PONE-D-24-41990Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-2 with CIITAPLOS ONE

Dear Dr. Park,

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.

Efforts to set up new experimental approaches to gain new evidence that could enhance our understanding of the mechanisms underpinning the severe outcome of COVID-19 are valuable. The authors aimed to tackle the challenge through computational analysis of biological networks, developing a new strategy DGN detector on severe and non-severe samples of COVID-19. Regarding this point, there is a wide discrepancy in the sample size. Could the authors explain this choice and if it might raise biases on the reliability of their statistical analyses?

The authors should add the bibliographical references missing in several phrases throughout the text. At the end of the introduction, the authors should summarize the results and briefly outline their meanings. Please avoid indicating the structure of the manuscript. The writing includes excessive technical jargon, making it difficult for readers to follow the strategy employed and understand the implications of the findings.

The conclusion appears vague. Could the authors delve into the novelty of their findings?

Please submit your revised manuscript by Jan 15 2025 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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We look forward to receiving your revised manuscript.

Kind regards,

Elisabetta Pilotti

Academic Editor

PLOS ONE

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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

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2. Thank you for stating the following financial disclosure: [The work of Heewon Park was supported by NRF (RS-2023-00276559).

This research was also supported by AMED under Grant Number 23tk0124003h0001, 24tk0124003h0002, JSPS KAKENHI Grant Number 24H00009/22H03692 and JST Grant Number JPMJCR20H2].

Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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Reviewers' comments:

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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: No

Reviewer #2: Yes

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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 topic of the article is very interesting. However, the article requires some revision. Some of the comments are presented as:

1) Avoid writing abbreviations in the abstract

2) The abstract should be comprehensive that indicate the clear picture of the work

3) The introduction needs more details based on the coronavirus literature

4) What is the novelty of this work

5) Highlight the novelty in the introduction section

6) Provide the organization of the paper at the end of introduction section

7) What are the merits and demerits of the proposed scheme?

8) Compare the results with state of art method

9) What is the stopping criteria of the scheme?

10) Update the conclusions

11) The introduction can be updated by referring to more recent and relevant articles such as

a. "Bio inspired heuristic computing scheme for the human liver nonlinear model." Heliyon 10.7 (2024).

b. "A computational framework to solve the nonlinear dengue fever SIR system." Computer Methods in Biomechanics and Biomedical Engineering 25.16 (2022): 1821-1834.

c. "An artificial neural network approach for the language learning model." Scientific reports 13.1 (2023): 22693.

Reviewer #2: The research foresees a significant contribution considering that the topic is topical, the methods are correct and the results are within the expected range, taking into account the review of the background described in the research.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-41990R1Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-2 with CIITAPLOS ONE

Dear Dr. Park,

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.

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

In the abstract, I recommend using the acronym COVID-19 instead of repeatedly writing "coronavirus disease 2019." The same applies to the term “Human Leukocyte Antigen.” They only need to be explained at the first mention in the introduction.

As in the first letter, I again suggested the authors end the introduction with the novelties of their experimental strategies and the importance of the findings and eliminate the paragraph from lines 112-117. There is no need to specify the structure of the manuscript.

On line 83, I propose rephrasing “It can be through our results that…” to improve clarity.

Moreover, I encourage the authors to succinctly convey the novelties of their studies in one concise sentence, avoiding the breakdown into multiple points. I also suggest avoiding statements such as “can effectively reveal the COVID-19 severity mechanisms of COVID-19” (line 104) since the authors rightly underlined the limitations of their study.

Could the author delve into the description of samples, clarifying what constitutes the severe and non-severe groups?

At the end of the conclusions, the paragraph from lines 400 to 408 is somewhat convoluted and feels redundant in expressing key claims. A more straightforward presentation of these ideas would enhance readability and comprehension.

Lastly, I noticed some errors in typing, so please amend them.

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

Please submit your revised manuscript by Feb 01 2025 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 rebuttal 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 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,

Elisabetta Pilotti

Academic Editor

PLOS ONE

Journal Requirements:

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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[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.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-2 with CIITA

PONE-D-24-41990R2

Dear Dr. Park,

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,

Elisabetta Pilotti

Academic Editor

PLOS ONE

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