-->PONE-D-25-67953-->-->Association between Red Cell Distribution Width (RDW)-Related Inflammatory Biomarkers and Prognosis in ICU Cirrhosis Patients: Evidence from MIMIC-IV-->-->PLOS One

Dear Dr. Li,

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.

Both reviewers found this interesting but there were concerns about:-->-->1. The frequency of testing (only baseline data)-->-->2. Missing laboratory parameters known to be important in outcomes in ICU mortality-->-->3. Overstatement of clinical extrapolation - the AUC was showed mild predictive value and both reviewers felt that this would not translate directly to clinical significance.-->--> -->-->Please submit your revised manuscript by May 15 2026 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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Reviewers' comments:

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

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Reviewer #1: Partly

Reviewer #2: Partly

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

Reviewer #1: No

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: Yes

Reviewer #2: Yes

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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: Summary

This retrospective cohort study using the MIMIC-IV database evaluates the association between RDW and RDW-derived indices (RAR, RPR, HRR) measured within 24 hours of ICU admission and short- and long-term mortality in critically ill patients with cirrhosis. The authors report statistically significant associations across multiple mortality endpoints and modest discrimination (AUC ~0.54–0.64), with small incremental improvements when adding RDW to established severity scores.

The topic is clinically relevant, and the dataset is appropriate. However, several important methodological and interpretative issues limit the strength of the conclusions in its current form. These concerns primarily relate to scaling and interpretability of effect sizes, potential overadjustment and collinearity, modeling of in-hospital mortality, and overstatement of clinical utility given modest predictive performance.

Substantial revision is recommended.

Major Comments

1. Interpretation and Scaling of Ratio Variables (Especially HRR)

The adjusted hazard ratios reported for HRR (~0.01 across endpoints) imply an implausibly large protective effect per unit increase. Given the narrow expected distribution of HRR, this likely reflects scaling or collinearity issues rather than a true biological magnitude of effect.

Although units are presented in Table 1, the manuscript does not clarify:

- The exact units used in constructing ratio variables

- The distribution and range of each ratio

- What a “1-unit increase” represents clinically

- Whether any transformations were applied

Hazard ratios should be reported per standard deviation or per interquartile range to improve interpretability. Additionally, variance inflation factor (VIF) analysis or other collinearity diagnostics should be provided, particularly because hemoglobin is adjusted for in models evaluating HRR.

Without clarification, the HRR results are difficult to interpret and potentially misleading.

2. Potential Overadjustment and Collinearity

The fully adjusted models include laboratory variables that are components of the derived indices (e.g., hemoglobin in models evaluating HRR; albumin and platelets in models evaluating RAR and RPR).

This raises concerns regarding:

- Collinearity

- Overadjustment

- Instability of regression coefficients

Sensitivity analyses excluding component variables from adjustment models would strengthen confidence in the reported associations.

3. Modeling of In-Hospital Mortality

In-hospital mortality is analyzed using Cox regression without detailed description of time origin, censoring assumptions, or consideration of discharge alive as a competing event.

Because discharge alive precludes subsequent in-hospital death, this is technically a competing risks scenario. At minimum, the authors should clarify the time-to-event structure and justify the use of standard Cox regression.

4. Modest Predictive Performance and Overstatement of Clinical Utility

The reported AUC values for RDW and derived indices range from approximately 0.54 to 0.64, indicating weak to moderate discrimination.

Although incremental AUC improvements when adding RDW to SAPS II, MELD, or SOFA are statistically significant, they are small (<0.02). The clinical relevance of such marginal improvements is uncertain (likely negligible).

Accordingly, statements suggesting that these biomarkers “enhance clinical decision-making” or “optimize resource allocation” should be tempered. The data support statistical association and modest incremental prognostic information, but not strong standalone predictive utility.

5. Cohort Derivation and Missing Data

Patients without RDW or derived index measurements within 24 hours were excluded. The manuscript does not report:

The number excluded for missing laboratory values

A flow diagram of cohort derivation

Comparison of included vs excluded patients

Given that laboratory testing intensity in ICU populations correlates with illness severity, exclusion based on missing laboratory data may introduce selection bias. Greater transparency in cohort derivation is required.

Minor Comments

Consider modeling biomarkers using restricted cubic splines to assess non-linearity rather than dichotomizing at the median in Kaplan–Meier analyses.

The limitations section should explicitly acknowledge:

- Modest discrimination

- Lack of external validation

- Potential collinearity and scaling concerns

Clarify laboratory units and ensure consistency (e.g., albumin in g/dL vs g/L).

Subgroup analyses appear exploratory; clarify whether interaction terms were formally tested and whether correction for multiple comparisons was considered.

Several grammatical and formatting issues should be corrected for clarity.

Overall Recommendation

The manuscript addresses a clinically relevant question using a well-established database. The associations observed are generally statistically robust. However, concerns regarding scaling and interpretation of ratio variables, potential overadjustment, modest predictive performance, and overstated clinical implications require substantial revision before the work can be considered for publication.

With careful methodological clarification and more restrained interpretation, this study could provide a useful contribution to the literature on readily available prognostic markers in ICU cirrhosis.

Reviewer #2: This manuscript presents a retrospective cohort study evaluating the prognostic value of the red cell distribution width (RDW) and related biomarkers (RDW-to-albumin ratio (RAR), RDW-to-platelet ratio (RPR), and

haemoglobin-to-RDW ratio (HRR)) in ICU patients with cirrhosis using the MIMIC-IV database. The topic is clinically relevant, as prognostic stratification in critically ill cirrhosis patients remains a major challenge. The use of a large, well-established database and multiple mortality endpoints (in-hospital, 90-day, 365-day) strengthens the study.

The authors demonstrate statistically significant associations between RDW-related indices and mortality outcomes, with RDW and HRR showing the strongest predictive value. However, while the study is methodologically comprehensive, there are several concerns regarding interpretation, clinical relevance, and presentation that should be addressed before the manuscript can be considered for publication.

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Reviewer #1: Yes:   Jody Rusch

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Reviewer Report PONE_D_25_67953.docx

Attachment

Submitted filename: PONE-D-25-67953_reviewer RDW Reviewer comments.pdf

Association between Red Cell Distribution Width (RDW)-Related Inflammatory Biomarkers and Prognosis in ICU Cirrhosis Patients: Evidence from MIMIC-IV

PONE-D-25-67953R1

Dear Dr. Li,

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,

Elizabeth S. Mayne, M.D.

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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: 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 #1: (No Response)

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: (No Response)

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: (No Response)

Reviewer #2: Reviewer Report – PLOS ONE

Manuscript ID: PONE-D-25-67953

Title: Association between Red Cell Distribution Width (RDW)-Related Inflammatory Biomarkers and Prognosis in ICU Cirrhosis Patients: Evidence from MIMIC-IV

Final Review Report

The authors have addressed the concerns raised in the previous round of review, and the revised manuscript has improved substantially in methodological rigor, clarity of reporting, and balance of interpretation.

In particular, the revisions appropriately addressed:

•Addition of sensitivity analyses and expanded discussion of residual confounding and external validity.

•More cautious and appropriate interpretation of ROC/AUC findings and clinical applicability.

•Expanded discussion regarding the limitations of retrospective single-centre analyses and the need for prospective validation.

The discussion and conclusion sections are now more appropriately tempered and aligned with the observed predictive performance. The manuscript no longer overstates the clinical applicability of the findings, and the limitations are adequately acknowledged.

Overall, I believe the authors have satisfactorily addressed my comments and that the manuscript is suitable for publication in its revised form.

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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.

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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: Yes:   Jody Rusch

Reviewer #2: Yes:   Dr Susan Louw (PhD), University of the Witwatersrand, Johannesburg, South Africa

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