PONE-D-21-28780Impaired Pulmonary Ventilation Beyond Pneumonia in COVID-19: A preliminary observationPLOS ONE

Dear Dr. Kim,

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: 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 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: No

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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 authors presented a retrospective study of analyzing the relationship of ventilation defect with pneumonia by CT-based FAN flow model for COVID-19 patients. Their results demonstrated the availability to assess functional impairment in COVID-19 from the integration of clinical imaging with computational modelling. In addition, the diagnostic accuracy in identifying dyspneic patients by the ventilation defect analysis with the FAN was also satisfying. The study addresses an important issue and the results are inspiring for clinicians. Some questions still remain to be cleared.

1, Since the FAN flow model is the foundational methodology of this work, the authors should provide more details about the flow calculation (may be in the supplementary material), such as the flow equations, model hypothesis, simulation method and so on. I understand that the modeling details have been described in their published studies as they referred to. However, it is better to explain the basic methodology in this paper for the readers who know the FAN model for the first time.

2, Is there a better way to display the results in Fig. 4? For example, the panels can be arranged based on the different groups.

3, The authors declared that there was an outlier (x=1.2%, y=7.8%) in Fig. 5. However, there are two more outliers in the figure, one is around (18%, 3%), the other is around (19%, 29%). Is there any analysis about this result?

4, In Fig. 6a & b, the authors showed the percentage ventilation and ventilation CV with different lobes indicated by different colors. The correlations showed in the text, however, were given by the total data. How are the correlations between ventilation with pneumonia on different lobes?

5, Some typos. For example, Page 16, Line 355, 356, extra space.

Reviewer #2: The authors reported interesting findings from a pilot study performed on patients with COVID-19 (n=25) and healthy controls (n=4). They provided a post-processing analysis to quantify regional lung ventilation. Dyspnoic CVOID-19 patients had both higher anatomical involvement and larger ventilation defect as compared to non-dyspnoic patients. A direct correlation linked anatomical involvment with ventilation defect; a single patient had a moderate non-concordance (eg higher ventilation defect as expected by the anatomical involvmente). This is a well performed stimulating study, very appealing from a technical point of view. My main concern regards the authors' hypothesis, that though intriguing, should be partly downgraded in light of the study result; indeed, the evident finding from the present study is the robustness of the FAN technique in the evaluation of COVID-19 pneumonia as compared to the traditional anatomical evalutaion. However, the possibility of FAN to provide additional information, though plausible, relys on a single outlier and should be more carefully reported.

Minor comments:

- If available, some few more data could be reported (i.e. dimer level, CRP, P/F etc. and their correlation with CT findings)

- Figure 5 could be displayed with dots of different colour according to the underlying study group (asymtpomatic, dyspnoic etc)

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Reviewer #1: No

Reviewer #2: No

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Impaired Pulmonary Ventilation Beyond Pneumonia in COVID-19: A preliminary observation

PONE-D-21-28780R1

Dear Dr. Kim,

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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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,

Ruud AW Veldhuizen

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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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: Thank you for addressing in a proper way the Reviewers' comments. I have no further comments to be made to the articlr.

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

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

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

Reviewer #1: No

Reviewer #2: Yes: Luca Arcari