PONE-D-23-04388Excess burden of respiratory and abdominal conditions following COVID-19 infections during the ancestral and Delta variant periods in the United States: An EHR-based cohort study from the RECOVER ProgramPLOS ONE

Dear Dr. Jay K Varma, 

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.

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Academic Editor

PLOS ONE

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"This research was funded by the National Institutes of Health (NIH) Agreement OTA OT2HL161847 as part of the Researching COVID to Enhance Recovery (RECOVER) research program."

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Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"This study is part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, which seeks to understand, treat, and prevent the post-acute sequelae of SARS-CoV-2 infection (PASC). This research was funded by the National Institutes of Health (NIH) Agreement OTA OT2HL161847 as part of the Researching COVID to Enhance Recovery (RECOVER) research program. NIH played a role in evaluating and developing the overall structure of the RECOVER research program, but not in the design and analysis of this specific study."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. One of the noted authors is a group or consortium "the RECOVER Consortium". In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

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: No

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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

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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: Thank you for the opportunity to review this manuscript. It is generally well written and clear, so my comments focus primarily on a few methodological questions and presentation.

In the methods, the authors state, “Patients were defined as having a comorbidity… 2 corresponding diagnoses documented during the baseline period.” I believe that I read earlier that the baseline period was as short as 7 days. Is it possible to have had 2 corresponding diagnoses during that short a time period? This is minor, but it does not make sense to me. Also, earlier in that paragraph “inpatients” should be “inpatient.”

Which covariates from Table 1 were included in the hazards ratio calculations? These should be stated in the methods.

The excess burden is quite different between the two time periods. Is it possible that more people died during the ancestral period, thus did not develop PASC? Were they included if they subsequently died? Was death considered a PASC? In any event, it seems that these differences in the magnitude of excess burden bears more discussion.

Figure 1 Legend: “Patient” should be “Patients,” suggest adding “(index date)” after “SARS-CoV-2.” The text about measurement dates following the title should be included in the methods.

Figure 1: There seem to be connector lines missing below the SARS cases and controls boxes and individual connector lines missing below the 6 boxes on the next row.

Figure 2: What is the significance of the dotted lines?

Figure 3: This figure is pretty, but a bit confusing. I do not believe that the figure of the person is necessary and should come out. You could more clearly present the data by adding a column to the left of the “all” column that indicates the system for each group of symptoms/conditions and also remove the color from those boxes. It might be helpful to state that the figure is a heat map and indicate that the “thermometer” is the legend.

I did not see reference to Supplemental Fig 2 in the text. Did I miss it?

Reviewer #2: I thank you the authors for the work they have done. I think the manuscript touches upon an important topic in medicine. The large sample makes the analysis robust, although this study is observational in nature. The main limitation of the study is that even though the data may reveal some associations, it has to be interpreted with caution due to the inherent limitations of the study design. I have some comments that would help to improve the overall quality of the manuscript:

-Can the authors comment how many facilities send data to the networks used to collect the data of the study?

-One important limitation for the study is that negative cases are only classified based on the data from the in-network facilities, but if a patient classified as “negative” had indeed a positive test reported in a different facility (or an in-house / over-the-counter test) it would be missed by the current study search strategy. The authors should state this important limitation in the discussion section of the paper.

-As the authors state, an important limitation is the fact that other infections can account for the PASC conditions. However, the authors should also mention that non-infectious conditions could account for some of these conditions, and that’s another limitation as the authors did not control for comorbid conditions.

-What does the U099/B948 code mean?

-The authors should also state in their limitations that the imputation of a missing ADI value with median ADI per site may be not an accurate estimation.

-Can the authors comment on the fact that the number of patients with positive tests during the time the Delta variant circulated was significantly lower than the number of positive tests during the time of the ancestral variant? As the Delta variant is believed to have spread faster, it is really surprising the authors found these differences. If this is related to the fact that most positive patients for the ancestral variant were diagnosed in NY state, the authors should elaborate on this. The same is true for the negative cases. There seems to be a significantly lower number of cases tested during the Delta period.

-Could the authors provide the data of how many positive cases and how many negative cases in each variant wave (ancestral vs. delta variant) were from New York, and how many were from Florida?

-I am not sure if the following sentence is appropriate for the discussion “In the absence of hypoxemia, no current treatment exists for persistent dyspnea, although novel strategies to help patients, such as breathlessness training, are being evaluated.18”it feels a little bit out of context to me.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-04388R1Excess burden of respiratory and abdominal conditions following COVID-19 infections during the ancestral and Delta variant periods in the United States: An EHR-based cohort study from the RECOVER ProgramPLOS ONE

Dear Dr. Varma,

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.

==============================

The requested changes have been made. However, some minor fixes are missing. Please follow what the reviewers suggest.

==============================

Please submit your revised manuscript by Feb 25 2024 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,

Roberto Scendoni

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.

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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: (No Response)

Reviewer #3: (No Response)

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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 #3: (No Response)

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

Reviewer #1: Yes

Reviewer #3: (No Response)

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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: Yes

Reviewer #3: (No Response)

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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 #3: (No Response)

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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: The authors have addressed my concerns, but on Figure 1, the last two boxes indicate that they were patients without targeted diagnosis. Just confirming that this should not be with targeted diagnosis.

Reviewer #3: Indeed, it is acceptable to request only a minor revision, specifying the need to expand the bibliography, as it is currently too concise. Specifically, include reviews on coinfections in hospitalized individuals, along with a brief comment (e.g., doi: 10.3389/fmed.2021.681469; doi: 10.3390/pathogens12050646; doi: 10.1186/s13054-023-04312-0; doi: 10.1016/j.ijid.2020.10.040).

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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 #3: No

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[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.

Excess burden of respiratory and abdominal conditions following COVID-19 infections during the ancestral and Delta variant periods in the United States: An EHR-based cohort study from the RECOVER Program

PONE-D-23-04388R2

Dear Dr. Varma,

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.

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Kind regards,

Roberto Scendoni

Academic Editor

PLOS ONE

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