Dear Dr.  Chen,

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Marwan Salih Al-Nimer, MD, PhD

Academic Editor

PLOS One

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Additional Editor Comments:

Major revision

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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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.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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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: This manuscript investigates the relationship between the Red Cell Distribution Width-to-Platelet Ratio (RPR) and in-hospital mortality in critically ill stroke patients using the eICU database. The study addresses a clinically relevant question regarding accessible biomarkers. However, the article has some methodological issues. Specifically, the rationale for covariate selection in the regression model is not sufficiently justified, and the distinction between "association" and "prediction" is blurred. Furthermore, crucial information regarding the calculation of the primary exposure (RPR) and the visual data (Figure 1) is missing or unclear. Given the retrospective nature of the study and the lack of external validation, the authors should refrain from overemphasizing "prediction" and focus on "independent association."

Reviewer #2: The study has the following shortcomings:

This study adopts a retrospective cohort design, which could reveal the association between the red cell distribution width-to-platelet ratio (RPR) and in-hospital mortality in critically ill stroke patients, but cannot establish a causal relationship between them. There is a possibility of reverse causation: the progression of the patient's condition may lead to an increase in red cell distribution width (RDW) and a decrease in platelets, thereby elevating RPR, rather than elevated RPR directly increasing the risk of death. This potential logical relationship has not been effectively excluded.

The study uses data from the 2014–2015 US multicenter eICU database, which is nearly a decade old. The research conclusions drawn based on outdated data have limited applicability in current clinical practice.

The database lacks key neurological information such as stroke subtype (ischemic or hemorrhagic), lesion location, and National Institutes of Health Stroke Scale (NIHSS) score. This makes it impossible to conduct stratified analysis for different subtypes of stroke patients and difficult to fully adjust for the impact of the degree of neurological impairment on prognosis, which may lead to confounding bias in the study results.

The data are only derived from the US population, lacking samples from other ethnic groups (such as Asians, Africans, etc.) and regions. Thus, the applicability of the findings to non-US populations remains unclear.

The study only uses a single RPR measurement within 24 hours of admission as the exposure variable, without considering the dynamic changes of RPR during hospitalization. Relying solely on a single measurement may fail to fully reflect the patient's disease progression and real prognostic risk. The NIHSS score is an important indicator for evaluating the degree of neurological impairment and prognosis in stroke patients, but it was not included as a confounding factor in the adjustment, which may lead to overestimation or underestimation of the association between RPR and mortality.

Ischemic stroke and hemorrhagic stroke differ significantly in pathophysiological mechanisms, treatment strategies, and prognosis, and the predictive value of RPR for mortality may vary between the two. However, the study did not perform subgroup analysis based on this key stratification factor, resulting in insufficient precision of the research conclusions.

The study mentions using the missForest algorithm for multiple imputation to handle missing data, but it does not detail the specific parameter settings of the algorithm, the convergence test results during the imputation process, nor fully compare the differences in data distribution characteristics before and after imputation (only stating that there were no significant differences in key variables). This makes it difficult to evaluate the rationality and reliability of the imputation method.

The study uses a multivariable logistic regression model to analyze the association between RPR and in-hospital mortality, but only reports the odds ratio (OR) and confidence interval without assessing the model's calibration (e.g., Hosmer-Lemeshow test). Thus, the consistency between the model's predicted results and actual observed results cannot be determined.

The study only briefly mentions that RPR integrates pathophysiological processes related to inflammation and coagulation function, but does not deeply analyze the molecular mechanisms and pathophysiological pathways through which RPR affects patient prognosis in combination with the specific pathological mechanisms of stroke, resulting in insufficient theoretical depth of the research.

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Peer Review Report1.docx

The Association between RDW-to-Platelet Ratio and In-Hospital Mortality in Critically Ill Stroke Patients: A Retrospective Cohort Study Based on the eICU Database

PONE-D-25-61250R1

Dear Dr. Yu Chen,

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,

Marwan Salih Al-Nimer, MD, PhD

Academic Editor

PLOS One

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