Dear Dr. colakoglu,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Jamal Akhtar

Academic Editor

PLOS One

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Additional Editor Comments (if provided):

Thank you for submitting your manuscript "Inflammatory Discordance Phenotype in COPD: Dissociation Between Neutrophil-to-Lymphocyte Ratio and Conventional Markers" (PONE-D-26-20604) to PLOS ONE. The manuscript has been reviewed by two expert reviewers whose comments are provided below. After careful evaluation, I am requesting a Major Revision before a final decision can be made.

The reviewers hold divergent views. One reviewer finds the concept of inflammatory discordance in COPD clinically meaningful, while the other raises concerns about novelty relative to the existing literature. I have reviewed both perspectives and determined that the manuscript addresses an important clinical question but requires substantive revision to address the following concerns:

1. NOVELTY AND POSITIONING IN THE LITERATURE (Reviewer 1 concern)

The manuscript must more clearly and explicitly articulate what is novel about the findings, specifically how the concept of "inflammatory discordance" between NLR and conventional markers (CRP, ESR, WBC) provides new insight beyond what is already established in the COPD inflammatory biomarker literature. A focused literature review paragraph in the Introduction and/or Discussion should demonstrate the gap this study fills. Simply confirming known associations is insufficient; the specific phenotypic characterization and clinical implications of the discordance must be highlighted.

2. MULTIVARIABLE REGRESSION MODEL AND SAMPLE SIZE ADEQUACY (Reviewer 2 concern)

The multivariable regression model for the LTOT subgroup includes 5 predictor variables with only 31 patients. This exceeds the commonly recommended minimum of 10 events per predictor variable and raises the risk of model overfitting. The authors should:

a) Comment explicitly on the sample size adequacy for the multivariable model in the Methods and/or Limitations section.

b) Consider reducing the number of predictors (e.g., by using a priori-defined variables based on clinical rationale) or applying penalized regression methods (e.g., ridge or LASSO regression).

c) Alternatively, provide a clear clinical and statistical justification for retaining the current model structure.

Please provide a point-by-point response to each reviewer comment in your revision. The manuscript has technical merit and addresses a clinically relevant phenotype in COPD; with appropriate revisions it may meet PLOS ONE's publication criteria.

We look forward to receiving your revised manuscript.

[Note: HTML markup is below. Please do not edit.]

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: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: At present the findings appear largely confirmatory rather than hypothesis generating. There is so much literature available on current topic or very much similar topic. i do not see any novelty in this manuscript.

Reviewer #2: This manuscript addresses a clinically relevant and conceptually interesting question. The study is clearly written, the statistical approach is generally appropriate, and the concept of "inflammatory discordance" is a meaningful contribution to COPD phenotyping literature. I recommend acceptance.

Comments:

With only 31 patients in the LTOT group, the multivariable regression model includes 5 predictor variables. This may exceed appropriate variable-to-event ratios for regression modeling and risk overfitting. The authors should comment on the adequacy of the sample size for the multivariable model, or consider limiting the number of predictors.

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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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Reviewer #1: Yes:  Devendra Tripathi

Reviewer #2: No

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Attachments

Attachment

Submitted filename: COPD, NLR -The topic is cli.textClipping

Inflammatory Discordance Phenotype in COPD: Dissociation Between Neutrophil-to-Lymphocyte Ratio and Conventional Markers

PONE-D-26-20604R1

Dear Dr. colakoglu,

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,

Chiara Lazzeri

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: (No Response)

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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

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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: thank you for addressing all the comments and making requested revisions. The manuscript has been substantially improved and i am satisfied with writers response. and i have no further concerns.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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Attachments

Attachment

Submitted filename: Review.docx