PONE-D-22-11784Creatinine levels on admission are main modulators of COVID-19 severityPLOS ONE

Dear Dr. Zalloua,

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 see attached comments. The paper as currently written does not meet PLOS publication standards. The methods need further technical detail, the conclusions are not fully appropriate given the results, and the writing needs significant improvement.==============================

Please submit your revised manuscript by Aug 08 2022 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.

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Eili Y. Klein, PhD

Academic Editor

PLOS ONE

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Additional Editor Comments:

The paper and results are interesting, but the paper suffers from many severe flaws. Please change the title. This is a correlational analysis of ~800 patients not an RCT, thus the claim in the title is not correct and misleading. The writing throughout is poor and needs revision, please have it proofread more carefully. Additionally, the structure of the paper should adhere to scientific writing standards, do not put methods in the results, for example, clearly explain your cohort, etc, and put the tables in the paper not as some additional download.

On the methods, there needs to be significantly more included on the data, including, for example, what symptoms were extracted and when during their stay. The statistical analysis is also lacking in detail. Please refer to other papers published for advice on how to expand this section, but for example, "Multivariate logistic regressions were performed using statsmodels (ver 0.12.0) (17) and coxph in R (survival ver 3.2.1, survminer ver 0.4.9) (18)" tells the reader almost nothing about the methods and sticks in that a cox was performed as if it were a logistic regression. Also, why would data be managed in pandas but stats run in R, that makes little sense, statsmodels has a survival function. On the results and interpretation, just because something is correlated does not make it causative. Please remove any reference to creatinine levels being the causitive. The reviewers both have additional substantial concerns about the methods employed and you must add a robust limitations section.

Overall, the results are interesting, but the paper needs a tremendous amount of work for further consideration in this journal.

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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: 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: No

Reviewer #2: 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: No

Reviewer #2: No

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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 present paper explores different patient-level factors related to COVID-19 severity and fatality in a tertiary care centre in Lebanon.

Major comments

� The abstract should be re-structured, accounting for the importance of creatinine on COVID-19 severity in the introduction, for example. Methods should reflect the statistical techniques used throughout the paper ( i.e., regression, correlation tests, etc.). The results lack statistical measures, including coefficients or p-values for the main predictors. The discussion should account for the step forward linking creatinine and COVID-19 severity and how policies could be oriented for better diagnosis or treatments, etc. Also, those correlations exhibited are positive? Negative? Etc. It’s worth expanding on the main results of the research in the abstract.

� Could you please clarify the epidemiological, demographic, clinical and laboratory data retrieved in the methods section? This should be in order and right after you mention them all. Now you only mention clinical data. Also, the measurement might differ from study to study; would you mind adding more information on those characteristics and how they were measured? (It could be added in the supplementary material).

� Could you please clarify the main outcomes and how they are measured in the methods section? The statistical analysis section is only for statistical inference approaches, and therefore, the “Categorical and quantitative variable definitions are defined in Table S1. The two main outcome variables tested were fatality or “severe” COVID-19…..” should be moved up to patients characteristics or data collection.

� Statistical analyses. You speak about correlation in the abstract, but you used a logistic regression model, as this section depicts. Try to be clear on the regression method used. Did you test your outcomes? (i.e., their distributions, model residuals, multicollinearity, etc.). Also, did you use robust standard errors and if not, why?

� Logistic model using severe COVID-19 as the outcome variable. Did you compare severe COVID-19 against those patients having mild COVID-19, asymptomatic COVID-19 and those who did not have it? I think this has to be clarified, and comparison groups should be ordered more clearly.

� You applied a Cox regression for the mortality outcome. Could you please mention it in the statistical analysis subsection? Also, you might explain a bit about the primary predictors/exposures, model structure, how time was handled, censoring, etc.

� The results section should be restructured. The explanation of variables incorporated in the modelling should be added in the methods section to facilitate readers’ understanding and information flow.

� Supplementary material Table S1 should contain more detailed information. Were the variables analysed continuous or categorical? Why were the variables re-scaled, and does that impact the analyses? If they were re-scaled and centred, how and why did you do that?

� No limitations are mentioned in the discussion section, and attention should be drawn to population characteristics and sample size, lack of weighting techniques or representability of the whole population, etc.

� What are the study's main implications, or how can we connect this information with the current situation in Lebanon where people are being vaccinated (40% at least with one dose, 35% with two doses, and 9% with booster)?

� Main results tables were not attached in the PDF file.

Minor comments

� Please add the line numbers for the next revisions and to facilitate the review

� Please consider revising the main text; there are some spelling, format and text errors. For instance, “..In January 2020, The..” : the “the” shouldn’t be written in capital letters.

� Spell out WHO once first mentioned

� The term ‘vs’ should be written in formal English.

� Avoid the following words: “at the time of this writing”. Try to use the exact date to refer to the time and only if it is strictly needed.

� Would you mind referring to the hospital analysed on the attended population, whether it is representative of the whole Lebanese population, etc.

� If you first use WHO, then do not use its full name throughout the text.

� Do not repeat over and over that 819 patients were admitted because it is mentioned in the methods and should be shown in descriptive stats tables.

� Please spell out the M and F in the passage “66.77% M and 33.33% F”.

� There are some inconsistencies with the use of decimal figures.

� For p=0.000 is better to use p<0.001

� There is no need to repeat ethical considerations two times throughout the manuscript.

� Spell out the acronyms once first mentioned

� Define that COVID-19 intensity is defined by whether patients were intubated.

� Consider reframing the title by adding that it is based in a tertiary-care hospital in Lebanon.

� Consider proofreading your manuscript.

Reviewer #2: Dear Authors

The current case report is interesting. But I have some opinions and doubts.

Title

Creatinine levels on admission are main modulators of COVID-19 severity.

In my opinion, it would be better to inform there is an association between severe COVID-19 and serum creatinine levels or kidney function.

In abstract

Results

Correlation analysis of various comorbidities revealed that hypertension, diabetes,

being overweight, kidney disease,.../What kind of kidney disease? Would it be CKD? AKI? Nephritis? Or AKD?

Methods

This study investigated 819 COVID-19 patients admitted to the COVID-19 ward at a

tertiary care center in Lebanon and evaluated their vital signs and biomarkers./ Are the biomarkers from hospital admission?

Materials and methods

Patients

Clinical data on admission included clinical symptoms, biochemical markers on admission, previous medical conditions.../

You should report what symptoms were studied, and what kinds of biochemical markers were used to compute.

What were the medical conditions you registered?

And about outcomes, did you compute the frequency of COVID-19-related AKI? And the need for kidney replacement therapy?

Results

In my opinion, you should put the results of the multivariate analysis in a table

-Common comorbidities for intubation and fatality

What was the type of kidney disease? Was it CKD? or glomerulonephritis with therapy immunosuppression?

We interrogated hypertension, diabetes, being overweight (BMI ≥ 25kg/m2), kidney disease, CVD...

What was the CI you used? Was it 95%?

Overall, the intubation of COVID-19 subjects was highly associated with fatality (OR 71.20, CI[41.33-122.64], p <0.001) and with the oxygen consumption volume (OR, 3.18 CI[0.02-0.06], p<0.001)… so forth

-Biomarkers of intubation and COVID-19 fatality

Again, what was the CI you used? Was it 95%?

We investigated serum levels of platelets, ferritin, CRP, Hb, creatinine, WBC, SGOT and SGPT and analyzed these using intubation as an independent variable. CRP (OR 1.48, CI [1.21-1.81], p=0.000), WBC (OR 2.70, CI [1.68-4.32], p=0.000), SGOT (OR 3.08, CI [1.88-5.03], p=0.000)./

I suggest to write p<0.001 rather than p=0.000. …so forth.

Discussion

In my opinion, you should report on the weaknesses of the study

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Reviewer #1: No

Reviewer #2: Yes: Miguel Angelo Goes

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PONE-D-22-11784R1Creatinine levels on admission are associated with COVID-19 severityPLOS ONE

Dear Dr. Zalloua,

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.

Thanks for your earlier revisions, they have improved the paper, but unfortunately, while the reviewers approved of your changes, the paper is still not meeting criteria for publication in PLOS One. The major issue as I detail below is that I can't follow the statistics. The methods describe multivariate regressions, but I don't really see the results - though this may just be a problem related to how the results are described. Which brings me to the second issue which is the presentation of the article. While the writing is improved, it still needs work (in line with publication criteria #5). It would greatly aid the paper if you used the STROBE guidelines as well to help ensure the study is fully described. Thanks for the efforts here and I look forward to your next revision.

Please submit your revised manuscript by Oct 15 2022 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,

Eili Y. Klein, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

While the reviewers were satisfied with the revisions, there are still some issues with the language in the paper that makes it confusing and hard to read. I have made many suggested edits in the revised draft. I would also suggest having a editor review the paper to ensure compliance with criteria for english presentation (see #5: https://journals.plos.org/plosone/s/criteria-for-publication). Additionally, I am unable to fully follow the results as it relates to the methods. The methods suggest that multivariate logistic regressions were done, yet I only see binomial regression results. This may just be mislabeled - but needs to be clarified in line with publication criteria #3. I would highly recommend that the authors follow the STROBE guidelines for reporting on observational studies (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870880/), that will ensure that the results are clear. Finally, the title suggests just creatinine levels were important, but that is only part of the story as creatinine was highly associated with hypertension, and it probably is beyond the capability of this study to disentangle the relationship. I would suggest that the title more accurately reflect the study type (as per STROBE guidelines) as well as more accurately reflect results. For instance Observational study of factors associated with Morbidity and Mortality from COVID-19 in Lebanon, 2020-2021 or something similar. Overall I still feel this can be a publishable paper, but still needs some work to meet PLOS One publication criteria.

Minor comments

1. Add timeframe to methods

2. Remove use of correlation where not appropriate

3. Reduce the introduction length by removing extraneous passages and unlinked information

4. Please ensure the correct tense is used throughout

5. Be more clear about the other biomarkers and why only creatinine is your focus given that it was so highly correlated with hypertension

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

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

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: 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: Congratulations to the authors of the article. The English can certainly improve but its legible. All comments I made were correctly addressed. Therefore, I dont have more comments for the authors.

Reviewer #2: (No Response)

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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 #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Manuscript Zalloua.02.07.2022.PLOS R1.2.Clean.docx

Observational study of factors  associated with Morbidity and Mortality from COVID-19 in Lebanon, 2020-2021.

PONE-D-22-11784R2

Dear Dr. Zalloua,

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,

Eili Y. Klein, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: