Dear Dr. Yang,

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.

ACADEMIC EDITOR's comment

1. Data Transparency and Model Structure Please revise the methodology section to improve the visibility and signposting of these data sources. Regarding the Markov model structure, the reviewers have proposed differing modifications concerning health states and transition logic. You are granted the autonomy to decide whether to modify the model structure or retain the current design; however, if the current structure is maintained, you must provide a robust justification in the discussion addressing why the suggested modifications (e.g., additional severity states or recovery transitions) were not adopted.

2. Specific Methodological Queries:  Please address the following specific points regarding your study design and parameters:

• Efficacy Data: Explicitly state whether the RESPECT trial was the sole source of efficacy data. If so, please articulate the rationale for this selection to the exclusion of other available trials.
• Time Horizon: Justify the selection of a 30-year time horizon rather than a lifetime horizon. Please explicitly state the life expectancy of the target population to demonstrate whether the chosen horizon serves as an appropriate proxy for lifetime analysis.
• Screening and Complications: Clarify whether the analysis includes the costs associated with screening for Patent Foramen Ovale, such as Transesophageal Echocardiography (TEE). Additionally, address whether the costs and clinical effects (disutilities) of potential procedural complications were incorporated; if not, please discuss the potential impact of these exclusions on the findings.

3.Please refer to the attached file for detailed comments from Reviewer#1

4.Please carefully evaluate any literature suggested for citation by the reviewers. You should only include references that are scientifically relevant to your study; you are under no obligation to cite works solely because they were suggested during peer review.

5.Please ensure the manuscript is written in a style accessible to a general audience. As PLOS ONE is a multidisciplinary journal, please avoid or clearly explain technical jargon specific to health economics or neurology to ensure the findings are clear to readers outside these specialized fields.

Please submit your revised manuscript by Feb 20 2026 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.

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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,

Jeerath Phannajit, M.D, Ph.D.

Academic Editor

PLOS One

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“This work was supported by the Fudan-Fosun Research Fund (Grant No. FNF202329). The funders had no role in study design, data collection and analysis, Manuscript Click here to access/download;Manuscript;full manuscript.docx decision to publish, or preparation of the manuscript.”

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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:

“This work was supported by the Fudan-Fosun Research Fund (grant number FNF202329). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

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Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

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6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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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?

Reviewer #1: Yes

Reviewer #2: Partly

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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

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Authors have written the manuscript beautifully and presented an interesting study. I will recommend that the authors carefully address all the comments to make the manuscript for final consideration.

Reviewer #2: Some suggestions are listed below:

1. The authors should reconsider the change of conclusion for general readership from the viewpoint of this journal.

2. The model uses transition probabilities from "contemporary clinical trials." Could the authors specify exactly which trials (e.g., RESPECT, CLOSE, REDUCE, etc.) were the primary source for the recurrent stroke rates and long-term event probabilities? Furthermore, were these probabilities adjusted for the Chinese patient population, and if so, what was the methodology for that adjustment?

3. The model includes stable, post-minor recurrent stroke, post-moderate recurrent stroke, and death. Why was a state for post-major/severe recurrent stroke not included? Given that severe stroke can significantly impact costs and QALYs, how does the exclusion of this state potentially bias the cost-effectiveness ratio (ICER)?

4. Please detail the source of the utility values (quality-of-life weights) used for each health state. Were these values derived from Chinese population studies using tools like the EQ-5D, or were they adopted from Western literature? If the latter, how was the transferability to the Chinese context validated?

5. A 30-year horizon is used. Given that the PFO closure procedure itself is a one-time cost with potentially lifelong benefits, how did the authors ensure that the long-term compliance and sustained efficacy of both PFO closure and medical therapy were accurately modeled over this extended period? Specifically, are the initial relative risk reductions from trials maintained throughout the 30 years, and is this assumption justified?

6. Since the analysis is from the Chinese healthcare payer perspective, what specific costs were included (e.g., procedure costs, hospitalization, initial and long-term medication, device/implant cost, stroke rehabilitation, long-term care)? Were indirect costs (like lost productivity), which can be substantial, excluded, and if so, how might their inclusion affect the dominance finding?

7. What is the breakdown of the initial PFO closure cost? Specifically, what cost was assumed for the PFO closure device itself, and does this cost reflect actual procurement prices negotiated by Chinese hospitals or a general market price?

8. The results state that psychological comorbidity costs exerted a great influence on the results. Could the authors elaborate on the nature and magnitude of these costs? How were they measured, and why do they have such a disproportionate impact on the model's output?

9. The PSA showed a 94.2% probability of cost-effectiveness. While this is high, could the authors provide the corresponding Cost-Effectiveness Acceptability Curve (CEAC)? This visual representation would be very helpful to see the probability of cost-effectiveness across a range of willingness-to-pay thresholds, not just the single stated threshold.

10. How do the authors expect these results to generalize across different tiers of hospitals or regions within China (e.g., tertiary hospitals in major cities vs. county-level hospitals), where costs, expertise, and patient profiles may vary significantly?

11. I will recommend authors to use (https://doi.org/10.3390/scipharm93010006 and https://doi.org/10.1093/narmme/ugae005 and https://doi.org/10.1002/ange.202215245 in addition to their references.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: RAHUL RANJAN

Reviewer #2: No

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[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.]

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Attachments

Attachment

Submitted filename: Commnets.docx

Dear Dr. Yang,

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Minor revision required:

1. Please reconcile the base-case discounting assumption because the manuscript Methods (“Model structure / time horizon and discounting”) states that costs and outcomes were discounted at 5% annually (line 159), but the one-way sensitivity analysis table uses 3% as the base-case discount rate (Table 5).
2. Please recheck the price year because the Methods (“Cost Parameters”) states all costs were expressed in 2021 USD (line 195), while the base-case results table 3 is labeled as USD (2023).
3. Please resolve the mismatch where acute stroke management costs in the Methods (page 20, line 213) and Table 1 are around $1,901 (minor) and $2,513 (moderate), but Table 5 lists “Stroke treatment cost (acute)” as $28,500 (range $20,000–$40,000).
4. Please make sure aspirin dose consistent because Table 1 lists aspirin 75 mg daily, but the Methods text lists aspirin 100 mg daily.
5. Please consider use term moderate-to-severe stroke instead of moderate stroke consistently across the manuscript and tables, because the text explicitly states the category includes severe disability (mRS 4–5).
6. Results table should align with stated cost year and discounting assumptions: After harmonizing the price year and discount rate, please re-generate Table 3 so its totals, incremental values, and any dominance/ICER statements are consistent with the corrected assumptions

====================================

Please submit your revised manuscript by Apr 04 2026 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 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 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,

Jeerath Phannajit, M.D, Ph.D.

Academic Editor

PLOS One

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. 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.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

PLOS Data policy

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

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6. Review Comments to the Author

Reviewer #1: Every comment has been effectively addressed, point by point, and is suggested for publication in this esteemed journal.

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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.

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: RAHUL RANJAN

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[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.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Cost-Effectiveness of Percutaneous Patent Foramen Ovale Closure versus Medical Therapy for Cryptogenic Stroke Prevention: A Chinese Healthcare Perspective

PONE-D-25-45858R2

Dear Dr. Yang,

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.

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Kind regards,

Jeerath Phannajit, M.D, Ph.D.

Academic Editor

PLOS One