PONE-D-23-20018Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: a nationwide population-based studyPLOS ONE

Dear Dr. Kim,

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

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PLOS ONE

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REVIEWER 1

Kim et al. demonstrated the impact of the longitudinal cumulative burden of METS on RVO in a young population. Given the significant impact of eye diseases in the young population, this research holds considerable value. Moreover, the examination of cumulative burden is an interesting aspect of the study. However, there are several points that need to be addressed:

1. While it is acknowledged that disease burden is higher in the young population, it would be beneficial to mention how the RVO incidence in the 20-40 age group compares to the overall population incidence or the incidence in the elderly. Since there have been similar studies conducted in Korea previously, referencing these studies for comparison would enhance the discussion.

2. On line 82, Figure 2 precedes Figure 1 in the manuscript. It is advisable to reverse the order for clarity.

3. Regarding line 82, please provide a rationale for the selection of a 1-year lag period.

4. Regarding Figure 2, does this study include individuals who underwent health examinations four times between 2009 and 2012? If so, the index data should presumably be in 2012. However, in Figure 2, it mentions the exclusion of cases diagnosed with RVO from 2002 to 2009 and within one year from the index date. Does this mean that individuals diagnosed with RVO in 2010 were not excluded? I assume that individuals diagnosed with RVO before the index date might have been excluded. The flow chart requires further clarification to provide a clearer understanding.

5. On line 167, the conclusion "among the five metabolic components, increased WC had the greatest increase in RVO risks" needs further clarification. What criteria were used to reach this conclusion? Among the components, it appears that impaired fasting glucose has the highest risk when there are four times serial abnormalities. Please elaborate.

6. On line 177, the statement, "it can be inferred that the risk of RVO increases more than four times in people diagnosed with MetS during health examinations," requires additional clarification. It is crucial to elucidate the specific findings or results that led the author to draw such a conclusion. What specific data or analysis supports this assertion?

7. On line 191, it is suggested to tone down the statement: "Therefore, among the components of MetS, reducing WC is particularly important for reducing the risk of RVO," as the results of this study suggests an association and cannot establish a causal relationship.

8. On line 201, please consider referencing a study that suggests menopause may influence RVO risk, such as:

Hwang S, Kang SW, Choi KJ, Son KY, Lim DH, Shin DW, Choi D, Kim SJ. Early menopause is associated with an increased risk of retinal vascular occlusions: a nationwide cohort study. Sci Rep. 2022 Apr 12;12(1):6068. doi: 10.1038/s41598-022-10088-0. PMID: 35414644;

9. The limitations inherent in this type of research, which relies on claim data, should be thoroughly addressed. Specifically, the inability to independently verify diagnoses and the fact that the study only captures patients who visited healthcare services need to be acknowledged.

10. It is important to note that the initial study sample of 6,891,399 individuals primarily comprises those who underwent health examinations, potentially limiting its representativeness for the broader population. Additionally, the selection criteria, focusing on individuals who underwent health examinations four times over four years, may not accurately reflect 20s and 30s of general population. Furthermore, the high male representation within the study participants should also be acknowledged. Therefore, it is imperative to acknowledge these limitations within the manuscript for transparency and completeness.

REVIEWER 2

The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion. As described below, there are several areas for improvement.

1. there are serious concerns about selection bias in the selection of study subjects. Populations under the age of 40 who receive annual health checks are more likely to have more systemic diseases or higher socioeconomic status, and this should be taken into account.

2. Even among populations that receive annual health checks, data may be missing for some of the parameters examined in this study, such as waist circumference. Please explain how you handled this.

3. While most other studies set the washout period at a minimum of 2 years and sometimes longer, this study set it at 1 year. Therefore, it is possible that patients with previously diagnosed RVOs were included rather than patients with new onset, and this needs further explanation.

4. line 104 states that all RVOs were included based on ICD-10, and the legend to Figure 2 states that they were categorized using KCD disease classification codes. To my knowledge, the two-digit decimal codes used for figure legends have been in use since KCD-6 in 2010. Please explain the exact classification used in this study in the Methods section.

5. The chronic kidney disease diagnosis code does not indicate a specific diagnosis, so it is better to use the eGFR measurements rather than CKD code.

6. If you used multiple models in your evaluation, please describe your results using the commonly used Charlson-Comorbiditi index.

7. The survey items were slightly different for each year, which may have resulted in inconsistent survey questions for certain items such as alcohol drinking and exercise. Please explain how you handled this.

8. The incidence of metabolic syndrome and RVO was very low in people under age 30, which may be due to a stronger association with systemic diseases such as leukemia other than metabolic syndrome. Have you done any further analysis on this?

9. You mentioned that there is a difference between men and women, but the study was based on younger people, so it is possible that the difference is due to contraceptive use. If you have analyzed differences due to contraceptive use, please present the results.

10. You cited another study in the discussion section, did this study also find differences in other parameters including WC based on DM? Please present the results.

[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: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: 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: Yes

Reviewer #2: Yes

**********

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

**********

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: Kim et al. demonstrated the impact of the longitudinal cumulative burden of METS on RVO in a young population. Given the significant impact of eye diseases in the young population, this research holds considerable value. Moreover, the examination of cumulative burden is an interesting aspect of the study. However, there are several points that need to be addressed:

1. While it is acknowledged that disease burden is higher in the young population, it would be beneficial to mention how the RVO incidence in the 20-40 age group compares to the overall population incidence or the incidence in the elderly. Since there have been similar studies conducted in Korea previously, referencing these studies for comparison would enhance the discussion.

2. On line 82, Figure 2 precedes Figure 1 in the manuscript. It is advisable to reverse the order for clarity.

3. Regarding line 82, please provide a rationale for the selection of a 1-year lag period.

4. Regarding Figure 2, does this study include individuals who underwent health examinations four times between 2009 and 2012? If so, the index data should presumably be in 2012. However, in Figure 2, it mentions the exclusion of cases diagnosed with RVO from 2002 to 2009 and within one year from the index date. Does this mean that individuals diagnosed with RVO in 2010 were not excluded? I assume that individuals diagnosed with RVO before the index date might have been excluded. The flow chart requires further clarification to provide a clearer understanding.

5. On line 167, the conclusion "among the five metabolic components, increased WC had the greatest increase in RVO risks" needs further clarification. What criteria were used to reach this conclusion? Among the components, it appears that impaired fasting glucose has the highest risk when there are four times serial abnormalities. Please elaborate.

6. On line 177, the statement, "it can be inferred that the risk of RVO increases more than four times in people diagnosed with MetS during health examinations," requires additional clarification. It is crucial to elucidate the specific findings or results that led the author to draw such a conclusion. What specific data or analysis supports this assertion?

7. On line 191, it is suggested to tone down the statement: "Therefore, among the components of MetS, reducing WC is particularly important for reducing the risk of RVO," as the results of this study suggests an association and cannot establish a causal relationship.

8. On line 201, please consider referencing a study that suggests menopause may influence RVO risk, such as:

Hwang S, Kang SW, Choi KJ, Son KY, Lim DH, Shin DW, Choi D, Kim SJ. Early menopause is associated with an increased risk of retinal vascular occlusions: a nationwide cohort study. Sci Rep. 2022 Apr 12;12(1):6068. doi: 10.1038/s41598-022-10088-0. PMID: 35414644;

9. The limitations inherent in this type of research, which relies on claim data, should be thoroughly addressed. Specifically, the inability to independently verify diagnoses and the fact that the study only captures patients who visited healthcare services need to be acknowledged.

10. It is important to note that the initial study sample of 6,891,399 individuals primarily comprises those who underwent health examinations, potentially limiting its representativeness for the broader population. Additionally, the selection criteria, focusing on individuals who underwent health examinations four times over four years, may not accurately reflect 20s and 30s of general population. Furthermore, the high male representation within the study participants should also be acknowledged. Therefore, it is imperative to acknowledge these limitations within the manuscript for transparency and completeness.

These points, once addressed, will significantly enhance the quality and comprehensibility of the manuscript.

Reviewer #2: The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion. As described below, there are several areas for improvement.

1. there are serious concerns about selection bias in the selection of study subjects. Populations under the age of 40 who receive annual health checks are more likely to have more systemic diseases or higher socioeconomic status, and this should be taken into account.

2. Even among populations that receive annual health checks, data may be missing for some of the parameters examined in this study, such as waist circumference. Please explain how you handled this.

3. While most other studies set the washout period at a minimum of 2 years and sometimes longer, this study set it at 1 year. Therefore, it is possible that patients with previously diagnosed RVOs were included rather than patients with new onset, and this needs further explanation.

4. line 104 states that all RVOs were included based on ICD-10, and the legend to Figure 2 states that they were categorized using KCD disease classification codes. To my knowledge, the two-digit decimal codes used for figure legends have been in use since KCD-6 in 2010. Please explain the exact classification used in this study in the Methods section.

5. The chronic kidney disease diagnosis code does not indicate a specific diagnosis, so it is better to use the eGFR measurements rather than CKD code.

6. If you used multiple models in your evaluation, please describe your results using the commonly used Charlson-Comorbiditi index.

7. The survey items were slightly different for each year, which may have resulted in inconsistent survey questions for certain items such as alcohol drinking and exercise. Please explain how you handled this.

8. The incidence of metabolic syndrome and RVO was very low in people under age 30, which may be due to a stronger association with systemic diseases such as leukemia other than metabolic syndrome. Have you done any further analysis on this?

9. You mentioned that there is a difference between men and women, but the study was based on younger people, so it is possible that the difference is due to contraceptive use. If you have analyzed differences due to contraceptive use, please present the results.

10. You cited another study in the discussion section, did this study also find differences in other parameters including WC based on DM? Please present the results.

**********

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

**********

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

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

PONE-D-23-20018R1Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: a nationwide population-based studyPLOS ONE

Dear Dr. Kim,

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 04 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,

Jiro Kogo

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.

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

**********

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: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

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

Reviewer #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. 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: All comments have been addressed.

One more comment to add. Please double-check and amend the discrepancy between the methodology section, which states the use of the National Health Insurance Service (NHIS)'s Database, and the acknowledgment and data availability statement, which indicate the use of Health Insurance Review and Assessment Service (HIRA) data.

Reviewer #2: The authors examined the impact of the cumulative burden of metabolic syndrome on the incidence of retinal vein occlusion in young adults. They concluded that rapid detection and treatment of metabolic disorders in young adults is important to reduce the risk of retinal vein occlusion.

All comments has been addressed well.

**********

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

**********

[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.

Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: a nationwide population-based study

PONE-D-23-20018R2

Dear Dr.KIm

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,

Jiro Kogo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: