PONE-D-21-35192Identified risk factors for dry eye syndrome: A systematic review and meta-analysisPLOS ONE

Dear Dr. Wei,

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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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: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Manuscript ID: PONE-D-21-35192

Title: Identified risk factors for dry eye syndrome: A systematic review and meta-analysis

The authors report on a meta-analysis of an important topic – risk factors for dry eye syndrome. I thank the authors for their persistence with this large and complex analysis, however their analysis is limited by multiple methodologic and reporting concerns. The quality of evidence used to make these conclusions is also suspect, given the large proportion of cross-sectional studies that are susceptible to recall bias and variability in the adjustment for confounding factors across studies.

Specific comments are provided below:

1. Methods, Abstract: The model used for meta-analysis should be specified, as well as the inclusion and exclusion criteria for study selection.

2. Conclusion, Abstract: The authors should elaborate on their conclusion section to discuss the implications of their findings and/or areas for future research.

3. Introduction: expand on the risk factor ‘visual display terminal’ for readers who may be unfamiliar with this term.

4. Introduction: “However, the presence of other comorbidities and individuals’ characteristics on the risk of DES were not illustrated.” The authors should specify that there is conflicting or negative evidence for these other characteristics as opposed to these being uninvestigated characteristics.

5. Methods: “The following search terms were used: ("Dry Eye Syndromes"[Mesh]) AND "Risk Factors"[Mesh].” The search strategy provided by the authors is quite simplistic and does not account for other formulations of the same concept found in these major databases. No text-based searches are also integrated to ensure maximal literature coverage.

6. Methods: Did the authors investigate the gray literature as part of this systematic review?

7. Methods: specify with initials the authors that independently screened studies and extracted data.

8. Methods: the authors note that all studies reporting on dry eye risk factors were considered. Were interventional studies assessing the impact of dry eye treatment also included?

9. Methods: was the systematic review prospectively registered in the PROSPERO database?

10. Methods: The authors note that studies which assessed risk factors in at least 3 cohorts were included. Some studies assessing risk factors for dry eye may have only focused on one risk factor and would therefore be excluded under the current methodology. This overly restrictive inclusion criterion seems arbitrary and unwarranted.

11. Methods: Was a GRADE evaluation performed to assess the certainty of findings?

12. Methods: “Identified risk factors for DES were analyzed based on the effect estimate, with its 95% CI, in 99 individual studies.” What effect estimate was considered? Elaborate on the exact methods used. For continuous variables like age, how were they categorized into binary groups for analysis?

13. Methods: Only one subgroup analysis based on country was considered in the analysis. There are likely multiple potential confounders in this analysis that can be investigated for using subgroup analysis, including severity of dry eye, individuals with dry eye secondary to another condition eg Sjogren’s, evaporative vs aqueous deficient dry eye, study design, etc.

14. Methods, statistical analysis: specify the measure of association used to report the results – ie odds ratio with 95% confidence interval.

15. Results: what proportion of results of studies was derived from a multivariable analysis that controlled for confounding parameters versus a univariable analysis?

16. Results: provide more information in the study characteristics section on the type and severity of dry eye, observational vs interventional studies, the recency of publication, the pooled gender and age distribution, and other relevant baseline parameters for this analysis.

17. Results: expand on the results of the risk of bias assessment – what was the most frequent reason for downgrading the risk of bias?

18. Results: It would be important to clarify the definition of DES used in the analysis, and whether this definition was different across included studies.

19. Results: When reporting the results for each risk factor, it would be helpful to provide the proportion of the characteristic in the DES vs no DES groups, e.g. mean age, % female, race distribution, etc.

20. Results: For endpoints that had significant statistical heterogeneity, was the heterogeneity changed in the subgroup analysis?

21. Results: For glaucoma as a risk factor, it would important to clarify the therapy received, as this likely impacts the risk of DES.

22. Results: For eye surgery as a risk factor, clarify what type of surgeries were considered.

23. Results: In the reporting of the various risk factors, certain risk factors are grouped with others in the same paragraph. It is unclear how the various risk factors were grouped. It would be helpful to add subheadings to clarify this.

24. Results: “systemic disease” as a risk factor is not helpful or clinically relevant. This needs to be specified as to which specific systemic disease was considered or otherwise removed from the analysis.

25. Discussion: “we noted that other races versus white race were associated with an increased risk of DES, which is significantly related to the climate type.” Is race a risk factor independent of climate type? Elaborate on how climate type mediated this effect.

26. Discussion: “anti-hypertensive medication could increase the risk of DES”. What is the mechanism of this association?

27. Discussion: “The role of rosacea could be explained by its significant relation to corneal neovascularization and perforation, which could induce vision loss and ocular comorbidities.[85]” This relation is poorly described. Rosacea is a well known risk factor for DES due to is pro-inflammatory effects that induce meibomian gland dysfunction and evaporative DES.

28. Discussion: “Studies have already found that thyroid disease is significantly related to ocular surface damage, elevated lip aperture” – ‘elevated lip aperture’ should read ‘eyelid retraction’

29. Discussion: a major limitation is that the impact of confounding variables is unaddressed by certain studies, and multivariable associations were only reported for certain risk factors. Given the large proportion of cross-sectional studies, recall bias is likely a significant issue in these results.

30. Figure 2: p-value column – unsure why the p-values displayed in this way, as if multiple numbers are written on top of one another? What is the significance of the blue/gray background behind the forest plot for each endpoint?

Reviewer #2: This is a very well written meta-analysis regarding the potential risk factors for dry eye syndrome. Nevertheless, risk factors for DES are widely known, therefore, my question to the authors is:

In which way this meta analysis contributes to the literature already published regarding the risk factors for DES.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-35192R1Identified risk factors for dry eye syndrome: A systematic review and meta-analysisPLOS ONE

Dear Dr. Wei,

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 19 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,

Michael Mimouni

Academic Editor

PLOS ONE

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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: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

**********

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: The reviewer thanks the authors for their attempt at revising the manuscript. While improved, the manuscript still has a few limitations as noted below:

1. Conclusion, Abstract: “This study reported the comprehensive risk factors for dry eye syndrome, including demographic information, clinical characteristics, and comorbidities.” This sentence is not suitable as the last sentence of the abstract. Instead, the authors should discuss the implications of their research (i.e. why identification of these risk factors is important to improve clinical care) or alternatively discuss other areas of research that could be explored.

2. The manuscript should be thoroughly proofread by a native English speaker. For instance, this sentence contains multiple grammatical errors: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could explained by decreases blink rate and increases the proportion of incomplete blinks could causing the increased exposure of the ocular surface to the environment”. A more appropriate sentence would be: “Moreover, the occupational risk factor of visual display terminal (VDT) use was related to the progression of DES, which could be explained by a decreased blink rate and increased proportion of incomplete blinks that could be caused by the increased exposure of the ocular surface to the environment”. In some sections, the language is so poor that it is uninterpretable: “which restricting the assessment of causality relationships between risk factors and DES”.

3. The search strategy is still insufficient to permit replication of the search by an independent researcher. The authors should specify the search strategy in a line-by-line format in a table that outlines clearly what term was searched, how terms were combined, and whether any restrictions were applied. The search should be updated to March 2022. In the table, the authors should highlight whether each term was a MeSH subject heading or a text based term.

4. The authors note that studies which assessed risk factors in at least 3 cohorts were included. The authors should cite the meta-analysis in Lancet Global Health that they followed for this methodology. I would advise changing ‘cohorts’ to ‘studies’ to make this sentence clearer in the Methods.

5. The authors note that “this study contained cross-sectional, retrospective, and prospective observational studies, and the GRADE evaluation was not applied for certainty of findings.” This reviewer believes it is important to conduct a GRADE evaluation for this meta-analysis especially because the evidence comes primarily from observational studies which are by their nature susceptible to bias. To provide readers with an indication of the certainty of evidence, the GRADE evaluation should be integrated.

6. The authors have discussed the variable definitions of DED in the limitations section, however in the baseline characteristics section of the results the authors should specify how different studies defined DED. This is important for readers to understand.

7. The sentence “we noted that other races versus white race were associated with an increased risk of DES, which is significantly related to the climate type” should be deleted because there is not evidence to support the notion that DES in different races is attributable to climate type as opposed to other factors.

Reviewer #2: Thank you for addressing my question and improving the shortcoming section. I do not have any more questions or comments to the authors.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[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.

Identified risk factors for dry eye syndrome: A systematic review and meta-analysis

PONE-D-21-35192R2

Dear Dr. Wei,

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,

Michael Mimouni

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: 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: 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

**********

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: The reviewer thanks the author for revising the manuscript based on earlier feedback. I have no further comments.

Reviewer #2: I do not have more comments for the authors. Thank you for answering all the reviewers questions and improving the script.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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