-->PONE-D-25-56864-->-->Multi-Omics and Network-Based Dissection of Left Bundle Branch Pacing in Heart Failure: Immune Remodeling, Hub Gene Identification, and Drug Repurposing Opportunities-->-->PLOS One

Dear Dr. Jin,

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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?

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: No

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: No

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

Reviewer #4: 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

Reviewer #3: No

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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: In “Multi-Omics and Network-Based Dissection of Left Bundle Branch Pacing in Heart Failure: Immune Remodeling, Hub Gene Identification, and Drug Repurposing Opportunities“ Sun et al. re-analyse three rather old gene expression data sets (published between 2006-2016) in order to gain (molecular) insights into heterogeneous clinical responses to left bundle branch pacing (LBBP). Note that LBBP was introduced in 2017! So it is not clear to me how diffentially expressed genes are detected given that the three data sets - on top – have rather different study designs. The rest of the paper is built on top of this rather unclear basis and the authors continue with method descriptions that are rather generic with very little transparency with regard to what has actually been done.

Reviewer #2: How the preprocessing carried out and other classification, PCA and Matrix details could be explained with mathematical mode. which tool supported the authors to conclude their findings. Gene sequence and other medicine terms may not be verified by my review.

Reviewer #3: I preface this review by reminding the editors and author that I am not a Cardiologist. I am not, outside of the nature of the datasets used. My review will be related to the machine learning methodology, reproducibility of the results and statistics.

Reproducibility: I would request that the authors submit, in some fashion, the source code for the project. Without it, reproducibility would be extremely challenging.

Data Quality:

Although the GEO Datasets are publicly available as stated, they are Heart Failure datasets, not specific datasets for the modality LBBP. The datasets do not contain individuals, that I could see, underwent LBBP.

This creates a circular logic problem for the model and the outputs are heart failure biology, not LBBP specific. Without the full dataset to evaluate and the source code, the unified transcriptomic resource created is for heart failure. Prehaps review of the full dataset will reveal some specific LBBP data but current data and design do not support author claims.

To complete a comprehensive review for the manuscript both the raw and processed data and source code would need to be submitted.

Reviewer #4: The research paper “Multi-Omics and Network-Based Dissection of Left Bundle Branch Pacing in Heart Failure” presents a comprehensive integrative transcriptomic analysis aimed at characterizing the molecular landscape associated with left bundle branch pacing (LBBP). While the study appears promising, the manuscript would benefit from a more detailed explanation of the statistical models and computational algorithms used for differential expression analysis, functional enrichment, immune infiltration profiling, weighted gene co-expression network analysis (WGCNA), hub gene identification, and drug–pathway prediction.

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Reviewer #1:  Yes: André Scherag

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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Multi-Omics and Network-Based Exploration of Potential Molecular Pathways in Heart Failure Relevant to Left Bundle Branch Pacing Response Heterogeneity: Immune Remodeling, Hub Gene Identification, and Drug Repurposing Hypotheses

PONE-D-25-56864R1

Dear Dr. Jin,

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,

Redoy Ranjan, MS (CV&TS), Ch.M. (Edin), 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 #3: 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 #3: Yes

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

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 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 #3: 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 #3: 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 #3: The authors did an excellent job of absorbing and incorporating changes to the paper, making it a much stronger manuscript. The workflow is well constructed and all data processing steps named precisely and accurately and the thoroughness of the methodology shines through in this version of the paper. The datasets afford sufficient availability, the R code transparency allows for improved explainability through reproducibility and the authors do a significantly better job of interpreting the outputs in this version. The revised framing, in my mind, appropriately identifies and calls out the model capabilities and identifies next steps which could potentiate clinical readiness.

This paper now does exactly what it states that it will do with the data, generates hypotheses which with further exploration could have substantial clinical impact.

The authors visualizations of the immune mediated remodeling and the effects of on connectivity are exciting findings and I would encourage continued exploration of these findings, perhaps longitudinally or with specific time series analyses.

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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 #3: No

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