PONE-D-22-10820Association between breastfeeding, host genetic factors, and calicivirus gastroenteritis in a Nicaraguan birth cohortPLOS ONE

Dear Dr. Vielot,

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.

This manuscript was evaluated by three reviewers whose comments are included below. Overall, the reviewers provided positive feedback but requested revisions to address points pertaining to reporting and aspects of the data analyses and results. Please address all of the reviewers' comments through revisions to your manuscript.

Please submit your revised manuscript by Oct 11 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,

Renee Hoch, Ph.D.

Managing Editor, PLOS Publication Ethics

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for stating in your Funding Statement: 

"This study was supported by award R01AI127845 from the National Institute of Allergy and Infectious Diseases (NIAID). SBD is supported by K24AI141744 from NIAID; FG, YR, and LG are supported by an international research capacity-building award from the NIH-Fogarty International Center, D43TW010923. "

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. 

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

5. 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.

[Note: HTML markup is below. Please do not edit.]

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: Yes

********** 

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

********** 

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: No

Reviewer #3: No

********** 

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

********** 

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: PONE-D-22-10820

This study provides important information on associations between breastfeeding and acute gastroenteritis (AGE) caused by norovirus and sapovirus among children in a birth cohort in Leon, Nicaragua. This study has very rich weekly data on breastfeeding and AGE and monthly data on other risk factors, enabling the authors to conduct a time-varying Cox hazard analysis. Results are interesting. Some of them align with previous findings and others don’t, and the authors provide good discussion on each point, which was helpful. I have a few comments.

Results

- Regarding the protective effect of the consumption of high-risk foods and eating food outside, I agree that it is surprising. The authors discuss potential reasons behind this in the Discussion, which was helpful. Could you also include an interaction term between the variable for the comsumption of high-risk foods and the variable for the socioeconomic status in your Cox hazard model? That might be helpful in interpreting the relationship.

Discussion

- I do not know any background in Nicaragua, and did not understand why exclusive breastfeeding was associated with travel time to a health center. What does a health center/post do with breastfeeding?

- Are there any studies or articles you could cite about cultural and social factors associated with short-term exclusive breastfeeding that you talked about in LIne 236-238 (e.g., prolonged breastfeeding negatively affecting breast shape and volume)?

- I guess a natural question from readers would be “so what about other pathogens tested in this study?” but I guess the authors have a plan to write another report on that.

Reviewer #2: In this study, Vielot and coauthors analyzed the association between breastfeeding practices, child/mother genetic factors, and norovirus/sapovirus AGE using a birth cohort data obtained in Nicaragua. Authors found strong associations between child secretor status and norovirus infections in their first year of life but authors could not find conclusive evidence of associations between breastfeeding and protection against AGE caused by norovirus and sapovirus due to a limited sample size and the fact that majority of mothers performed exclusive breastfeeding for only a few weeks.

While this study could not provide conclusive evidence of associations between breastfeeding and viral AGE, findings provided in this study are important to further conduct and understand the roles of exclusive and non-exclusive breastfeeding on norovirus/sapovirus AGE. Thus, it implies that non-exclusive breastfeeding may not protect children from norovirus/sapovirus AGE, and warrants further studies with different population where exclusive breastfeeding is performed commonly for a long duration or under the lactation support. Please find below the comments/suggestions to improve the manuscript before publication.

1. Authors claimed that "most norovirus episodes occurred among secretor positive and Lewis positive children...", but it could be confusing and mislead an incorrect conclusion as most of the children enrolled and studied in this cohort were secretor positive and Lewis positive. In fact, authors analyzed the HR with host genetic factors in Table 3 to show that there is no association between Lewis profiles and norovirus/sapovirus AGE. I would suggest to rephrase the section "Maternal and child HBGA profiles" or omit or combine this section with the next section.

2. One of the interesting findings in this study is that they did not find any associations between host genetic factors (neither secretor nor Lewis) and sapovirus AGE. Is there any other studies that indicate the roles (or no roles) of host genetic factors on sapovirus infections? If so please consider to include findings from such previous studies and provide more discussions on the roles of secretor status on sapovirus infections.

3. Another interesting observation is that consumption of high-risk foods was protective against sapovirus AGE. Authors suggested that it could be due to confounding factors such as nutritional practices or socioeconomic status, and I agree with authors but please also consider the epidemiological observations that foodborne ourbreaks are less common in sapovirus as compared to norovirus. I believe there is no conclusive evidence on the risk of food consumption on sapovirus AGE, but if the risk is lower in sapovirus than in norovirus, it may explain the differences of the observation between norovirus AGE and sapovirus AGE in this study. Thus, it showed significant protective associations only among sapovirus AGE but not in norovirus AGE as food consumption could work as a risk factor only (or more) in norovirus AGE.

4. I understand typing of host genetic factors was performed in their previous study, but please consider to describe again in this manuscript how the host genetic factors were determined in the method section.

Reviewer #3: Violet et al studied the association between calicivirus AGE and exclusive breastfeeding or host HBGA status in a Nicaragua birth cohort from June 2017 to July 2018. This study was very well planned out and its findings on how maternal and child secretor status influences norovirus disease risk is not unexpected, nevertheless very interesting. This manuscript is very well written.

Minor questions and comments:

Were there seasonal trends in sapovirus and norovirus positivities? Were they consistent with what's typically seen in the region?

Line 181-182, diarrhea lasting more than 7 days is not considered as acute gastroenteritis in most clinical definitions. Consider reword/or update definition of AGE in methods.

Line 201-202, If secretor positive were a dominate trait, it would means 3/4 progeny would have the trait from AaXAa heterozygous parents, all progeny if one parent is AA and 1/2 if from AaXaa parents. I wouldn't call it surprising to see more secretor positive children than mothers. Also, it is a bit more complicated than a simple Mendelian hereditary pattern since there are weak secretor alleles that are semi-functional. I would suggest not to get into the genetics of HBGA here.

********** 

6. 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

Reviewer #3: No

**********

[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.

Association between breastfeeding, host genetic factors, and calicivirus gastroenteritis in a Nicaraguan birth cohort

PONE-D-22-10820R1

Dear Dr. Vielot,

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. Please let me disclose that I participated as a reviewer for the initial evaluation of this manuscript, and now I am working as an Academic Editor to make this decision. As an editor, I have a very minor comment and I would suggest to clarify the terms, socioeconomic status and nutrition, in the manuscript. I believe you used the presence of a toilet (a surrogate measure of house income) as socioeconomic status and consumption of specific food as nutrition, but it is not clearly explained in the method section. 

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Kentaro Tohma

Guest Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: