Peer Review History

Original SubmissionNovember 12, 2020
Decision Letter - Yoshihiro Fukumoto, Editor
Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

PONE-D-20-35592

Association of premature menopause with incident pulmonary hypertension: A cohort study

PLOS ONE

Dear Dr. Natarajan,

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Yoshihiro Fukumoto

Academic Editor

PLOS ONE

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2.) During our internal checks, the in-house editorial staff noted that you conducted research or obtained samples in another country. Please check the relevant national regulations and laws applying to foreign researchers and state whether you obtained the required permits and approvals. Please address this in your ethics statement in both the manuscript and submission information.

3.) Thank you for stating the following in the Funding Section of your manuscript:

'Dr. Honigberg is supported by the U.S. National Heart, Lung, and Blood Institute

[T32HL094301-07]. Dr. Patel is supported by the U.S. National Heart, Lung, and Blood Institute

[T32HL007208]. Dr. Lahm is supported by grants from the U.S. National Heart, Lung, and

Blood Institute [R01HL144727-01A1] and the U.S. Department of Veterans Affairs [VA Merit

Award 1I01BX002042-07]. Dr. Ho is supported by the U.S. National Heart, Lung, and Blood

Institute [R01HL134893, R01HL140224]. Dr. Natarajan is supported by grants from the U.S.

National Heart, Lung, and Blood Institute [R01HL1427, R01HL148565, and R01HL148050],

Fondation Leducq [TNE-18CVD04], and a Hassenfeld award from the Massachusetts General

Hospital.'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Funding section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

'The authors received no specific funding for this work.'

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

'Dr. Lahm reports consulting income and speaker fees from Bayer, all unrelated to this work. Dr. Ho reports research support from Bayer, research grant funding from Gilead Sciences, and research supplies from EcoNugenics, all unrelated to this work. Dr. Kohli reports employment by Vertex Pharmaceuticals. Dr. Natarajan reports grant support from Amgen, Apple, and Boston Scientific, consulting income from Apple, and spousal employment by Vertex Pharmaceuticals, all unrelated to this work.'

We note that one or more of the authors have an affiliation to the commercial funders of this research study : Vertex Pharmaceuticals.

a.) Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement.

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We will update your Data Availability statement on your behalf to reflect the information you provide.

6.) 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.

[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: Yes

**********

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: This is an interesting manuscript describing the association of premature menopause with incident PH in UK Biobank participants.

I have one comment.

I recommend the authors to add the data of men for reference.

Reviewer #2: In this manuscript, the authors described the possibility of premature menopause as an independent risk factor for PH in women. This study addresses very important issue and indicated interesting results. I have one question. The authors described that incidence rates of PH were 6.6/10,000 person-years among women with premature menopause and 2.8/10,000 person-years among women without. I think the incident rate of PH in both groups seems to be a little higher. Please give your opinion about this issue.

**********

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Reviewer #1: No

Reviewer #2: No

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Revision 1

Response to Editors and Reviewers

We thank the editors and reviewers for their feedback and for the opportunity to submit a revised manuscript.

Editors

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

Author Response: We revised the manuscript and supporting documents in accordance with the journal’s style requirements.

Manuscript Change: We revised the manuscript and supporting documents in accordance with the journal’s style requirements.

2.) During our internal checks, the in-house editorial staff noted that you conducted research or obtained samples in another country. Please check the relevant national regulations and laws applying to foreign researchers and state whether you obtained the required permits and approvals. Please address this in your ethics statement in both the manuscript and submission information.

Author Response: We have a valid, approved data agreement with the UK Biobank, which is a resource available to researchers worldwide with appropriate credentials upon application.

Manuscript Change: “The UK Biobank is approved by the North West Multi-Centre Research Ethics Committee, and this research was conducted under UK Biobank application #7089.”

3.) Thank you for stating the following in the Funding Section of your manuscript:

'Dr. Honigberg is supported by the U.S. National Heart, Lung, and Blood Institute

[T32HL094301-07]. Dr. Patel is supported by the U.S. National Heart, Lung, and Blood Institute

[T32HL007208]. Dr. Lahm is supported by grants from the U.S. National Heart, Lung, and

Blood Institute [R01HL144727-01A1] and the U.S. Department of Veterans Affairs [VA Merit

Award 1I01BX002042-07]. Dr. Ho is supported by the U.S. National Heart, Lung, and Blood

Institute [R01HL134893, R01HL140224]. Dr. Natarajan is supported by grants from the U.S.

National Heart, Lung, and Blood Institute [R01HL1427, R01HL148565, and R01HL148050],

Fondation Leducq [TNE-18CVD04], and a Hassenfeld award from the Massachusetts General

Hospital.'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Funding section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

'The authors received no specific funding for this work.'

Author Response: We removed this text from the manuscript file. This paragraph summarizes the authors’ current research support. However, as stated, the authors received no specific funding for this particular work.

Manuscript Change: We updated the funding statement to read: “Dr. Honigberg is supported by the U.S. National Heart, Lung, and Blood Institute [T32HL094301-07]. Dr. Patel is supported by the U.S. National Heart, Lung, and Blood Institute [T32HL007208]. Dr. Lahm is supported by grants from the U.S. National Heart, Lung, and Blood Institute [R01HL144727-01A1] and the U.S. Department of Veterans Affairs [VA Merit Award 1I01BX002042-07]. Dr. Ho is supported by the U.S. National Heart, Lung, and Blood Institute [R01HL134893, R01HL140224]. Dr. Kohli reports employment by Vertex Pharmaceuticals, unrelated to this work. Dr. Natarajan is supported by grants from the U.S. National Heart, Lung, and Blood Institute [R01HL1427, R01HL148565, and R01HL148050], Fondation Leducq [TNE-18CVD04], and a Hassenfeld award from the Massachusetts General Hospital. The authors received no specific funding for this work.”

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

'Dr. Lahm reports consulting income and speaker fees from Bayer, all unrelated to this work. Dr. Ho reports research support from Bayer, research grant funding from Gilead Sciences, and research supplies from EcoNugenics, all unrelated to this work. Dr. Kohli reports employment by Vertex Pharmaceuticals, unrelated to this work. Dr. Natarajan reports grant support from Amgen, Apple, and Boston Scientific, consulting income from Apple, and spousal employment by Vertex Pharmaceuticals, all unrelated to this work.'

We note that one or more of the authors have an affiliation to the commercial funders of this research study : Vertex Pharmaceuticals.

a.) Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement.

“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

Author Response: To clarify, Vertex Pharmaceuticals did not fund this study and had no role in this study. Dr. Kohli’s employment with Vertex is entirely unrelated to this work. There was no commercial funding for this study. As stated, the authors received no specific funding for this work.

Manuscript Change: We updated the funding statement to read: “Dr. Honigberg is supported by the U.S. National Heart, Lung, and Blood Institute [T32HL094301-07]. Dr. Patel is supported by the U.S. National Heart, Lung, and Blood Institute [T32HL007208]. Dr. Lahm is supported by grants from the U.S. National Heart, Lung, and Blood Institute [R01HL144727-01A1] and the U.S. Department of Veterans Affairs [VA Merit Award 1I01BX002042-07]. Dr. Ho is supported by the U.S. National Heart, Lung, and Blood Institute [R01HL134893, R01HL140224]. Dr. Kohli reports employment by Vertex Pharmaceuticals, unrelated to this work. Dr. Natarajan is supported by grants from the U.S. National Heart, Lung, and Blood Institute [R01HL1427, R01HL148565, and R01HL148050], Fondation Leducq [TNE-18CVD04], and a Hassenfeld award from the Massachusetts General Hospital. The authors received no specific funding for this work.”

b.) Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.

Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests:http://journals.plos.org/plosone/s/competing-interests

Author Response: We updated the Competing Interests statement.

Manuscript Change: We updated the Competing Interests statement as follows: “Dr. Lahm reports consulting income and speaker fees from Bayer, all unrelated to this work. Dr. Ho reports research support from Bayer, research grant funding from Gilead Sciences, and research supplies from EcoNugenics, all unrelated to this work. Dr. Kohli reports employment by Vertex Pharmaceuticals, unrelated to this work. Dr. Natarajan reports grant support from Amgen, Apple, and Boston Scientific, consulting income from Apple, and spousal employment by Vertex Pharmaceuticals, all unrelated to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

5.) We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

Author Response: As is presumably well known to the PLOS ONE staff, the UK Biobank does not permit us to share its data publicly. However, as stated, UK Biobank data is available to researchers by application. Researchers may apply for UK Biobank data access at http://ukbiobank.ac.uk/enable-your-research/apply-for-access.

Manuscript Change: We provide an updated web address in the cover letter for researchers interested in obtaining UK Biobank data access.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Author Response: As above, the UK Biobank does not permit us to share its data publicly.

6.) 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.

Author Response: We updated supporting information and citations thereof in accordance with journal style guidelines.

Reviewer #1

This is an interesting manuscript describing the association of premature menopause with incident PH in UK Biobank participants.

I have one comment. I recommend the authors to add the data of men for reference.

Author Response: We thank the Reviewer for this suggestion. We added additional background summarizing data on female predominance in pulmonary hypertension.

Manuscript Change: Introduction: “Prior studies suggest a female predominance in PH of up to 4-fold, with greatest sex imbalance observed in PAH and among younger patients [3].”

Reviewer #2

In this manuscript, the authors described the possibility of premature menopause as an independent risk factor for PH in women. This study addresses very important issue and indicated interesting results. I have one question. The authors described that incidence rates of PH were 6.6/10,000 person-years among women with premature menopause and 2.8/10,000 person-years among women without. I think the incident rate of PH in both groups seems to be a little higher. Please give your opinion about this issue.

Author Response: We thank the Reviewer for the opportunity to clarify our results. As stated, the cumulative incidence rates of pulmonary hypertension over a median 11.1 years of follow-up were 0.73% and 0.31% in women with and without a history of premature menopause, respectively. Incident PH was diagnosed in 38 women with premature menopause over 57,910 person-years of follow-up, and in 409 women without premature menopause over 1,462,840 years of follow-up. These numbers correspond to incidence rates of 6.6/10,000 person-years and 2.8/10,000 person-years in women with and without a history of premature menopause, respectively. We added total person-years of follow-up to the results so that readers can more easily understand how these incidence rates were calculated.

Manuscript Change: Results: “Follow-up occurred over a median 11.1 (interquartile range 10.5-11.8) years of follow-up. Incident PH was diagnosed in 447 women (overall cumulative incidence 0.33%), including 38 (0.73%) with premature menopause and 409 (0.31%) without, over 57,910 person-years and 1,462,840 person-years of follow-up, respectively. Incidence rates were 6.6/10,000 (95% CI 4.5-8.6/10,000) person-years among women with premature menopause and 2.8/10,000 (95% CI 2.5-3.1/10,000) person-years among women without (difference +3.8/10,000 [95% CI 1.7-5.9/10,000] person-years, P<0.001).”

Decision Letter - Yoshihiro Fukumoto, Editor

Association of premature menopause with incident pulmonary hypertension: A cohort study

PONE-D-20-35592R1

Dear Dr. Natarajan,

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,

Yoshihiro Fukumoto

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

**********

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: (No Response)

Reviewer #2: In this manuscript, the authors described the possibility of premature menopause as an independent risk factor for PH in women. This study addresses very important issue and indicated interesting results. The response to my comment is fully addressed in the revised manuscript. I have no more comments.

**********

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

Formally Accepted
Acceptance Letter - Yoshihiro Fukumoto, Editor

PONE-D-20-35592R1

Association of premature menopause with incident pulmonary hypertension: A cohort study

Dear Dr. Natarajan:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Yoshihiro Fukumoto

Academic Editor

PLOS ONE

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