PONE-D-24-38811Association between red blood cell distribution width-to-albumin ratio at admission and all-cause mortality in patients with acute pancreatitis based on the MIMIC-III databasePLOS ONE

Dear Dr. Wu,

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 Jan 10 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,

Jian Wu, M.D, Ph.D

Academic Editor

PLOS ONE

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Reviewers' comments:

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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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

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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: The manuscript by Wu et al presents a retrospective analysis investigating the prognostic significance of the RAR in AP patients. The study leverages data from the MIMIC-III database and demonstrates a significant association between RAR levels and 28-day and 60-day all-cause mortality. The topic is relevant and interesting, given the ongoing efforts to identify more reliable biomarkers for predicting outcomes in AP patients. However, revisions are required, I recommend major revisions before this manuscript can be considered for publication. I would like to suggest some points for improvement.

Major points:

1. The quartile divisions for RAR seem arbitrary. Were alternative methods of stratification (e.g., tertiles, clinical thresholds) considered? If not, justify why quartiles were chosen.

2. Subgroup analysis results need further interpretation. The lack of significance in diabetic patients and those with high SAPSII scores should be discussed.

3. I recommend sensitivity analyses should also be performed to test the robustness of findings.

4. The RAR AUC values (0.669 and 0.671) suggest only modest discrimination. Please compare these values with other commonly used scoring systems or biomarkers in acute pancreatitis.

Minor points:

1. Expand the background on the clinical utility of RAR.

2. It will be better to highlight variables with significant differences in table.1.

3. I recommend that the author considers language polishing to improve clarity and readability. For example, replace "thoroughgoing estimation" with "detailed evaluation".

Reviewer #2: 1. Statistical and Methodological Issues

Handling of Missing Data:

The article mentions the use of multiple imputation to handle missing data but does not clearly describe the imputation methods and steps. It should be clarified whether appropriate imputation models (e.g., regression-based or machine learning methods) were used.

It is recommended to explicitly report the proportion and distribution of missing data, especially for key variables like RAR-related metrics, to determine if there is systematic missingness.

Rationale for Grouping:

RAR was divided into quartiles for grouping, which, while convenient, may obscure potential nonlinear associations. Was the sensitivity of the results to grouping strategies (e.g., logarithmic partitioning or other clinically relevant thresholds) evaluated?

Multicollinearity of Variables:

Although the article mentions evaluating multicollinearity, it does not clearly explain which variables were adjusted or excluded. It is recommended to further elaborate in the results section on how multicollinearity issues were addressed, especially for interrelated variables such as Hb, BUN, and PT.

2. Interpretation of Results and Logical Consistency

Kaplan-Meier Analysis:

The Kaplan-Meier curves show significant differences in 28-day and 60-day survival rates, but the lack of significant difference between Q2 and Q3 at 28 days (p = 0.366) is not fully explained. This could indicate minor biological differences between these groups and should be further discussed.

Cox Regression Model:

The Cox regression analysis identifies RAR as a significant risk factor but does not sufficiently explain the logic for selecting adjustment variables. If potential confounders were not included in the model, this might affect the conclusions.

The results section does not mention whether the proportional hazards assumption was tested. It should be clarified if this assumption was met.

3. Clinical Interpretation and Applicability

Clinical Significance:

Although RAR is statistically significant, its actual clinical relevance has not been adequately explored. For instance, does RAR significantly improve the predictive power of existing scoring systems like SOFA or APACHE-II? A comparative analysis using ROC curves is suggested.

Comparison with Existing Studies:

The article mentions differences between RAR and other indicators (e.g., CRP/lymphocyte ratio) but does not discuss RAR's specific advantages (e.g., cost, ease of measurement). Are there direct comparative data available?

4. Potential Language and Expression Issues

Ambiguous Statements:

For example: "A significant positive correlation was noticed between RAR quartiles and all-cause mortality (p < 0.001)".

This statement is overly broad. It is recommended to specify what "significant" means in terms of effect size or HR range.

Suggested revision: "RAR quartiles demonstrated a dose-response relationship with all-cause mortality, with a hazard ratio of up to X.X in the highest quartile (p < 0.001)."

Inconsistent Terminology:

Terms such as "RAR" are sometimes referred to as a ratio and at other times as an index. Consistency should be maintained throughout the article, and its definition should be clarified when first introduced.

5. Potential Data Issues

Baseline Characteristics Imbalance:

Some baseline characteristics (e.g., ALT, PTT) show significant differences across groups in Table 1, but the article does not discuss their potential influence. It is recommended to address the potential biases introduced by these differences.

Lack of External Validation:

Reliance on a single database (MIMIC-III) limits the generalizability of the results. Mentioning the need for future validation with independent datasets in the discussion would strengthen the study.

6. Technical Details

ROC Analysis:

The reported AUC of 0.669, though statistically significant, indicates limited predictive ability. This should be acknowledged in the discussion, and the potential for combining RAR with other indicators to enhance predictive power should be explored.

Adjustment of Variables:

The article mentions adjusting for all variables with p < 0.05, but the comprehensiveness and methodology of the adjustments are unclear. For example, was the role of gender and other potential confounders thoroughly addressed?

7. Formatting and Citation Issues

Text Formatting:

Ensure that the reference style fully complies with journal requirements.

Citation Count:

The number of references appears to be relatively low. Consider adding citations to fully support the content of the article.

Conclusion:

The overall conclusions of the article are reliable, but there is room for improvement in the transparency of methods, interpretation of results, and discussion of clinical relevance. Addressing the above issues can significantly enhance the scientific quality and impact of the article.

Reviewer #3: This is an interesting study. Based on the MIME-III database, the authors explored the relationship between red blood cell distribution width and albumin ratio and all-cause mortality in patients with acute pancreatitis upon admission. The perspective is relatively novel and holds significant clinical value. I have a few main questions:

1. What is the rationale for setting the age threshold at 58.3 years?

2. Is there any additional data to further validate the relevant results and conclusions?

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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: No

**********

[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.]

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Attachments

Attachment

Submitted filename: review.docx

PONE-D-24-38811R1Association between red blood cell distribution width-to-albumin ratio at admission and all-cause mortality in patients with acute pancreatitis based on the MIMIC-III databasePLOS ONE

Dear Dr. Wu,

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 24 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.

Please include the following items when submitting your revised manuscript:

• 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Jian Wu, M.D, Ph.D

Academic Editor

PLOS ONE

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

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: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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: It seems that the authors did not address my comments. Could it be that they were overlooked? I am reiterating my previous comments below and kindly ask the authors to check the decision letters.

The manuscript by Wu et al presents a retrospective analysis investigating the prognostic significance of the RAR in AP patients. The study leverages data from the MIMIC-III database and demonstrates a significant association between RAR levels and 28-day and 60-day all-cause mortality. The topic is relevant and interesting, given the ongoing efforts to identify more reliable biomarkers for predicting outcomes in AP patients. However, revisions are required, I recommend major revisions before this manuscript can be considered for publication. I would like to suggest some points for improvement.

Major points:

1. The quartile divisions for RAR seem arbitrary. Were alternative methods of stratification (e.g., tertiles, clinical thresholds) considered? If not, justify why quartiles were chosen.

2. Subgroup analysis results need further interpretation. The lack of significance in diabetic patients and those with high SAPSII scores should be discussed.

3. I recommend sensitivity analyses should also be performed to test the robustness of findings.

4. The RAR AUC values (0.669 and 0.671) suggest only modest discrimination. Please compare these values with other commonly used scoring systems or biomarkers in acute pancreatitis.

Minor points:

1. Expand the background on the clinical utility of RAR.

2. It will be better to highlight variables with significant differences in table.1.

3. I recommend that the author considers language polishing to improve clarity and readability. For example, replace "thoroughgoing estimation" with "detailed evaluation".

Reviewer #2: (No Response)

Reviewer #3: The author has made appropriate modifications in response to the reviewer’s suggestions and has addressed the reviewer’s comments. Currently, I have no further comments, and I believe the current version is suitable for publication in the journal PLOS ONE.

**********

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 #1: No

Reviewer #2: No

Reviewer #3: No

**********

[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. Please note that Supporting Information files do not need this step.

Association between red blood cell distribution width-to-albumin ratio at admission and all-cause mortality in patients with acute pancreatitis based on the MIMIC-III database

PONE-D-24-38811R2

Dear Dr. Wu,

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,

Jian Wu, M.D, Ph.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

**********

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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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: The authors have addressed all the concerns and suggestions. The current version of the manuscript meets the standards for publication.

Reviewer #2: (No Response)

**********

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 #1: No

Reviewer #2: No

**********