Dear Dr Colhoun,

Thank you for submitting your manuscript entitled "Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): a population-based case-control study" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff [as well as by an academic editor with relevant expertise] and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Clare Stone, PhD,

PLOS Medicine

Dear Dr. Colhoun,

Thank you very much for submitting your manuscript "Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): a population-based case-control study" (PMEDICINE-D-20-02483R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jul 23 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*Please structure the abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions - "Methods and Findings" should be a single subsection heading).

*In the last sentence of the Abstract Methods and Findings section, please include a brief note about any keyl imitation(s) of the study's methodology.

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

*The authors could consider using an appropriate reporting guideline (eg, RECORD - https://www.equator-network.org/reporting-guidelines/record/ - designed to support reporting of observational studies using routinely-collected data) to enhance reporting of methods and findings in their study. If the authors choose to use this please upload the completed RECORD (or other) checklist as supporting information with the revised paper.

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Comments from the reviewers:

Reviewer #1: The authors used their unique linkage between administrative data holdings in Scotland to produce a case-control cohort of severely ill patients with COVID19, with general population controls (matched 1:7 on age, sex, and geography), documenting a series of risk factors for severe disease due to COVID19, potentially producing targeted populations for interventions in vulnerable cohorts. These validate previous reports from case series of severe disease, including prescription use, specific co-morbidities, age, and long-term care residence.

Unique aspects of this approach are the population-level data to provide robust and standardized data on controls, aiming to produce a reasonable case-control series that provides inference on relationships between specific risk factors and presence of severe disease.

Choice of matching by age/sex/geography is wise. Investigators have good experience with this dataset, and it appears cases and controls are reasonably well-matched in this regard.

Conclusions are appropriately tempered, based on the data provided, suggesting that any number of comorbidities are associated with risk.

Full case ascertainment of severe disease arguably limited by LTC deaths that do not reach hospital not accounted for, and may bias the rate ratios described.

Some further comments

- Challenges are the sheer number of univariate comparisons reported, and the limited corrections for multiple comparisons in place. Table 5 and 6, for example, are not particularly useful in interpreting the data, and arguably could be placed in the supplementary appendix, unless the purpose is to emphasize the non-specificity of the associations.

-The presence of less robust associations in common conditions such as ischemic heart disease, and more robust associations in rare diseases like chronic kidney disease, is notable. This is mentioned in the discussion, but should be understood better, given the conclusions.

-A great deal of the Results should be moved to the Methods, such as the multivariable model construction, and the prescription association data.

-Removing neoplasms from the prespecified list because of inability to discern who has already been shielded belies the fact that shielding is i) not 100% applied in populations; ii) not practiced in other regions, making the association between neoplasm and outcome an important one to consider for policy in other regions.

-Abbreviation 'scrip' in Table 4 not universal, would use 'prescription'

-Very hesitant, given the sample size, the inaccurate labelling problem, the exclusive examination of one ethnic group, and the limited generalizability, to include any reporting or conclusions on the ethnicity-based risk factors. Would suggest excluding altogether, and reporting on the need for more robust ethnicity-based data collection strategies

-

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Reviewer #2: See attachment

Michael Dewey

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Reviewer #3: The article confirmed the previously reported or suspected risk factors, for example age, sex, underlying diseases, for severe COVID-19. The new findings were any previous admission to hospital, or any prescription and many comorbidities beyond those designated by public health agencies were also associated with severe COVID-19. Being a care home resident had the highest risk.

The authors defined severe COVID-19 as those who had entered a critical care unit or died within 28 days of first positive nuclei acid test. There were a total of 2755 severe cases. It would be informative if the authors could break down the severe cases into those that were due to death within 28 days without admission to critical care units, those that were admitted to critical care units and survived, those admitted to critical care but perished. Under normal circumstances, one would expect most of the death cases would be among the critical care unit cases. However, If a large proportion of the severe cases in the study were due to death within 28 days without critical care admission, one could still argue that those cases actually needed critical care, but were not admitted because of lack of critical care beds and subsequently perished, therefore were truly severe cases. However, one could also argue that a large portion of the severe COVID-19 cases were not "severe COVID-19 "cases and therefore, were not admitted to critical care unit, but died of other sudden events such as stroke, myocardial infection and so forth. Being a care home resident had the highest risk of severe cases, it would be interesting to analyze whether what proportion of severe cases among care home residents were death within 28 days without admission to critical care units. Providing the severe cases breakdown and a more in-depth discussion will further strengthen the conclusions.

Table 3 showed association of Care Home, Any prescription, Any admission, and preexisting conditions with severe COVID-19. Since the authors concluded that many preexisting conditions were associated with severe COVID-19, may consider adding ANY comorbidity in the Table.

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr. Colhoun,

Thank you very much for re-submitting your manuscript "Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): a population-based case-control study" (PMEDICINE-D-20-02483R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by one of the reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Aug 07 2020 11:59PM.

Sincerely,

Clare Stone, PhD

Acting Chief Editor

PLOS Medicine

plosmedicine.org

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Requests from Editors:

Line 8 – Scottish ? national database?

Abstract – please include p values (here and throughout) for quantifiable data and where 95% Cis are given. In addition, please add summary demographic information to the abstract and the study dates also need to be quoted. Please begin the "Conclusions" subsection of the abstract "In this study, we observed that ... were associated" or similar.

Author Summary, please look at published examples, as your summary needs to be reformatted. It should be in bullet form with 3 headings. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Methods – the mention of the pre specified plan: Please provide a call out to where that can be accessed.

Please remove “Declarations” on page 11 as these are pulled in automatically from EM in the metadata.

Please use sections and paragraphs in reporting checklists as page number scan change in formatting and revisions.

At line 400, is this study available as a preprint that can be cited, for example?

In the reference list, where you cite preprints please add "[preprint]".

Comments from Reviewers:

Reviewer #2: The authors have addressed my points.

Michael Dewey

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr. Colhoun,

On behalf of my colleagues and the academic editor, Dr. Srinivas Murthy, I am delighted to inform you that your manuscript entitled "Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): a population-based case-control study" (PMEDICINE-D-20-02483R3) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

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A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Clare Stone, PhD

Managing Editor

PLOS Medicine

plosmedicine.org