PONE-D-21-19578Diagnostic performances of serum Pepsinogens and Gastrin-17 for atrophic gastritis and gastric cancer in Mongolian subjectsPLOS ONE

Dear Dr. Lonjid,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Muhammad Tarek Abdel Ghafar, M.D

Academic Editor

PLOS ONE

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Additional Editor Comments:

The sample size appears to be small. Please add a justification for the sample size used in this study.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript entitles "Diagnostic performances of serum pepsinogens and Gastrin-17 for atrophic gastritis and gastric cancer in Mongolian subjects" by Dondov G et. al have assessed the efficacy of serum pepsinogens and gastrin-17 levels as biomarkers for gastric cancer in Mongolia. It is a well-reported phenomenon that serum pepsinogens and Gastrin-17 exhibit the potential to be used as diagnostic markers for gastric cancer. Given the discomfort associated with endoscopy, serum markers can pave the way for an easy diagnosis of the disease. This article provide novel insights about the levels of pepsinogens and gastric-17 in Mongolian population which has not been studied yet. The only serious drawback or limitation of the study is its small population size, which the authors have mentioned.

I would recommend this paper for publication.

Reviewer #2: The topic is important and the manuscript is well-structured.

-Please provide a reference for the score used to combine the biomarkers with other risk factors.

-The sensitivity and specificity is relatively low, even after applying the score. I think this is not sufficient to reach this conclusion.

Reviewer #3: This is an interesting paper in some regards. The authors selection of a matched case study was good, the study arms are balanced and well controlled.

Unfortunately, there are a number of issues with the study results and interpretation, listed below:

1. The data plotted in Figure 1 demonstrate a very substantial overlap between the control population and the two disease populations, Atrophic Gastritis and Gastric Cancer. The graph of the PGR biomarker (pepsinogen ratios) shows a believable trend towards decrease with advancing disease. This is known from the literature. The data presented here and in Table 2, although showing a "significant" statistical difference in the populations, demonstrate that the serum assay cannot distinguish the benign from malignant disease. The data in both the figure and table demonstrate a very low clinical sensitivity for separation of the two disease populations from the healthy population.

2. The authors proposed a combined biomarker using 4 scoring factors. This is an interesting approach. However, not enough data was provided on the application of the 4 factor biomarker score on this study. A Table and Figure covering the population data set for all patients for the proposed marker should be included.

3. There is a Figure 2 in the manuscript, showing ROC plots for the two biomarkers selected for analysis, PGI (serum pepsinogen I) and PGR (serum pepsinogen I-II ratios). The plots appear to show a somewhat better performance of the markers when comparing gastric cancer to normal vs gastric atrophy to normal. The tabular analysis demonstrates that the serum marker levels will not distinguish the two diseases. Therefor the authors need to provide a cogent argument on how the serum assay would actually be useful in the clinic and what would be the benefit of a low sensitivity biomarker assay that cannot distinguish benign from malignant disease; the authors point out the lack of available endoscopy facilities in Mongolia but also point out that only pathology workup can distinguish benign from cancerous lesions; does this mean that endoscopy is unlikely to be useful or will endoscopy replace the serum assay in most circumstances due to better capability of separating normal from diseased (benign plus cancer) populations.

Other items to be addressed:

Line 80; Solution is misspelled

Line 96; change wording to "following the manufacturer's package insert"

Line 105; automatically washed, this probably means with a plate washer; please specify including model used

Lines 138-144; demonstrate that there is not an adequate rationale for including the PG-II and G17 measurements in the data analyses

Line 162-164; given that there is no measurable difference across the populations for PG-II and G17, there inclusion to make the data more statistically significant is not justified

Table 2; there are two columns labelled as positive likelihood ratio. presumable one should be labelled negative; this reviewer does not understand what the authors mean by a positive likelihood ratio. is this just that the biomarker is positive or is this a probability of disease. if the latter, is it restricted to cancer or is it either benign or cancer.

Line 225; the high background incidence of H pylori in Mongolia is a critical factor in understanding this study; this sentence should be moved to the introduction.

Lines 252-272; this paragraph is unnecessarily long and redundant, and should be reworked.

Line 280 is unsupported by the data presented, and yet is likely the most important outcome of this study if true.

Reviewer #4: Review: PONE-D-21-19578

The authors reported the levels of PG1, PGR, Gastrin-17 as diagnostic markers for gastric cancer in the

Mongolian subjects. The authors used the GastroPanel (ELISA, BioHit) to measure the levels of these

three molecules and H. pylori IgG. GastroPanel has been extensively used to identify healthy gastric

mucosa, H. pylori infection, anacidic stomach, atrophic gastritis and guide risk patients to gastroscopy.

These four molecules have been extensively studied in the Asian population due to high prevalence of

gastric cancer in this geography. The authors reported the H. pylori positive (58.8%) in the study groups

but did not incorporate H. pylori results as a risk factor for chronic atrophic gastritis or gastric cancer. H.

pylori IgG, age, gender, and smoking status have been reported as risk factors for gastric cancer. The

authors did not cite either old or recent publications describing these four molecules for gastric cancer,

for examples:

1) Cao et al. (2007) in Journal of Digestive Disease, “Screening of atrophic gastritis and gastric cancer by

serum pepsinogen, gastrin-17 and Helicobacter pylori immunoglobulin G antibodies”, where H. pylori

IgG results were also incorporated in the analyses with PGI and PGR. These authors reported the

significant increase in G-17 in the gastric cancer group.

2) Reviewed publications, Kim N. & Jung C. (2010) Gut Liver “The role of serum pepsinogen in the

detection of gastric cancer”.

3) Wang & Chen (2020) Scientific Reports, “Prevalence of atrophic gastritis in southwest China and

predictive strength of serum gastrin-17: A cross-sectional study (SIGES)”

4) Shen et al. (2021) Gastroenterology Research and Practice “The diagnostic value of serum gastin-17

and pepsinogen for gastric cancer screening in eastern China”.

A few highlights for authors to consider:

Line 80, “simethicone silution” should be “solution”.

Line 83, the authors described the collection of biopsies, but nowhere in the manuscript described the

results from these samples.

Line 92 of the manuscript “The fasting blood samples were collected in an EDTA tube from all subjects.”

The presence of EDTA as anticoagulant in the tube is for plasma collection, not serum, as the authors

used “serum” throughout the manuscript.

Line 224, “In this study, H. pylori IgG was not associated with atrophic gastritis and gastric cancer”.

Nowhere in the manuscript the authors described the analyses for PGI, PGR, and G-17 relative to H.

pylori IgG positive and negative subgroups.

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Reviewer #1: No

Reviewer #2: Yes: Dina M. El-Guindy

Reviewer #3: No

Reviewer #4: No

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PONE-D-21-19578R1Diagnostic performances of Pepsinogens and Gastrin-17 for atrophic gastritis and gastric cancer in Mongolian subjectsPLOS ONE

Dear Dr. Lonjid,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 14 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Tarek Abdel Ghafar, M.D

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Please provide a reference for similar scoring.

Why the score variables are different regarding AG and GC?

The score used need to be clearly mentioned in the methods section.

The aim and title need to be modified as the authors didn't evaluated pepsinogen and gastrin 17 alone.

Reviewer #3: (No Response)

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

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PONE-D-21-19578R2Diagnostic performances of Pepsinogens and Gastrin-17 for atrophic gastritis and gastric cancer in Mongolian subjectsPLOS ONE

Dear Dr. Lonjid,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 26 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Tarek Abdel Ghafar, M.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Please resubmit the revised manuscript and point-by-point response files while deleting any redundant files from the previous revisions.

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Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-21-19578R3Diagnostic performances of Pepsinogens and Gastrin-17 for atrophic gastritis and gastric cancer in Mongolian subjectsPLOS ONE

Dear Dr. Lonjid,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Tarek Abdel Ghafar, M.D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors didn't provide a reference for the used score.

Have the authors proposed this score?

If so, then the conclusion needs to be modified as they are not evaluating a well established score.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Dina M. El-Guindy

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Diagnostic performances of Pepsinogens and Gastrin-17 for atrophic gastritis and gastric cancer in Mongolian subjects

PONE-D-21-19578R4

Dear Dr. Lonjid,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Muhammad Tarek Abdel Ghafar, M.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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