PONE-D-23-12441Atrial Fibrillation as a Novel Risk Factor for Retinal Stroke: A Protocol for A Population-Based Retrospective Cohort StudyPLOS ONE

Dear Dr. Mac Grory,

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.

==============================

We have invited 4 reviewers Please kindly address the concerns of the 4th reviewer==============================

Please submit your revised manuscript by Nov 24 2023 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.

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Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Competing Interests section:

““I have read the journal's policy and the authors of the manuscript have the following interests: J.B. Lusk is supported by the American Heart Association. Dr Biousse is supported by the National Institutes of Health National Eye Institute core grant P30-EY06360 (Department of Ophthalmology, Emory University School of Medicine) and by a departmental grant from the Research to Prevent Blindness (New York, NY) and is a consultant for GenSight Biologics and Neurophoenix. Dr Schrag reports compensation from the REVISION trial for data and safety monitoring services; compensation from Raymond James for consultant services; grants from the National Institutes of Health; and compensation from Labaton Sucharow for consultant services. Dr Poli reports grants from the Helena Laboratories Corporation, Bristol Myers Squibb, Boehringer Ingelheim, and the Daiichi Sankyo Company; compensation from Alexion Pharmaceuticals, Inc, Portola Pharmaceuticals LLC, Werfen USA LLC, and AstraZeneca for consultant services; and compensation from Boehringer Ingelheim, Bristol Myers Squibb, the Daiichi Sankyo Company, and Bayer Healthcare for other services. Dr Piccini reports compensation from Biotronik, Inc, Philips, Medtronic, Boston Scientific Corporation, ResMed Foundation, Ablacon, LivaNova USA, Inc, AltaThera Pharmaceuticals LLC, AbbVie Biotherapeutics, Abbott Laboratories, ElectroPhysiology Frontiers, Itamar Medical, Inc, ARCA biopharma, Pfizer, Bristol Myers Squibb, Sanofi US Services, Inc, and Milestone Scientific, for consultant services; employment by the Duke University; and grants from the American Heart Association and iRhythm Technologies. Dr O’Brien reports compensation from Boehringer Ingelheim for consultant services and employment by the Duke University. B. Mac Grory is supported by a grant from the National Institutes of Health (K23HL161426). The other authors report no conflicts.”

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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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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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

Reviewer #3: Yes

Reviewer #4: 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: I believe that this protocol paper is well written and the research plan is important. Thank you for the opportunity to review your excellent research plan.

Reviewer #2: Dear Authors,

I read your protocol with great interest. I think this will be a very important study, at least partially filling the knowledge gap about CRAO. I do not have major comments on the text of manuscript.

Reviewer #3: Previous study by the corresponding author suggested that the rate of AF detection after CRAO is higher than that seen in age-, sex-, and comorbidity-matched controls and comparable to that seen after ischemic cerebral stroke.[1]

Current study is designed to determine if AF is a risk factor for CRAO independent of other vascular risk factors, and whether use of anticoagulation would modifies the risk of CRAO.

For Aim 1, study design is very comprehensive and included all the vascular risk factors into covariates analysis.

For Aim 2, to compare the hazard of CRAO among patients treated with any oral anticoagulant agent vs those not treated. The group not treated with anticoagulant (probably because of their comorbidity eg: Gastrointestinal bleeding, peptic ulcer disease, intracranial haemorrhage) maybe offered alternative such as Left Atrial Appendage occluder device. The effect of anticoagulation is affected by compliance and dosage. It is stated in the study limitation that there is lack of access to clinical data. We do need to be caution when interpreting the results and drawing conclusions relating to anticoagulation.

In Table 2, symbol * was referring to reference 22 that claims data do not sensitively identify patients with hyperlipidemia. However this symbol also appear under multiple ICD-9 and ICD-10 coding. Please identify if this is intentional or typing error.

Reference:

1. Brian Mac Grory, Sean R. Landman, Paul D. Ziegler, Chantal J. Boisvert, Shane P. Flood, Christoph Stretz, et al. Detection of Atrial Fibrillation After Central Retinal Artery Occlusion. Stroke. 2021;52:2773–2781. Available from https://doi.org/10.1161/STROKEAHA.120.033934

Reviewer #4: # General comments

Although the study claims to be studying a risk factor, in practice, the authors are trying to establish some causal relationships between the risk factor (AF) and the outcome (retinal stroke). This can be seen from the use of propensity scores whose main purpose is to form two or more similar groups for comparisons in order to generate the evidence for causal relationships as well as mentions of trial emulation methodology.

# Adjustment covariates

Under the context of this being a study aimed at estimating causal effects, a causal diagram is required. This causal diagram needs to include all the outcomes of interests and the variables used for adjustment to make the case that the adjustments are appropriate. Some of the covariates appear to lie on the causal path between AF and retinal stroke and a causal diagram would be able to clarify that. Variables lying on the causal pathway should not be adjusted for.

# Propensity score matching

It is unclear how the propensity scores are to be estimated and how they are to be used. What weighting scheme is used and why? Are there risks to under-representation of groups of patients that do not have matched samples and if there are, what is done to mitigate this?

Are there any attempts at assessing unmeasured confounding (treatment - outcome confounding) using sensitivity analyses or other methods? This needs to be done in order to have a reasonable assessment of the robustness of your results.

# Regression modeling

- How do you intend to analyse CRAO over time and across states? No details are offered on this.

- Again, the adjustment for covariates needs to be justified using a causal diagram.

- Is the sequential adjustment an attempt to identify a best-fit model? If not please explain what you mean by sequential adjustment.

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Reviewer #1: Yes: Kanta Tanaka

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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PONE-D-23-12441R1Atrial Fibrillation as a Novel Risk Factor for Retinal Stroke: A Protocol for A Population-Based Retrospective Cohort StudyPLOS ONE

Dear Dr. Mac Grory,

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 make the suggested changes and resubmit.

==============================

Please submit your revised manuscript by Jan 15 2024 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,

Yee Gary Ang, MBBS MPH

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. 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 #5: 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 #5: 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 #5: 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 #5: No

********** 

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 #5: 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 #5: In this study protocol, a retrospective matched controls study is being proposed to determine if prevalent AF is a risk factor for CRAO and if anticoagulant use changes the risk of CRAO.

Minor revisions:

1- Sample size calculation: Indicate the statistical testing method which attains 90% power.

2- Descriptive analysis: Perhaps the statement, “We will summarize count data using . . .” can be clarified by stating, “We will summarize categorical data using . . .”

3- Tables 7 and 8: Clarify that the “Unadjusted Model” reports univariate results whereas the “Adjusted Model” reports multivariate results.

4- Below Table 7: Indicate the statistical method that will be used to graphically displaying the adjusted cumulative incidence of CRAO.

5- Identify the software that will be used for the statistical analysis.

6- Provide details about the characteristics on which the matched controls will be selected.

7- To assist in the review process, add line numbers to the document.

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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 #5: No

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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.

Atrial Fibrillation as a Novel Risk Factor for Retinal Stroke: A Protocol for A Population-Based Retrospective Cohort Study

PONE-D-23-12441R2

Dear Dr. Mac Grory,

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 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,

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #5: 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 #5: 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 #5: 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 #5: No

**********

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 #5: 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 #5: All comments have been adequately addressed.

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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 #5: No

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