-Jyh; National Taiwan University Hospital, Internal medicine Liou, Jyh-Ming; National Taiwan University Hospital, Internal medicine Liao, Wei-Chih; National Taiwan University Hospital, Internal Medicine; National Taiwan University, Graduate Institute of Epidemiology and Preventive Medicine Lai, Yo-Ping; National Taiwan University Hospital, Internal medicine Wang, Chen-Ping; National Taiwan University Hospital, Ko, Jenq-Yuh; National Taiwan University Hospital, Wang, Hsiu-Po; National Taiwan University Hospital and National Taiwan University College of Medicine, Internal Medicine Chiang, Hung; Taipei Institute of Pathology, Lin, Jaw-Town; National Taiwan University, Department of Internal Medicine, College of Medicine Chen, Tony Hsiu-Hsi; National Taiwan University, Division of Biostatistics, College of Public Wu, Ming-Shiang; National Taiwan University Hospital, Internal Medicine

ly

on

Primary Subject Heading:

Gastroenterology and hepatology

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 1 of 61

Secondary Subject Heading: Keywords:

Gastroenterology and hepatology, General practice / Family practice GASTROENTEROLOGY, Endoscopy < GASTROENTEROLOGY, Adult gastroenterology < GASTROENTEROLOGY

w

ie

ev

rr

ee

rp Fo ly

on

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open


BMJ Open

Lee et al 1

Accuracy of fecal occult-blood test and Helicobacter pylori stool antigen test for detection of upper gastrointestinal lesions

Short title: Stool tests for the upper gastrointestinal lesions

rp Fo

Authors and affiliations:

Yi-Chia Lee MD,1, 2 Han-Mo Chiu MD,1, 2 Tsung-Hsien Chiang MD,1, 3 Amy Ming-Fang Yen

ee

PhD,4 Sherry Yueh-Hsia Chiu PhD,5 Sam Li-Sheng Chen PhD,4 Jean Ching-Yuan Fann PhD,6 Yen-Po Yeh MD,7 Chao-Sheng Liao MD,8 Tsung-Hui Hu MD,9 Chia-Hung Tu MD,1

rr

Ping-Huei Tseng MD,1 Chien-Chuan Chen MD,1 Mei-Jyh Chen MD,1, 3 Jyh-Ming Liou MD,1, 2

ev

Wei-Chih Liao MD,1, 2 Yo-Ping Lai MD,1 Chen-Ping Wang MD,10 Jenq-Yuh Ko MD,10

ie

Hsiu-Po Wang MD,1 Hung Chiang MD,11 Jaw-Town Lin MD,1, 8, 12, 13 Hsiu-Hsi Chen PhD,2, 14

Ming-Shiang Wu MD,1, 14

w

1.

ly

on

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 61

Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

2.

Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan

3.

Department of Integrated Diagnostic and Therapeutics, National Taiwan University


Page 3 of 61

Lee et al 2 Hospital, Taipei, Taiwan 4.

School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan

5.

Department and Graduate Institute of Health Care Management, Chang Gung University, Tao-Yuan, Taiwan

6.

rp Fo

Department and Graduate Institute of Health Care Management, Kainan University, Tao-Yuan, Taiwan

ee

7.

Changhua County Public Health Bureau, Changhua County, Taiwan

8.

Division of Gastroenterology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

9.

ev

rr

Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang

ie

Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

w on

10.

Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

11.

Taipei Institute of Pathology, Taipei, Taiwan

12.

School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

13.

Department of Internal Medicine, E-Da Hospital, Kaohsiung County, Taiwan

14.

Drs H. H. Chen and M. S. Wu contributed equally to this article.

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open


BMJ Open

Lee et al 3

Correspondence to: Hsiu-Hsi Chen, PhD Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan Room 533, No. 17, Hsuchow Road, Taipei, Taiwan

rp Fo

Tel: +886-2-33668033, Fax: +886-2-23587707 E-mail: [email protected]

ee

and Ming-Shiang Wu, MD, PhD

Department of Internal Medicine and Department of Primary Care Medicine, National

rr

Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan

ev

Telephone: +886-2-23123456 ext. 65410, Fax: +886-2-23947899 E-mail: [email protected]

w

ie on

Keywords: Diagnostic accuracy, guaiac-based fecal-occult blood test, fecal immunochemical test, Helicobacter pylori stool antigen test

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 61

Word count: abstract: 281; text: 3682 (main text only; this does not include the title page, abstract, figure/table legends, and references.)


Page 5 of 61

Lee et al 4

Licence Statement: I, Ming-Shiang Wu, the Corresponding Author of this article contained within the original manuscript which includes any diagrams & photographs, other illustrative material, video, film or any other material howsoever submitted by the Contributor(s) at any time and related to the Contribution (“the Contribution”) have the right to grant on behalf of all authors and do grant on behalf of all authors, a licence to the BMJ Publishing Group Ltd

rp Fo

and its licensees, to permit this Contribution (if accepted) to be published in BMJ Open and any other BMJ Group products and to exploit all subsidiary rights, as set out in the licence at:

ee

(http://group.bmj.com/products/journals/instructions -for-authors/BMJOpen_licence.pdf)

w

ie

ev

rr ly

on

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open


BMJ Open

Lee et al 5

ABSTRACT Objective: Highly sensitive guaiac-based fecal occult-blood (Hemoccult SENSA) and Helicobacter pylori stool antigen testing might help detect upper gastrointestinal lesions when appended to a colorectal cancer screening program with fecal immunochemical testing; We evaluated the diagnostic accuracies of two stool tests in detecting upper gastrointestinal

rp Fo

lesions.

Design: Cross-sectional design.

ee

Setting: Hospital- and community-based screening settings. Participants: A hospital-based deviation cohort of 3172 subjects to evaluate test

rr

performance and a community-based validation cohort of 3621 to verify the findings.

ev

Interventions: Three types of stool tests with bidirectional endoscopy as the reference standard.

w

ie

Outcomes: Sensitivity, specificity, and positive and negative likelihood ratios.

on

Results: For detecting upper gastrointestinal lesions in cases with negative immunochemical

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 61

tests, the sensitivity, specificity, and positive and negative likelihood ratios of the guaiac-based and H. pylori antigen tests were 16.3% (95% confidence interval: 13.3–19.8%), 90.1% (88.9–91.2%), 1.64 (1.31–2.07), and 0.93 (0.89–0.97), respectively, and 52.5% (48.1–56.9%), 80.6% (79.0–82.1%), 2.71 (2.41–3.04), and 0.59 (0.54–0.65), respectively. For detecting upper gastrointestinal lesions in cases with normal colonoscopy, the results of the


Page 7 of 61

Lee et al 6 guaiac-based and H. pylori antigen tests were 17.9% (14.8–21.5%), 90.1% (88.9–91.2%), 1.81 (1.45–2.26), and 0.91 (0.87–0.95), respectively, and 53.1% (48.6–57.4%), 80.7% (79.1–82.2%), 2.75 (2.45–3.08), and 0.58 (0.53–0.64), respectively. Within the community, positive predictive values of the immunochemical and H. pylori antigen tests were 36.0% (26.0–46.0%) and 31.9% (28.3–35.5%), respectively, for detecting lower and upper

rp Fo

gastrointestinal lesions, which were similar to expected values. Conclusion: The H. pylori stool antigen test is more accurate than the guaiac-based test in

ee

the screening of upper gastrointestinal lesions in a population with prevalent H. pylori infection and upper gastrointestinal lesions.

rr

Trial registration: NCT01341197 (ClinicalTrial.gov)

ie

ev

ARTICLE SUMMARY Article focus

on

w

Fecal occult-blood tests include guaiac-based tests and immunochemical tests; the

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open

former looks for heme while the latter looks for globin. Because globin can be digested by enzymes in the upper gastrointestinal tract, the immunochemical test is more specific to colorectal diseases.

To differentiate lesions in the upper gastrointestinal tract from lesions in the lower gastrointestinal tract, the highly sensitive guaiac-based test (Hemoccult SENSA)


BMJ Open

Lee et al 7 combined with the fecal immunochemical test may be helpful.

In addition to the highly sensitive guaiac-based test, the Helicobacter pylori stool antigen test may be an alternative choice for mass screening because H. pylori is well-known as a major cause of peptic ulcers and gastric cancer.

Key messages

rp Fo

In subjects with normal colonoscopies, the highly sensitive guaiac-based test can detect occult blood from the upper gastrointestinal tract in approximately one-fourth of

ee

cancerous lesions and the detectability increases with cancer stage.

In subjects with negative immunochemical tests or normal colonoscopies, the H. pylori

rr

stool antigen test is more accurate than the highly sensitive guaiac-based test in the

ev

detection of upper gastrointestinal lesions.

ie

In the community setting, it is applicable to add the H. pylori stool antigen test into the

w

colorectal cancer screening with the fecal immunochemical test. Strengths and limitations of this study

ly

on

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 61

This is the first study to determine the diagnostic accuracy of commercially available stool tests in the detection of upper gastrointestinal lesions.

Further randomized controlled trials are needed to confirm the long-term efficacy and cost-effectiveness of using a two-in-one strategy to simultaneously screen for upper and lower gastrointestinal lesions.


Page 9 of 61

Lee et al 8

INTRODUCTION Upper and lower gastrointestinal diseases have an impact on global health and economics.[1, 2] Although mass screening can detect early lesions,[3] coordination of different methods to simultaneously screen lesions at different depths is required.[4] Thus, an efficient alternative screening method is needed.

rp Fo

A campaign against colorectal cancer has suggested that the use of fecal occult-blood tests can efficiently reach the population and decrease mortality.[5] Fecal occult-blood tests

ee

include guaiac-based test and fecal immunochemical test (FIT); the former test measures heme, while the latter test measures globin. Because globin can be digested by enzymes in

rr

the upper gastrointestinal tract,[6] the guaiac-based test combined with the immunochemical

ev

test may help differentiate lesions in the upper gastrointestinal tract from lesions in the lower gastrointestinal tract.[7, 8]

w

ie

Other than occult blood, stool tests detecting molecular markers are under continuous

on

development; however, most stool tests are not widely available commercially.[9] One

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open

exception is the Helicobacter pylori stool antigen test (HPSA) because H. pylori is well-known as a major cause of peptic ulcers and gastric cancer.[10] As the absolute number of patients with gastric cancer is increasing due to advancing age of the global population,[11] it makes sense to combine 2 specific tests (HPSA and FIT) into 1 panel for the detection of both upper and lower gastrointestinal lesions.


BMJ Open

Lee et al 9 In Taiwan, the incidence of colorectal cancer is rapidly increasing, and upper gastrointestinal pathologies remain highly prevalent.[12] Beginning in 2004, the Taiwanese Government initiated a nationwide colorectal cancer screening program using biennial FIT.[13] Thus, a unique opportunity exists to evaluate the diagnostic accuracies of the guaiac-based and HPSA for detecting upper gastrointestinal lesions, which was the primary

rp Fo

aim of our study.

ee

METHODS

STUDY DESIGN

rr

We recruited consecutive subjects from the hospital- and community-based screening

ev

sources; the former (deviation cohort) was used to evaluate the test performance and the latter

ie

(validation cohort) was to confirm the reproducibility and applicability of the screening

w

strategy in the community. All participants provided signed informed consent before

on

enrollment. Both studies were approved by the Hospital Institutional Review Board (numbers IRB201101016RC and 201205030RIB).

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 61

DEVIATION COHORT Recruitment of study subjects First, beginning on 1 March 2011, we recruited participants at the National Taiwan


Page 11 of 61

Lee et al 10 University Hospital (Health Management Center; Taipei, northern Taiwan) through advertising messages for cancer screening. Participants >18 years of age who had completed the FIT, guaiac-based test, HPSA, and bidirectional endoscopy were included. To enrich the deviation cohort with the sample of gastrointestinal tract cancers, we also recruited subjects in whom gastrointestinal tract cancers were suspected by the non-invasive screening test,

rp Fo

such as the radiology and oral inspection, at the Gastroenterologic or Otolaryngologic Clinics at National Taiwan University Hospital. Research staff recruited participants by explaining

ee

the purpose and eligibility requirements of the study. The participants were requested to complete 3 types of stool tests and undergo bidirectional endoscopy; however, those

rr

participants who underwent only 1 endoscopy for detection of a cancerous lesion were still

ev

eligible because it was rare (approximately 0.9%) for 1 subject to have important lesions in

ie

both the upper and lower gastrointestinal tracts in the cancer screening group. All of the stool

w

samples were collected before confirmatory endoscopic diagnoses were available.

on

In the deviation cohort, we ensured that bleeding was occult by excluding those

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open

participants who had overt gastrointestinal bleeding, including hematemesis, tarry stools, melena, or hematochezia. We also excluded subjects with histories of a gastrectomy and/or colectomy, and pregnant or lactating women. Stool tests Ten days before cancer screening, we mailed 1 collection card for the highly sensitive


BMJ Open

Lee et al 11 guaiac-based test (Hemoccult SENSA Single Slides; Beckman Coulter, Inc., USA), and 2 sampling tubes for the HPSA (Easy One Step Test; Firstep Bioresearch, Inc., Taiwan) and the FIT (OC-SENSOR; Eiken Chemical Co., Ltd., Tokyo, Japan) to eligible subjects. We used the one-day method for all stool tests and advised participants to start diet and drug restrictions 3 days before they obtained the stool samples and to obtain stool samples within 2

rp Fo

days before starting the bowel preparation. Stool samples were brought to the hospital on the screening day and tested immediately. Two technicians executed the guaiac-based and H.

ee

pylori stool antigen tests and read the results independently; disagreements were resolved by consensus. For the cancer group, they were also requested to follow the same rule for stool

ev

sample collection.

rr

The sensitivity and specificity of the HPSA for the determination of H. pylori infection

ie

status were 88% and 99%, respectively.[14] The FIT was processed at the hospital central

w

laboratory using an automated reader and the cutoff concentration was set at 100 nanograms

on

of hemoglobin per milliliter of buffer (equivalent to 20µg hemoglobin per gram of feces).[15] Bidirectional endoscopy

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 61

Endoscopic findings and histologic results served as the reference standard. Participants were given polyethylene glycol for bowel preparation, which they drank at least 4 hours before endoscopic examinations. This bowel preparation scheme had been shown with less than 5% poor or inadequate preparation in our population.[16] The participants were advised


Page 13 of 61

Lee et al 12 to stop anticoagulant or antiplatelet therapy for 7 days. Esophagogastroduodenoscopy and colonoscopy were performed by 9 experienced endoscopists, each with a minimum experience of 5000 colonoscopies. Endoscopic findings were recorded electronically with information on quality of preparation, completeness of colonoscopy, endoscopic findings, and whether or not a biopsy was performed. Subjects who declined endoscopy or had an

rp Fo

incomplete colonoscopy, including failed cecal intubation and poor bowel preparation, were excluded.

ee

Definition of the important lesions

Lesions consistent with occult bleeding were defined as important, and were classified into

rr

three major categories, as follows in flow diagrams: neoplastic; inflammatory; and

ev

vascular.[7, 17] Important upper gastrointestinal lesions included cancer, an ulcer >0.5

ie

centimeters in diameter, reflux esophagitis with a severity of Los Angeles grade C or D,[18]

w

Barrett’s esophagus, esophageal varix with a severity of grade II or III,[19] and gastric antral

on

vascular ectasia. Gastritis and ulcer scars were not included. Important lower gastrointestinal

ly

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open

lesions included colorectal cancer, advanced adenomas, ulcers or colitis, and angiodysplasia. An advanced adenoma was defined as >10 millimeters in diameter or having a villous component or high-grade dysplasia.[11] Adenomas 18 years of age who had completed

2

the FIT, guaiac-based test, HPSA, and bidirectional endoscopy were included. Cancer

3

detection was the main purpose of the stool test; a small sample of cancers was obtained from

4

a single site. To enrich the deviation cohort with the sample of gastrointestinal tract cancers,

5

we also recruited subjects in whom gastrointestinal tract cancers were suspected by the

6

non-invasive screening test, such as the radiology and oral inspection, at the

7

Gastroenterologic or Otolaryngologic Clinics at National Taiwan University Hospital.

8

Research staff recruited participants by explaining the purpose and eligibility requirements of

9

the study. The participants were requested to complete 3 types of stool tests and undergo

rr

ee

rp Fo

10

bidirectional endoscopy; however, those participants who underwent only 1 endoscopy for

11

detection of a cancerous lesion were still eligible because it was rare (approximately 0.9%)

12

for 1 subject to have important lesions in both the upper and lower gastrointestinal tracts in

13

the cancer screening group. All of the stool samples were collected before confirmatory

14

endoscopic diagnoses were available.

w

ie

ly

on

15

ev

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open


16

participants who had overt gastrointestinal bleeding, including hematemesis, tarry stools,

17

melena, or hematochezia. We also excluded subjects with histories of a gastrectomy and/or

18

colectomy, and pregnant or lactating women.

19

Stool tests


BMJ Open

Lee et al 11 1

Ten days before cancer screening, we mailed 1 collection card for the highly sensitive

2

guaiac-based test (Hemoccult SENSA Single Slides; Beckman Coulter, Inc., USA), and 2

3

sampling tubes for the HPSA (Easy One Step Test; Firstep Bioresearch, Inc., Taiwan) and the

4

FIT (OC-SENSOR; Eiken Chemical Co., Ltd., Tokyo, Japan) to eligible subjects. We used

5

the one-day method for all stool tests and advised participants to start diet and drug

6

restrictions 3 days before they obtained the stool samples and to obtain stool samples within 2

7

days before starting the bowel preparation. Stool samples were brought to the hospital on the

8

screening day and tested immediately. Two technicians executed the guaiac-based and H.

9

pylori stool antigen tests and read the results independently; disagreements were resolved by

rr

ee

rp Fo

10

consensus. For the cancer group, they were also requested to follow the same rule for stool

11

sample collection.

ie

ev

12


13


14


15

of hemoglobin per milliliter of buffer (equivalent to 20µg hemoglobin per gram of feces).[14]

16

Bidirectional endoscopy

ly

on

17

w

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 109

Endoscopic findings and histologic results served as the reference standard. Participants

18

were given polyethylene glycol for bowel preparation, which they drank at least 4 hours

19

before endoscopic examinations. This bowel preparation scheme had been shown with less


Page 13 of 109

Lee et al 12 1

than 5% poor or inadequate preparation in our population.[15] The participants were advised

2

to stop anticoagulant or antiplatelet therapy for 7 days. Esophagogastroduodenoscopy and

3

colonoscopy were performed by 9 experienced endoscopists, each with a minimum

4

experience of 5000 colonoscopies. Endoscopic findings were recorded electronically with

5

information on quality of preparation, completeness of colonoscopy, endoscopic findings, and

6

whether or not a biopsy was performed. Subjects who declined endoscopy or had an

7

incomplete colonoscopy, including failed cecal intubation and poor bowel preparation, were

8

excluded.

9


rr

ee


ev

10

rp Fo

11


12


13


14


15


16

lesions included colorectal cancer, advanced adenomas, ulcers or colitis, and angiodysplasia.

17

An advanced adenoma was defined as >10 millimeters in diameter or having a villous

18

component or high-grade dysplasia.[11] Adenomas 18 years of age who had completed

2

the FIT, guaiac-based test, HPSA, and bidirectional endoscopy were included. Cancer

3

detection was the main purpose of the stool test; a small sample of cancers was obtained from

4

a single site. To enrich the deviation cohort with the sample of gastrointestinal tract cancers,

5

we also recruited subjects in whom gastrointestinal tract cancers were suspected by the

6

non-invasive screening test, such as the radiology and oral inspection, at the

7

Gastroenterologic or Otolaryngologic Clinics at National Taiwan University Hospital.

8

Research staff recruited participants by explaining the purpose and eligibility requirements of

9

the study. The participants were requested to complete 3 types of stool tests and undergo

rr

ee

rp Fo

10

bidirectional endoscopy; however, those participants who underwent only 1 endoscopy for

11

detection of a cancerous lesion were still eligible because it was rare (approximately 0.9%)

12

for 1 subject to have important lesions in both the upper and lower gastrointestinal tracts in

13

the cancer screening group. All of the stool samples were collected before confirmatory

14

endoscopic diagnoses were available.

w

ie

ly

on

15

ev

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

BMJ Open


16

participants who had overt gastrointestinal bleeding, including hematemesis, tarry stools,

17

melena, or hematochezia. We also excluded subjects with histories of a gastrectomy and/or

18

colectomy, and pregnant or lactating women.

19

Stool tests


BMJ Open

Lee et al 11 1

Ten days before cancer screening, we mailed 1 collection card for the highly sensitive

2

guaiac-based test (Hemoccult SENSA Single Slides; Beckman Coulter, Inc., USA), and 2

3

sampling tubes for the HPSA (Easy One Step Test; Firstep Bioresearch, Inc., Taiwan) and the

4

FIT (OC-SENSOR; Eiken Chemical Co., Ltd., Tokyo, Japan) to eligible subjects. We used

5

the one-day method for all stool tests and advised participants to start diet and drug

6

restrictions 3 days before they obtained the stool samples and to obtain stool samples within 2

7

days before starting the bowel preparation. Stool samples were brought to the hospital on the

8

screening day and tested immediately. Two technicians executed the guaiac-based and H.

9

pylori stool antigen tests and read the results independently; disagreements were resolved by

rr

ee

rp Fo

10

consensus. For the cancer group, they were also requested to follow the same rule for stool

11

sample collection.

ie

ev

12


13


14


15

of hemoglobin per milliliter of buffer (equivalent to 20µg hemoglobin per gram of feces).[14]

16

Bidirectional endoscopy

ly

on

17

w

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 60 of 109

Endoscopic findings and histologic results served as the reference standard. Participants

18

were given polyethylene glycol for bowel preparation, which they drank at least 4 hours

19

before endoscopic examinations. This bowel preparation scheme had been shown with less


Page 61 of 109

Lee et al 12 1

than 5% poor or inadequate preparation in our population.[15] The participants were advised

2

to stop anticoagulant or antiplatelet therapy for 7 days. Esophagogastroduodenoscopy and

3

colonoscopy were performed by 9 experienced endoscopists, each with a minimum

4

experience of 5000 colonoscopies. Endoscopic findings were recorded electronically with

5

information on quality of preparation, completeness of colonoscopy, endoscopic findings, and

6

whether or not a biopsy was performed. Subjects who declined endoscopy or had an

7

incomplete colonoscopy, including failed cecal intubation and poor bowel preparation, were

8

excluded.

9


rr

ee


ev

10

rp Fo

11


12


13


14


15


16

lesions included colorectal cancer, advanced adenomas, ulcers or colitis, and angiodysplasia.

17

An advanced adenoma was defined as >10 millimeters in diameter or having a villous

18

component or high-grade dysplasia.[11] Adenomas