-->PONE-D-25-57450-->-->Economic Burden of Pulmonary Arterial Hypertension in Switzerland.-->-->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: Yes

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.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.-->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.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: The issue of medical costs in PH treatment is a major challenge that is a common topic around the world. I would like to point out a few issues.The issue of medical costs in PH treatment is a major challenge that is a common topic around the world. I would like to point out a few issues.The issue of medical costs in PH treatment is a major challenge that is a common topic around the world. I would like to point out a few issues.The issue of medical costs in PH treatment is a major challenge that is a common topic around the world. I would like to point out a few issues.

1.Annual cost estimates in this study are derived by extrapolating short observation periods, which introduces uncertainty that requires clearer justification and sensitivity analysis.

Patient-reported outcomes were collected for the preceding 4 weeks and annualized by multiplication, while healthcare utilization data from medical records covered 6 months and were annualized by doubling. Although commonly used in cost-of-illness studies, this approach assumes temporal stability of costs.

PAH is characterized by episodic exacerbations, hospitalizations, treatment changes, and possible seasonal effects; therefore, short-term observations may not be representative of average annual resource use. Extrapolation using fixed factors (e.g., ×13 or ×2) may lead to under- or overestimation.

To strengthen the robustness of the findings, I recommend clarifying the rationale for the chosen extrapolation factors and performing sensitivity analyses using alternative annualization assumptions (e.g., varying the 4-week factor within ×10–14). Demonstrating that the main conclusions remain consistent across these scenarios would substantially improve transparency and confidence in the annual cost estimates.

2.Cost estimates by disease severity, particularly for the ESC/ERS high-risk group, appear unstable due to very small subgroup sizes. In rare diseases such as PAH, mean costs can be strongly influenced by a few high-cost cases, increasing the risk of chance effects.

To improve robustness, I recommend reporting medians and measures of dispersion in addition to means, providing uncertainty estimates (e.g., bootstrap confidence intervals), and considering complementary analyses modeling disease severity as a continuous variable rather than relying solely on categorical stratification.

Reviewer #2: This reviewer has the following comments to be addressed.This reviewer has the following comments to be addressed.This reviewer has the following comments to be addressed.This reviewer has the following comments to be addressed.

1) In table 2, epoprostenol is lacked. In addition, p.o., i.v., s.c., or inhalation should be clearly stated. And, steroids and immunosuppressants in patients associated with connective tissue disease (CTD) are better to be added.

2) Did the presence or absence of i.v./s.c. prostacyclin analogues affect healthcare costs and national burden?

3) In CTD-associated PAH, SSc and non-SSc are clearly distiguished in ESC/ERS PH guideline. Did the difference between SSc vs. non-SSc affect healthcare costs and national burden in CTD-PAH patients? Furthermore, did the presence or absence of steroids and immunosuppressants affect in those patients?

4) Which of WHO-FC, ESC/ERS 2022 risk strata, PAH subgroup clinical classification, and the presence or absence of i.v./s.c. prostacyclin analogues had the greatest impact on healthcare costs/burden?

5) How are the results of Switzerland in this study expected to differ from those in the United States, Europe, and Asia?

6) Can the authors consider in more depth the clinical impact of this study results, its potential effect on reducing the burden on patients, and its impact on the future of PAH treatment?

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Reviewer #1: No

Reviewer #2: No

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Economic Burden of Pulmonary Arterial Hypertension in Switzerland.

PONE-D-25-57450R1

Dear Dr. Tomonaga,

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.

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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

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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.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.-->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.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: I believe that the revised manuscript has been carefully and thoroughly revised, and that all reviewer comments have been adequately addressed. I have no further comments.

Reviewer #2: (No Response)

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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 published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->..-->

Reviewer #1: No

Reviewer #2: No

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