PONE-D-20-17227

Prediction of true Helicobacter pylori uninfected status by using a combination of Helicobacter pylori antibody, serum pepsinogen, and other factors: Logistic regression analysis

PLOS ONE

Dear Dr. Suzuki,

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.

Prediction of a condition without invasive procedures is always interesting. I myself have also worked with that problem years back (Borch, K., Axelsson, C. K., Halgreen, H., Nielsen, M. D., Ledin, T., & Szesci, P. B. (1989). The ratio of pepsinogen A to pepsinogen C: a sensitive test for atrophic gastritis. Scandinavian journal of gastroenterology, 24(7), 870-876; Burman, P., Karlsson, F. A., Lööf, L., Szecsi, P. B., & Borch, K. (1991). H+ K+-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia. Scandinavian journal of gastroenterology, 26(2), 207-214) however gastroscopy is still the choice.

A predictive model has rather stick demands, especially with sensitivity if invasive procedure could be avoided. I would like a discussion on negative predictive value in light of the relative low incidence of the disease, even in higher risk areas.

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Pal Bela Szecsi, M.D. D.M.Sci.

Academic Editor

PLOS ONE

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Reviewers' comments:

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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: Partly

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: Yes

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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: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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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 is an interesting study which to discriminate uninfected individuals from the subjects with past or current Hp infection “without endoscopic examination”. These are suggestions to improve the manuscript.

Major comments:

1. Main flaw of this study is the discrepancy found between the results and conclusions. Although uninfected subjects were younger in age, showed negative Hp serology test finding, higher serum PG I concentration, and lower PG II concentration, there is no combination of these four significant variables even in Figure 2. Because the authors stick too much to all 6 variables, it was concluded that a combination of 6 noninvasive parameters (sex, age, HP antibody, PGI, PGII and the PGI/II ratio). is useful in predicting true HP uninfected individuals without endoscopic examination. Please do not stick on comparing between the accuracies of 6 variables and 3 variables (HP antibody, PGI and PGI/II ratio).

2. Because the “true uninfected individuals” were determined by a negative stool antigen test and the lack of advanced CAG (> closed-type 1) or MG on endoscopic finding, there might be a discrepancy with the results derived by using 6 noninvasive parameters (sex, age, HP antibody, PGI, PGII and the PGI/II ratio). For clarification, the cutoff values of age, serum PG I level, and PG II level should be shown with their accuracies.

3. For better clinical application of the prediction formula, 467 subjects with past eradication should be tested as well.

Minor comments:

1. Rewrite the Methods and Results under the subheading, and please do not insert the tables and figures between the main body. Put them at the end of the manuscript.

2. The title looks less scientific because of “other factors”.

Reviewer #2: The authors developed accurate HP prediction model. The prediction model had higher sensitivity and specificity than conventional model. However, The authors did not explain the meaning of HP prediction. Accurate HP prediction model cause effective screening. The authors must discuss the usefulness of the study.

1. The purpose of ABCD classification is not only prediction of HP infection status, but also evaluation of gastric cancer risk. Risk stratification by ABCD classification might enable personalized prevention of gastric cancer. The new HP status prediction might lead better gastric cancer screening, however, nothing was described concerning gastric cancer prevention.

2. Age was one of the significant variable to predict HP infection in the study. However, some evidences suggested birth cohort (birth year) rather than age was truly associated with HP infection. I am interested in the model including birth cohort as a predictor.

3. Sex was included in the 6-parameter prediction formula, although it did not have significant impact on HP infection status. Did it improve the discriminatory ability of the model?

4. Describe a definition of sensitivity and specificity in the study. In usual case, sensitivity means a proportion of test positives among diseased subjects and specificity means a proportion of test negatives among healthy subjects. Although no definition of sensitivity and specificity in the study, I guessed a proportion of uninfected defined by test (true uninfected) among all uninfected subjects was sensitivity. Thus, the definition of sensitivity and specificity were opposite to the usual ones. It would confuse readers to assess the results.

5. The study design aimed to specify true uninfected population. Why the authors specify uninfected population by the prediction model? Some intervention would be necessary for HP infected group to prevent gastric cancer, while uninfected people do not need any help. Therefore, it is natural to find HP infected (current HP infection + spontaneously eradicated) by the prediction model.

6. Suppose the prediction model is used for gastric cancer prevention, high risk population (HP infected population) should be detected for effective screenings. Examination with high sensitivity was relevant for screening despite of relatively less specificity, because of less false negatives. As for gastric cancer screening, minimum number of cases who were HP infected but judged as HP uninfected by examinations, should be required. Were the cut-off value of 91.3% sensitivity and 89.7% specificity appropriate?

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Reviewer #1: No

Reviewer #2: No

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Prediction of true Helicobacter pylori-uninfected status using a combination of age, serum antibody and pepsinogen: Logistic regression analysis

PONE-D-20-17227R1

Dear Dr. Suzuki,

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,

Pal Bela Szecsi, M.D. D.M.Sci.

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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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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 #1: Yes

Reviewer #2: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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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 #1: Yes

Reviewer #2: (No Response)

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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 #1: No

Reviewer #2: (No Response)

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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 #1: Thank you for answering to my queries. Methods and Results are still written without subtitles, but I have nothing to mention further if it matches the journal format.

Reviewer #2: (No Response)

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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 #1: No

Reviewer #2: No