PONE-D-25-00880Dietary Factors and Predominant Eye Diseases in Sub-Saharan African Populations: A Comprehensive Systematic Review ProtocolPLOS ONE

Dear Dr. Osei Duah Junior,

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 Apr 24 2025 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,

Amin Sharifan

Academic Editor

PLOS ONE

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

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

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2. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

Additional Editor Comments:

1) As this is a protocol, please ensure all verb tenses are in the future tense.

2) Please note that PRISMA-P and other reporting guidelines are designed to improve transparency in reporting and are not 'gold standards' or guidelines for designing a study. Please revise your text accordingly. You may consult this reference for further information: 10.1186/s13643-021-01671-z.

3) There are two versions of the Cochrane risk of bias tool for randomized controlled trials. Please clearly indicate which version you will use for your analysis.

4) You have selected quite broad search platforms. I recommend omitting Google Scholar and BioMed Central from your search strategy. Google Scholar may not be an ideal platform for systematic reviews due to its broad scope and limited search functionality. Studies in BioMed Central should already be accessible through PubMed or Scopus.

5) Please consider using MeSH terms in your PubMed search.

6) I concur with the reviewers that the protocol appears rather ambitious, which could pose significant challenges during the execution of your work and potentially impede the production of a final output. In addition to the points raised by the reviewers, please consider that including both experimental and observational studies in your meta-analysis may result in substantial heterogeneity. Consequently, the findings may lack meaningful interpretation. I recommend focusing on a single study design if you intend to conduct a meta-analysis, or selecting previously mentioned study designs if you wish to proceed with a narrative synthesis of the results. For the latter, you may consider incorporating the SWiM reporting guideline in your protocol (10.1136/bmj.l6890), and the meta-analysis portion of the protocol would need to be omitted.

7) Given that you have already stated your intention to use a random effects model for meta-analysis, please articulate in the text why you would assess heterogeneity both between and within studies.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Partly

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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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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: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This protocol describes a planned systematic review with meta-analysis of the relationship between dietary factors and a set of eye diseases, focusing on studies from sub-Saharan Africa. While the aim of this protocol is important, additional clarifications are needed before this protocol is ready for publication. I've recommended this manuscript for major revisions because I appreciate the time that will be required to consider and undertake the recommended revisions. I've organized my comments below into major and minor edits:

MAJOR:

1. Overall: This review is very broad, and the design risks combining effect sizes of different sizes and directions that are ultimately examining different underlying relationships, resulting in a series of statistically null pooled effect estimates but without clearly answering the research question. Additional clarification of the hypothesis would be helpful (see details below). If the aim is to identify any single factor or a small group of individual factors (e.g., antioxidants, as suggested in the Discussion) to improve ocular health, then such a broad approach is unnecessary; it would be better to instead focus on a few individual factors informed by the primary literature (and perhaps by pre-clinical studies). If instead the aim is to identify whether a diet characterized by healthier foods can reduce the risk of ocular disease, then it may be more useful to focus on dietary patterns or at least on a few food groups (e.g., fruits and vegetables, which are good sources of antioxidants).

2. Additional clarification is required to explain why another review on this topic is needed given the substantial number of other systematic reviews that show no statistically significant relationship or unclear conclusions and what we will learn from a new review that is specific to the region of sub-Saharan Africa. You clearly describe the higher prevalence of ocular diseases in this region and also the relatively lower diversity/quality of diets in this region. Please describe for readers how those 2 factors will result in a different/stronger conclusion in your proposed review. For example, is your hypothesis that these factors will give this review an improved signal-to-noise ratio, and thus greater ability to identify an effect?

3. As part of the clarification requested above, please shorten the Background to focus on the set-up to the review objective. At present, the included content is interesting, but some of it detracts from the main message.

4. Population: This section suggests that only participants with ocular diseases will be included, but the Outcomes section indicates that incidence rates will be considered. Please clarify either that the population are those at risk of ocular disease or the general population, or remove incidence from the outcomes.

5. Please describe how a medical librarian has/will contribute to the development of the search and/or peer review the search terms.

6. Data Analysis: Please describe how you will address evidence that cannot be meta-analyzed and which moderating variables you will examine. For the meta-regression, how do you propose grouping ages? Are there any other variable you will examine via subgroup analyses? Will all dietary factors be modeled together? It's not clear that all included factors listed are capturing the same biological pathway(s).

7. Measures of effect: Please describe how you will analyze the outcomes. Will you examine each of the above-mentioned diseases separately? How will you address the secondary outcomes? If so, that's a lot of models. If they are not truly independent, then p<0.05 may not be an appropriate cut-off for statistical significance.

MINOR:

1. Bridget Senya Boateng, Moses Awuni, and Dr Mary Adjepong listed in PROSPERO registration, but not here. If they have not met the criteria for authorship, please clarify their roles, using the Acknowledgement section if needed.

2. Background, Page 4, last paragraph: Please remove reference #47 from “with most reviews showing no significant association[46-49]” because it is not a review.

3. Intervention, Page 7, first paragraph, last sentence “to decrease either the prevalence, incidence, severity, and progression of the predominant eye diseases (cataract, uncorrected refractive errors, glaucoma, diabetic retinopathy, age-related macular degeneration, and dry eye disease).” Please remove this phrase, as it describes the outcome rather than the intervention.

4. Comparators section: “to mitigate the abovementioned eye diseases.” Please remove this phrase, as it describes the outcome rather than the comparator.

5. Study design: please add non-randomized trials and retrospective cohorts to either the list of inclusion or exclusion criteria, as appropriate.

6. Study design: Please remove the sentence “Data from national health examination surveys without clearly defined denominator, systematic reviews, opinions, commentaries will be excluded.” This is addressed below until “Exclusion criteria”

7. Please move the Header “Inclusion criteria” above “Population” to clarify that studies that include the above PICOS will be included. And please remove the first sentence currently under “Inclusion criteria”, as it is repeated above.

8. Exclusion criteria: What does “disproportionate or heterogeneous distributions” mean? Distributions of what?

9. Search terms: Will this search identify dietary patterns? This is not mentioned in the manuscript, but seems like a relevant dietary factor.

10. Screening and Selection of Studies: As written, it seems like all authors will independently screen each title, abstract, and full-text. Is that correct? 2 (or 3 if there is disagreement) seems appropriate.

11. ROBINS-I is appropriate for non-randomized interventions (see minor comment 5 if those will be included). For observational studies (cohort, case-control, and cross-sectional studies), please use ROBINS-E: https://www.riskofbias.info/welcome/robins-e-tool

12. Data Analysis: Please keep all descriptions of heterogeneity assessment together, either here in or below in a separate subsection.

13. Dealing with Missing Data: What does "incomplete" mean? If a study has an attrition rate >0%, will it be excluded?

14. Measures of Effect: Will you include Hazard Ratios, and how will you combine (or keep separate) the various ratios that will be reported?

15. Meta-Regression: This does not need to be repeated if included in the Data Analysis section.

16. Discussion: “Diet and dietary metabolites constitute the building…one-carbon metabolic cycle.” Please either directly link this to ocular function/disease risk or delete. As written, it is too general to be relevant.

Reviewer #2: Overall, I consider the topic to be relevant and of interest to the study population.

The most important issues I would like to highlight are firstly the overly broad research question. The list of nutrients (macro and micro) to be considered is too long, as well as the diseases to be researched. There are nutrients with known associations with visual health and related pathologies such as diabetes, hypertension, among others. The reason why these nutrients are chosen, or why they are all chosen, is not properly reflected in the background section. The fact that such a long list of nutrients has been chosen makes me doubt the feasibility of obtaining reliable, conclusive and concrete results.

On the other hand, in the case of finding studies in which, instead of measuring nutrients, they have given consumption as whole foods or dietary patterns, the source from which the nutritional composition data for certain foods would be obtained has not been specified.

The measures of outcomes, especially of severity or progression of the diseases described, are not specified.

The inclusion of the adverse effects study does not seem to be relevant to the research question.

In the exclusion criteria it is stated that articles in languages other than English will be excluded, yet in the search section and in the discussion it is stated that there will be no language restrictions. This is contradictory and needs to be corrected prior to publication.

The eligibility criteria for study designs are not sufficiently justified.

In the discussion there are no citations where appropriate.

The first reference in the reference list is incorrectly formatted, the author should be ‘Bourne R, et al.’.

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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: Yes:  Oana M. Craciun

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[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.]

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PONE-D-25-00880R1Dietary Factors and Predominant Eye Diseases in Sub-Saharan African Populations: A Comprehensive Systematic Review ProtocolPLOS ONE

Dear Dr. Osei Duah Junior,

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  May 14 2025 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,

Amin Sharifan

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.

Additional Editor Comments:

1) Please note that PRISMA-P and other reporting guidelines are designed to improve transparency in reporting and are not guidelines for designing a study or preparing a work. Please revise both the abstract and main text accordingly. You may consult this reference for further information: 10.1186/s13643-021-01671-z.

2) Please present your revised search strategy as a supplementary file instead of the main text to enhance the flow and readability of your work.

3) Please justify the use of both risk of bias assessment and quality assessment. The former may suffice for a systematic review.

4) Please ensure the future tense is used throughout the text. The patient and public involvement section still contains past tense. This does not apply to the reporting or dissemination plans of your work as these will be done in the future.

5) Please ensure that your references are reported in accordance with the PLOS One style. Your may consult the followings for further information: https://journals.plos.org/plosone/s/submission-guidelines; https://www.nlm.nih.gov/bsd/uniform_requirements.html.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for addressing most of my comments from the first review. This protocol is close to being ready for publication, but a few more edits will ensure it meets reporting standards. Please see my recommendations below:

MAJOR:

1. The review is still very broad, which will make the evidence synthesis challenging and highlights the need for a clear synthesis plan. Because you intend to follow SWiM guidelines, please detail your synthesis plan in the Data Synthesis section, specifically including how studies will be grouped together for synthesis. Will any of the primary outcomes be combined or will you address them each separately? What about the exposures? Will you combine evidence for children and adults in a single summary statement? Will any other key variables be considered in the synthesis?

2. The protocol does not yet describe how a medical librarian has developed, or peer reviewed, the search. Please add that to ensure that the search will be thorough and replicable.

MINOR:

1. Thank you for adding clarifications about the objective and rationale in the Introduction. It would also be helpful to shorten to Introduction to focus on the objectives and rationale.

2. Line 116-117: both “micronutrients” and “dietary vitamins or minerals” are listed here. Please select 1.

Reviewer #2: The manuscript contains some grammatical errors that affect clarity. A thorough revision of the English language, preferably with the assistance of a native speaker or professional proofreader, is recommended.

Abstract (Main text line 27, and abstract on submission form) change "propose" to "proposed"

Main text line 80: change to "hypothesizes" or "which is hypothesized to"

Main text line 90: change "imply" to "implies"

Main text line 172: change "perform" to "performed"

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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: Yes:  Oana M. Craciun

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[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.

Dietary Factors and Predominant Eye Diseases in Sub-Saharan African Populations: A Comprehensive Systematic Review Protocol

PONE-D-25-00880R2

Dear Dr. Osei Duah Junior,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Amin Sharifan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

1) Please ensure the title reflects only "systematic review." The term "comprehensive" is redundant because systematic reviews are inherently comprehensive by definition. For reference, see this article, which included 170 trials but appropriately used the title "systematic review". 10.1016/S0140-6736(22)00878-9.

2) Kindly update "PRISMA" to "PRISMA-P" in the abstract to align with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols statement.

3) Page 7, line 150: Please remove the abbreviation RCTS as this is only used for randomized controlled trials and the correct form is RCTs.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Nice work! Thank you for addressing my comments, both in the manuscript and in your response. This will be an important and interesting review, and I look forward to reading the final product. Good luck with the work ahead to complete this ambitious plan.

Reviewer #2: I believe it would be acceptable to be published at this stage.

Looking forward to the results of this systematic review.

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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: Yes:  Julie E.H. Nevins

Reviewer #2: Yes:  Oana M. Craciun

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