Dear Dr. Tang,

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.

Please submit your revised manuscript by Feb 03 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,

Fırat Aşir

Academic Editor

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?

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: I Don't Know

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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: No

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

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Revision Report for Manuscript PONE-D-24-45155

General Overview

The manuscript presents a robust study exploring the genetic overlap between abdominal aortic aneurysms and periodontitis through an innovative use of bioinformatics and machine learning approaches. While the survey enters a novel field and provides noteworthy contributions, the paper’s format and content organization require substantial revisions to ensure clarity, conciseness, and improved readability. Below, I outline the strengths, fundamental limitations, and detailed suggestions for improvement. I do not have corrected misspellings and grammatical errors.

Strengths of the Paper

The paper proposes an interdisciplinary approach based on bioinformatics, machine learning, and human disease. The use of multiple, validated, and independent datasets is a strength of the study and has noteworthy clinical relevance in identifying crucial genes and predicting targeted drugs, which potentially may help future research in this innovative field for future in vitro and in vivo clinical studies.

However, the paper presents several limitations and requires major revisions.

Sections 2 and 3 need to be rewritten in a more intelligible way; they are fragmented into numerous subsections that can be condensed, namely sections 2.3, 2.4, 2.5, 2.6, and 2.7. Extensive use of R libraries was also adopted in the analysis. Therefore, my major recommendation is to consolidate the subsection to streamline the methodology into fewer subsections and move the r libraries into footnotes or the appendix to clean the main text. In section 2.6, the authors should report the tuning of the algorithm used, such as n-fold CV in the LASSO method, and the lambda used, why they selected these among others, and why they are suitable for the analysis.

Another issue related to the text flow is assessing the core of the research question through section 3. I suggest splitting the section to consider the main result of the analysis on one side and show the robustness of the analysis on the other.

The discussion section is, on the contrary, too dense and requires careful review. The first part is more suitable for the conclusion section; the second, third, and fourth paragraphs are too long and partially should be moved to a subsection, while the last paragraph should be moved to the conclusion section. Therefore, I recommend condensing the discussion by focusing on the most critical findings in a dedicated subsection and highlighting the study results coherent with the literature cited. Then, move to the authors’ comments.

I also recommend expanding the conclusion section and summarizing the limitation of the study here, providing a more concrete outlook for future research, especially (as the authors note) for in vitro and in vivo studies, considering that the survey is purely computational with no experimental validation.

Specific suggestion.

Introduction:

Clarify the main research questions and how bioinformatics and machine learning address gaps in understanding the genetic overlap between AAA and periodontitis.

Materials and Methods (Section 2):

Simplify and consolidate subsections where possible.

Move detailed descriptions of software packages and tools to an appendix and include a brief explanation of critical methodologies in the main text.

Results (Section 3):

Ensure results are presented, focusing on the most impactful findings.

Consider using figures or summary tables to make data more accessible.

Discussion:

Shorten this section by removing repetitive descriptions of results and focusing on the biological significance of the findings.

Discuss limitations more comprehensively, including the need for experimental validation, and suggest how future studies could address these gaps.

Conclusion:

Expand this section to highlight the key outcomes of the study and its relevance.

Provide a more robust outlook on future research directions, particularly the potential for experimental studies and clinical trials.

Figures:

All figures must be uploaded in vectorial format and high quality to improve the readability, both on paper and in the supplementary material. Figure 3A adjusts the label of the . Figure 7, add the value of the area under the curve and group the ROC plots according to the training and validation set of the two diseases.

Provide also a git repository of the R-script and the datasets.

Conclusion

The manuscript is well-conceived and presents a novel approach to understanding the genetic interplay between AAA and periodontitis. However, significant revisions are needed to improve the readability and structure of the paper, provide a more straightforward narrative, and acknowledge limitations. Addressing these issues will make the study more compelling and accessible to a broader audience.

Reviewer #2: Periodontitis is a chronic inflammatory disease, which exacerbates systemic inflammatory response. Abdonimal aortic aneurysms (AAA) are linked to inflammatory responses. It is reasonable to postulate the association between the two. The authors sought to identify genes involved in the comorbidity mechanism of AAA and periodontitis. To improve prediction accuracy and robustness, multiple machine learning models were employed. In this study, the authors identified IL1B, PTGS2 and SELL, which are all significant mediators in inflammatory response. Those gene polymorphisms are associated with the host susceptibility. Although the authors did validate the study model, a few clarifications would make this research article more meaningful. The authors should provide more detailed information regarding the periodontal status and AAA conditions:

1. What are the staging and grading of the periodontal cases included in the study? Were there more severe cases among unstable AAA? Any correlation between the severity of periodontitis with AAA diameter and volume?

2. It is well understood that periodontitis is a site-specific disease. Can the authors provide more periodontal parameters such as probing depth (>6mm) of the cases?

3. Besides of reducing inflammation, what is the clinical implication of this study?

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Reviewer #1: No

Reviewer #2: No

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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.

Dear Dr. Tang,

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.

• 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 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,

Yang Shi, PhD

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.

Additional Comments from the Academic Editor:

1. Reviewer 1 and Reviewer 2 were the reviewers of the initial submission. Reviewer 3, an expert in biomedical research with expertise in genetics and molecular biology, was newly invited by me to assess the biological significance of this manuscript. This reviewer has provided constructive suggestions for the authors to enhance their discussion of the biological significance and insights of their findings, which I hope the authors will address in the revised manuscript.

2. As noted by Reviewers 1 and 3, the manuscript would benefit from professional language editing to improve clarity and readability. There are grammatical errors and ambiguous expressions throughout the manuscript that the authors need to correct in the revised version.

3. Please ensure that all figures are appropriately referenced and provided in high resolution in the revised version, as noted by Reviewers 1 and 3. There are a few other minor issues noted by these two reviewers that I hope the authors can address.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: **Manuscript Title**: Revealing potential interfering genes between abdominal aortic aneurysm and periodontitis through machine learning and bioinformatics analysis

General Assessment

The authors provided detailed respones to the previous review, as well as for they improvement into revise the manuscript. The manuscript has resulted in more coherent and improved in depth. The emphasis on limitations have all been improved and they improved the clarity of the methodological descriptions, the organization of the results. Overall, the study now presents its findings in a clearer and more professional manner, demonstrating better scientific rigor and transparency. However minor revision are needed.

Summary of Revisions and Assessment

- Methods and Organization:

The structure of the paper has been improved and consolidated. Moving the technical details (e.g., R packages) to the appendix was an improvement, which now allows the main narrative to flow more naturally.

Parameter Reporting: While the authors mention model tuning was adjusted, it would still be beneficial to ensure explicit mention of cross-validation strategy and hyperparameter settings within the main Methods text or a table, even briefly. Moreover, would be appreciated further consolidation in the Methods section especially when considering in section 2.3 "power value of 8" and "sensitivity parameter of 3" add meaningful detail or references, and section 2.5 "score set to 0.4".

- Results Section

Summary Tables: The addition of summary tables in Section 3 provides clear at-a-glance insights into the key findings and strengthens data accessibility for readers.

Redundancy Removed: The text now avoids repetitive descriptions and instead focuses on main outcomes, which sharpens the analytical focus of the Results.

- Discussion Section

The authors have made commendable improvements in the review process by removing overly dense paragraphs and enhancing the critique of their own study, which contributes to a more balanced interpretation. Additionally, by explicitly acknowledging the lack of experimental validation and suggesting follow-up studies, they provide important context that positions the work for greater translational relevance.

- Conclusion

The conclusion now provides a more rounded synthesis of key findings and implications, which was previously lacking, especially for future research process. The author should also provide further details/advices for future research.

- Figures and Reproducibility

Figure 7 Clarifications: The authors claim that AUC values and groupings are clearly delineated. This should now be visually apparent and appropriately annotated in the figure legend and/or captions. Also provide a vectorial form for figures in supplementary material.

Code Accessibility: The availability of code via GitHub is a critical improvement, supporting reproducibility and further validation by the community. Ensure that the repository is well-documented (README, data notes, usage instructions) to enhance reproducibility. Highlights the presence of the GitHub in the Data and Method section.

Additional Minor Points to Check Before Acceptance

- Ensure high-resolution/vector-quality figures are provided for final production, especially for complex visuals like ROC curves and enrichment analyses.

- Confirm that the GitHub link is clearly mentioned in the manuscript (preferably in Methods and Data Availability sections).

- Consider including a table of gene-drug interactions mentioned in the final section for improved readability.

- One final editorial sweep is recommended to check for grammar, spelling, and formatting consistency. E.g. sect 3.2 In brief or Briefly.

Final Recommendation: Minor Revisions

The manuscript has significantly improved and effectively addresses the primary concerns raised during the initial review. The authors have demonstrated responsiveness, transparency - especially with the public repository for reproducibility - and a commitment to scientific rigor. With the minor clarifications mentioned above, I am confident that this manuscript is now suitable for publication and will contribute meaningfully to our understanding of the genetic interplay between abdominal aortic aneurysms and periodontitis.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

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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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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

Reviewer #3: Yes:  Yin Wan

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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

Attachments

Attachment

Submitted filename: PONE-D-24-45155_comments.docx

Revealing potential interfering genes between abdominal aortic aneurysm and periodontitis through machine learning and bioinformatics analysis

PONE-D-24-45155R2

Dear Dr. Tang,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Yang Shi, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: The authors have thoroughly addressed all previous comments, significantly improving the manuscript. The revised paper now meets the standards for publication. I recommend acceptance.

Reviewer #3: (No Response)

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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 #3: No

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