PONE-D-22-33830Risk of Cancer in Patients with Insomnia: Nationwide Retrospective Cohort Study (2009-2018)PLOS ONE

Dear Dr. Shin,

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 Feb 16 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.

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,

Dong Keon Yon, MD, FACAAI

Academic Editor

PLOS ONE

Journal requirements:

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

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

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

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

2. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Additional Editor Comments:

Thank you for submitting your manuscript. The reviewers and I believe it is of potential value for our readers. However, the reviewers have raised a number of very important issues, and their excellent comments will need to be adequately addressed in a revision before the acceptability of your manuscript for publication in the Journal can be determined.

[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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: Yes

**********

5. Review Comments to the Author

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

Reviewer #1: • This is a retrospective cohort study from the Korean National Health Insurance (KNHIS) database seeking to understand a potential link between the incidence of insomnia and risk of cancer diagnoses in this population.

• Adults (>=20 years old) enrolled in the KNHIS got standard exams every 2 years, which included lifestyle questionnaires and labs.

• Cohort selected 40% of subjects from 2009, followed over time until 2018. Previous cancer diagnoses excluded. Missing data excluded.

• Disease diagnoses classified by ICD-10 coding (including insomnia and cancers). Insomnia diagnoses stratified by incident or prevalent and timing. Cancer diagnoses included combined ICD-10 and insurance claim codes.

• Analyses for Hazard adjusted for age, sex, income, smoking, EtOH, Dm-2, HTN, HLD, BMI.

• 3.98M subjects included in analysis. Cancer diagnosis in older subjects (56.8 vs 48.3 years). No difference in sex between CA and non-CA diagnoses. CA diagnoses were higher waist circumference, metabolic syndrome (DM-2, HTN, HLD), lower income, higher insomnia, smoking, alcohol use, BMI, etc.

• Per specific cancers, insomnia group had higher rates of certain cancers (i.e. colorectal, leukemia), and lower in others (ovarian, stomach), which was different by gender as well. No difference in cancer diagnoses rates by type of insomnia (existing, newly diagnosed, etc).

• Summary – The authors present intriguing data regarding a potential association between a diagnosis of insomnia and the risk of developing cancer diagnoses. Strengths include a large and relatively comprehensive dataset utilizing the resources of a national healthcare system in Korea, and a robust analysis.

Comments

• The authors attempt to explain the lower rate of certain malignancies in insomnia patients (Discussion second paragraph), noting that insomniac patients may have higher rates of screening uptake for malignancy like colonoscopy. However, they go on to suggest the stomach cancer rate is potentially related to H. Pylori infection, however I fail to see how this is linked to insomnia, and I would remove that potential explanation (one could posit any number of comparable explanations, like they consume more food with nitrates that is linked to stomach cancer, but explanations to link insomnia to lower malignancy rates should require further justification).

• In the fourth discussion paragraph, the third sentence should probably indicate the authors explaining a link between insomnia and oral cancer in females (“…insomnia could independently be a risk factor for oral cancer in female patients”).

• In the fifth discussion paragraph, I would not report the hazard from the cited reference itself, the reference is already provided. Additionally, the following sentence (the third sentence) should read “…there was a higher risk of nervous system cancer in female patients”. The following sentence should indicate the cancers themselves as well, “However, we could not independently validate this association as we did not collect data on peripheral and nervous system cancers specifically”.

• In the eight discussion paragraph, discussing the stratification of insomnia and risk of cancer, the authors suggest the existing insomnia (within 5 years) is not long enough to fully evaluate the risk of cancer. This is a theory, not a fact, and should be treated as such, “…multiple sequential mutations from the exposure of possible causes (19), the 5-year duration may not be long enough to evaluate the risk of cancer development”.

• In the 9th discussion paragraph, the link between insomnia and lower cancer rates, secondary potentially to medical-care-seeking behavior, should be rephrased. (“…attributed to insomnia associated with personality traits such as hypochondriasis or anxiety, may inadvertently promote early detection of premalignant lesions…”).

• The authors fail to discuss or entertain a number of limitations in their study, namely the reliance on ICD-10 codes (and the inaccuracies therein), the lack of generalization outside a Korean population, the possibility of reporting bias (older subjects, who are more likely to develop cancer, may also be more likely to report insomnia, and age may be a significant confounder -see several references linking increased insomnia to advanced age, for example Miner B, et al. Sleep Med Clin 2017;12(1):31-38.), and how age may be a significant confounder in this analysis (the use of multivariable adjustment alone may not be sufficient to address this confounding).

• Why did the authors not perform a validation analysis on a subset of subjects from their database to ensure their findings could be replicated? They only used 40% of the initial dataset in the initial analysis, they should have data for a validation of a subset (i.e. 20% of the remaining dataset) to validate their initial findings. This is pertinent particularly given some of the unusual associations between insomnia and lower rates of malignancy they have observed.

• Age is a significant concern regarding confounding. The authors should consider performing a sub-analysis, where they stratify their data by age strata (i.e. every 5 or 10 year age groups as of 2009) and perform multivariable analyses on these subjects to assess insomnia with malignancy. This would better enable them to see if the association has the same value across age groups, They appear to have the dataset size to do this, and it would help alleviate concerns regarding the confounding nature of age in this longitudinal study. Understandably, older age groups would have less follow-up time, but additionally they would be more at risk of malignancy development, so I would be curious to see the results of this type of analysis, and if their findings of an association are maintained.

Reviewer #2: Insomnia is the most common sleep disorder and has been shown to be associated with an increased risk for numerous disorders, including cardiovascular, neurological and psychiatric disorders. As such, it merits particular attention in the research community. Yoon et al. describe the association between insomnia in various types of cancer in the Republic of Korea between 2009 and 2018. The authors show that insomnia is associated with an increased risk for several cancers, but also decreased risk for some types of cancer, including colorectal cancer. Due to the inconclusive nature of the connection between insomnia and various types of cancer, this study presents a valuable contribution to the existing literature and understanding behind this connection. While the article is easy to understand and fluent to read, there are several suggestions that, in my opinion, would make the article more comprehensive and novel, thus suitable for publication.

Abstract:

- Please write exact P values in the abstract where possible.

- Please be slightly more specific (most important/reliable findings) in the conclusion of the abstract.

Introduction:

- Please add very brief paragraph about the health implications of chronic insomnia after the first paragraph to fluently transition to the second paragraph about the association between insomnia and cancer.

- In the second paragraph, please add more background on why the results associating insomnia and cancer are inconsistent (and what cancers in particular) citing relevant literature.

- In the last paragraph, please clearly explain why your study is different compared to already published studies and how it may add value to the field (apart from being another group of patients).

Methods:

- Please explain the reasoning behind including 40% and not all of the patients.

- Please elaborate whether patients with all cancer stages were included and whether you grouped them in any way, which might add significant value to the literature. I would suggest grouping patients by either cancer stage (early/late…) and/or by age group/sex which would add another novelty factor to your research.

- Please explain the sleep history of these patients prior to inclusion if possible since presence/duration of insomnia/other sleep disorders might be an important factor in cancer development. I would suggest grouping patients by insomnia severity and duration to see whether there is any association with different types/stages of cancer, which would be another differentiating factor for your study.

- Please elaborate whether all patients had insomnia during the whole period (2009-2018), how their insomnia was followed and whether patients with cured insomnia between 2009 and 2018 were still included in the study till the very end.

Results:

- Please elaborate on why subjects with newly diagnosed cancer within one year of screening examination were excluded.

Discussion:

- Please elaborate in the discussion whether your findings could be influenced by the region you studied since some cancers are more/less common in the Asian population in general.

Figures:

- I suggest adding a figure (e.g. Forest plot) that will highlight the most important results in a visually appealing way, in addition to the tables where you can write all the results.

These suggestions are likely to make the article more comprehensive and novel and I feel they are necessary for this article to be accepted for publication.

Reviewer #3: Dear authors,

I have now completed the review of the manuscript titled "Risk of Cancer in Patients with Insomnia: Nationwide Retrospective Cohort Study (2009-2018)."

In the present study, the authors investigated the association between insomnia and the risk of various cancers using data from the Korean National Health Insurance Service database.

The manuscript is interesting and, in general, fair written.

I have some minor suggestions before recommending an "accept."

1. The background section introduced some relevant articles. Please summarize the results with effect sizes.

2. I suggest authors clarify how other researchers can obtain the original data.

3. How many people have F510 (nonorganic insomnia) or G470 (insomnia) each? Could you also compare the rate with previous studies?

4. In the ‘Statistical Analysis’ section, the paragraph is quite long but there are no references for selecting your method. Please add two references to the following sentence:

Student’s t-test was performed for the comparison of continuous variables and the χ2-test was used for categorical variables [1, 2].

[1] https://doi.org/10.54724/lc.2022.e1

[2] https://doi.org/10.54724/lc.2022.e3

5. What is the future scope of the proposed research, authors have described the limitations in a good way, and I suggest that these can be the future scope of the work.

**********

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: Yes: Arun Jose

Reviewer #2: No

Reviewer #3: No

**********

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

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

PONE-D-22-33830R1Risk of Cancer in Patients with Insomnia: Nationwide Retrospective Cohort Study (2009-2018)PLOS ONE

Dear Dr. Shin,

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 01 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.

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,

Dong Keon Yon, MD, FACAAI

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 :

Thank you for submitting your manuscript. The reviewers and I believe it is of potential value for our readers. However, the reviewers have raised a number of very important issues, and their excellent comments will need to be adequately addressed in a revision before the acceptability of your manuscript for publication in the Journal can be determined. We cannot guarantee that your revised paper will be chosen for publication; this would be solely based on how satisfactorily you have addressed the reviewer comments.

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

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

Reviewer #3: 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

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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 authors have done a good job of responding to my critiques. I find the stratification of insomnia by age to be quite interesting, significantly higher risk in the younger population, but curiously a decreased hazard in the holder age group, and the interaction between age, duration of insomnia, and other associated characteristics (health seeking behavior, hypochondriasis, etc.) is quite interesting.

• I would recommend the authors indicate the limitations of their database as it relates to why they had to use only 40% of the initial cohort, and also why it would be difficult for others to gain access to their data for validation. Per the authors, “according to institutional regulations, we could only get a 40% simple random sampling database of the subjects who underwent a health-screening examination in 2009. Also, there is a limitation to the access of the KNHIS database due to institutional regulation. That is, we need approval from the institution to get access to the closed server, and we also need to make a reservation to use the database for a limited time.”. I suggest paraphrasing this explanation go in the Methods – Study population section.

Reviewer #2: I would like to thank the authors for addressing my concerns and I think the article is ready to be accepted.

Reviewer #3: All comments have been addressed. Thank you to the authors and editors for considering my opinion on this manuscript.

**********

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: Arun Jose

Reviewer #2: No

Reviewer #3: No

**********

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

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

Risk of Cancer in Patients with Insomnia: Nationwide Retrospective Cohort Study (2009-2018)

PONE-D-22-33830R2

Dear Dr. Shin,

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,

Dong Keon Yon, MD, FACAAI

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This is an excellent paper.

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

**********

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: (No Response)

**********

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

Reviewer #1: (No Response)

**********

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 Response)

**********

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: (No Response)

**********

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: (No Response)

**********

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: Arun Jose

**********