PONE-D-25-24494Leveraging Dynamic Stability to Infer Regulation in Protein-Protein Interaction Networks: A Study of Infectious Vulnerability in COPD.PLOS ONE

Dear Dr. Broderick,

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Academic Editor

PLOS ONE

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This work was supported by Rochester Regional Health (G. Broderick) in conjunction with the US Department of Defense Congressionally Directed Medical Research Programs (CDMRP) under Peer Reviewed Medical Research Program (PRMRP) award W81XWH1910804 (Broderick - PI; Sethi - Partnering PI). VIDO receives operational funding from the Canada Foundation for Innovation through the Major Science Initiatives Fund and from the Government of Saskatchewan through Innovation Saskatchewan and the Ministry of Agriculture (G. Broderick).”

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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.

Reviewer #1: No

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: 1. This manuscript presents a novel computational approach to infer directed regulatory relationships from undirected protein-protein interaction networks using cross-sectional data from COPD patients. The work addresses an important clinical problem and introduces an innovative methodological framework. From informatics point of view, I believe this is an important work in network biology field and have shown potentially a new method of analysis this type of data.

2. However, as a reader who is interested in implementing this pipeline, I would suggest all the codes and data be made available in accordance to the open science standard. The current methods section describes the fundamental of the method but lacking the implementation or codes related to the implementation. The codes can be made available in a GitHub repository.

3. Apart from that, are the data for the LC-MS available in a database? The link to the data should be made available.

4. The availability of the entire pipeline and use case data is important in order for this analysis to be implemented on other datasets from different diseases.

Reviewer #2: Here are my comments:

1. The experiments appear to have been conducted exclusively on male subjects. This raises concerns about potential gender bias in the results. Including female subjects would have strengthened the study by improving the generalizability and robustness of the findings

2. In Figure 7, the gene network visualization displays various connections or interactions among genes. However, the meaning of the different edge colors is not explained. Additionally, are there certain genes within the network that play a more central or influential role? Clarifying these aspects would provide greater biological insight into the findings.

3. It would enhance the paper if the authors compared their proposed method against other established approaches, such as those referenced in [3, 4]. A comparative analysis would better highlight the strengths and potential limitations of the proposed method.

4. All figures should be positioned close to their corresponding references in the main text. As currently presented, it is difficult to follow the narrative without frequently scrolling between the text and the figures. This disrupts the flow of reading and makes it harder to interpret the results effectively.

5. Several figures, particularly Figure 3, lack a proper legend. Including clear legends is essential for readers to understand the plotted information without ambiguity.

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Reviewer #1: No

Reviewer #2: No

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Leveraging Dynamic Stability to Infer Regulation in Protein-Protein Interaction Networks: A Study of Infectious Vulnerability in COPD.

PONE-D-25-24494R1

Dear Dr. Broderick,

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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Kind regards,

Hong Qin, PhD

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

**********

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: My concerns have been addressed. The access to data and codes will help the field and allow other groups to replicate the work onto other datasets. Thank you.

Reviewer #2: The authors addressed all of my concerns I raised before. They did additional experiments and added new plots to answer my questions. They have used topological data analysis techniques to find out the important genes from a network. I want them to add the full description of the TDA technique they used in this version.

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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: No

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