PONE-D-20-35523

COVID-19 Treatment Combinations and Associations with Mortality in a Large Multi-Site Healthcare System

PLOS ONE

Dear Dr. Coppock,

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 Apr 10 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Juan Carlos Lopez-Delgado, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them.

3. In statistical methods, please refer to any post-hoc corrections to correct for multiple comparisons during your statistical analyses. If these were not performed please justify the reasons. Please refer to our statistical reporting guidelines for assistance (https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting).

4. In your statistical analyses, please state whether you accounted for clustering by hospital. For example, did you consider using multilevel models?

5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[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?

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

**********

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

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

**********

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: No

**********

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: This is a well constructed paper that reports the findings from a sound and interesting study in the era of COVID-19. The paper reassesses the impact of pharmacological interventions on COVID-19 mortality over time using a logistic regression model. Some specific areas to attend to are noted below:

1. One concern I have is whether assumptions of logistic regression were met. Please clarify how you validated the assumptions of logistic regression. It’s important that the data used meet major assumptions of logistic regression for the analysis to be valid.

2. In the abstract, the author says that ‘multivariate logistic regression’ was used, but ‘multivariate’ and ‘multivariable’ are two distinct approaches. In the results section the author says that “for all patients, four treatment combinations were associated with lower mortality: …, and anticoagulation, corticosteroids and remdesivir (OR 0.42, p <0.026).” I believe the author meant to say (OR 0.42, p=0.026).

3. In line 35, the authors report that ‘In the United States, mortality related to COVID-19 has been on the decline. This may be due to a change in treatment strategies, a change in patient characteristics, or a combination of both.” A reference/evidence to support this statement might be helpful. Does the data used for the study support shift in treatment patterns as well as shift in patient demographics?

4. Table 1 reports the mean/percentage of patient demographics and clinical characteristics. Reporting a measure of variability (standard deviation or standard error of the mean) for inpatient length of stays (days) or showing a general distribution of the length of stay might be helpful. The author may also recode patient length of stay as a categorical variable.

5.Table 4 reports the differences in mortality between the two time periods. I thought a figure showing variability over time would serve this paper well, especially in showing outcome changes over time (showing confounding). Again, a measure of variability (confidence interval or standard deviation) might be helpful in understanding the results.

6. How was the model validated? Reporting a goodness of fit statistic (for example, the Hosmer Lemeshow goodness of fit test) might be helpful in evaluating how well the proposed model fits or predicts a set of observations.

Reviewer #2: Coppock et al. shared experience of COVID treatment and decreased COVID-19 mortality in a large health care system. The finding of RDV and steroid combination was associated with lower mortality coincide with the clinical trial result.

It is hard to separate each COVID-19 treatment effect retrospectively, as disease severity and situation can be varied. The author simplified using the binary model and hinted association of anticoagulation use in morality.

It is reassuring to find the decrease in mortality over time in the paper, but a few additions may make the paper more informative.

(1) Was disease severity (mild, moderate, severe, critical) divided among the group? I assumed most hospitalized patients had the severe or critical disease. However, in-hospital transmission cases or patients with other comorbid conditions might have been admitted for the mild or moderate disease. One must be cautious looking into the morality as critical COVID patients may receive certain drugs versus mild COVID patients may not receive other than a routine stand of care prophylactic anticoagulation but have better outcomes.

(2) Over 90% received anticoagulation in COVID 19 patients. Were there specific criteria for anticoagulation use?

(3) Regarding the cause of death in the ICU group without anticoagulation, were there higher thromboembolic events?

(4) Consider including recent Multi-platform trial data regarding anticoagulation in the discussion section.https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients

In the discussion, the author mentioned that improved medication alone might not explain the decrease in mortality over time, which illustrates COVID 19 care's complexity in a real-life setting.

**********

6. 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: Yes: Dong Heun Lee

[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.

COVID-19 Treatment Combinations and Associations with Mortality in a Large Multi-Site Healthcare System

PONE-D-20-35523R1

Dear Dr. Coppock,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Juan Carlos Lopez-Delgado, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear authors,

All questions from the previous reviewers have been addressed. All apologies for the delay, it was very difficult to find reviewers for the present manuscript in pandemic times.

However, remember PLOS One do not have editorial services and your manuscript has to be in perfect scientific english. Please, review in order to avoid any editorial mistake or minor error.

Take care & keep safe in these pandemic times. Warm regards,

Juan Carlos

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 #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 #2: Yes

Reviewer #3: Yes

**********

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

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 #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 #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 #2: Author appropriately addressed the comments and revised manuscript. I would like to congratulate the authors for sharing important findings in timely manner.

Reviewer #3: The revision of the present manuscript has been delayed due to the difficulties in finding appropriate reviewes in these pandemic times. All apologies for this delay. All concerns have been addressed. Remember to review english scientific language before editing.

**********

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 #2: Yes: Dong Heun Lee

Reviewer #3: No