Description and analysis of representative COVID-19 cases–A retrospective cohort study

Yannis Herrmann; Tim Starck; Niall Brindl; Philip J. Kitchen; Lukas Rädeker; Jakob Sebastian; Lisa Köppel; Frank Tobian; Aurélia Souares; André L. Mihaljevic; Uta Merle; Theresa Hippchen; Felix Herth; Britta Knorr; Andreas Welker; Claudia M. Denkinger

doi:10.1371/journal.pone.0255513

Peer Review History

Original SubmissionMarch 23, 2021
10 May 2021 Decision Letter - Tai-Heng Chen, Editor PONE-D-21-06695 Description and analysis of representative COVID-19 cases – a retrospective cohort study PLOS ONE Dear Dr. Denkinger, 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 Jun 24 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. 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, Tai-Heng Chen, M.D. Academic Editor PLOS ONE Journal requirements: 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. Thank you for stating the following in the Funding Section of your manuscript: [This work was supportedby internal COVID funds of the Heidelberg University Hospital] We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 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: [The authors received no specific funding for this work.] Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 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 #2: Yes Reviewer #3: Partly Reviewer #4: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #3: No Reviewer #4: 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 #2: Yes Reviewer #3: Yes Reviewer #4: 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 #2: Yes Reviewer #3: Yes Reviewer #4: Yes ****** 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 #2: The authors conducted a retrospective survey on the COVID-19 patients in Southern German, described clinical features and assessed potential risk factors for hospitalization. Overally, the article is well written and well designed. In my opinion, it need only some minor revisions. 1.Statistics: what kind of multivariate logistic regression model was performed, backward stepwise or others？ 2.I thinck hospitalization is influenced potentially by many factors, e.g., disease severity, compliance of patients, the affordability of health care system, and even management policy in each country. For example, in China, even asymptomatic and mild COVID-19 patients are hospitalized. So, I suggest this should be discussed in section of limitation. 3.P value is not a trend. So the sentences should be expressed in a more appropriate way (Page 20, line 358, line 364). Reviewer #3: 1. This is an interesting study but the findings are not of sufficient originality and there is a lack of novelty as compared to a number of similar studies already published on the topic. In addition, there are some concerns need to be thought carefully. 2. Patients enrolled from February 7 to June 30 were included in the follow-up, and the paper needs to explain when the retrospective investigation was conducted. 3. There are major problems with the study design. The study design of this paper is not a retrospective cohort study, not based on the exposure of certain risk factors, but divided the outcomes of the cases into different study levels and collected relevant data retrospectively, which should be a cross-section investigation design and then do case-control study and risk factors analysis. 4. In the study, 30% cases lost to follow-up may affect the distribution of the pathogen of the disease, making the results less reliable. So, suggest to analysis the basic situation of the lost. 5. Regarding to the risk factor analysis, it is more appropriate for the authors to conduct univariate analysis firstly to find meaningful variate and then do multiple logistic regression. 6. The authors should notice that all COVID-19 including are required to hospital for isolation in China. 7. Line 212-213, page 19, please check the number of percent and its corresponding type of patients. It is inconsistent with the figure presented in Table 2. Reviewer #4: General Comments Thank you very much for choosing me as a reviewer of this manuscript. I think this article is well written and it looks into an important and concerning problem nowadays as is COVID-19. This study is a demographic and epidemiological analysis of a German cohort representative of an administrative district. They found that age, male sex and pre-existing lung conditions were associated with severe illness. The statistical analysis is well done and well discussed. Although is difficult to assess the real incidence of SARS-CoV-2 infection in this cohort and asymptomatic patients’s rate could be infra estimated, they analyzed 69% of all COVID-19 registered cases with an important underrepresentation of the group of severe disease. All these limitations are reported at the discussion by the authors. Finally, I have provided some specific comments point by point. Discussion Data regarding BMI index is missing in the study and it has also been related to worse outcomes in other large community-based cohort study (Gao M, Piernas C, Astbury NM, Hippisley-Cox J, O'Rahilly S, Aveyard P, Jebb SA. Associations between body-mass index and COVID-19 severity in 6•9 million people in England: a prospective, community-based, cohort study. Lancet Diabetes Endocrinol. 2021 Apr 28:S2213-8587(21)00089-9). Please, add this comment to the discussion section. Supplementary material Please translate the questionnaire into English ****** 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 #2: Yes:** Liang Chen Reviewer #3: No Reviewer #4: 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/. 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Revision 1
22 May 2021 Author Response Journal comments to the author: 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 Response: thank you for this comment. We have made appropriate adaptions throughout the document. 2. Thank you for stating the following in the Funding Section of your manuscript: [This work was supportedby internal COVID funds of the Heidelberg University Hospital] We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 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: [The authors received no specific funding for this work.] Response: we excluded the funding statement in the manuscript and wish to keep the following statement (“This work was supported by internal COVID funds of the Heidelberg University Hospital.”) 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Response: thank you for this remark. Appropriate changes have been incorporated throughout. Reviewer 1: 1. The authors conducted a retrospective survey on the COVID-19 patients in Southern German, described clinical features and assessed potential risk factors for hospitalization. Overally, the article is well written and well designed. In my opinion, it need only some minor revisions. Response: we appreciate the reviewer’s comment. 2. Statistics: what kind of multivariate logistic regression model was performed, backward stepwise or others？ Response: thank you for this comment! We did not use any stepwise model selection algorithms but selected the variables for the multivariate analysis from a series of univariate screening models. We clarified this in lines 134-138 3. I think hospitalization is influenced potentially by many factors, e.g., disease severity, compliance of patients, the affordability of health care system, and even management policy in each country. For example, in China, even asymptomatic and mild COVID-19 patients are hospitalized. So, I suggest this should be discussed in section of limitation. Response: we appreciate the reviewer’s comment and have added this to the limitation section (line 443-446) 4. P value is not a trend. So the sentences should be expressed in a more appropriate way (Page 20, line 358, line 364) Response: thank you for this comment, we have changed the sentences (line 417-423) Reviewer 3: 1. Patients enrolled from February 7 to June 30 were included in the follow-up, and the paper needs to explain when the retrospective investigation was conducted. Response: thank you for your remark. We added information on the period of conduct (line 60-61). Data collection started on March 19, 2020 and concluded on June 30, 2020. 2. There are major problems with the study design. The study design of this paper is not a retrospective cohort study, not based on the exposure of certain risk factors, but divided the outcomes of the cases into different study levels and collected relevant data retrospectively, which should be a cross-section investigation design and then do case-control study and risk factors analysis. Response: we appreciate the reviewer’s valuable feedback. A case control study or prospective cohort study might have been of higher value. However, given the dynamics of the early pandemic this was not feasible. We believe that or study fills all the formal criteria for a retrospective cohort study in that it: - Describes a cohort selected by the occurrence of an outcome - Retrospectively evaluates risk factors that might have contributed to said diseases, i.e. accumulated significantly in our population Retrospectively assesses said risk factors contribution to the severity of the disease (thus stratifying the populations into groups, e.g. age, smoking status and using this stratification as case-control setup) 3. In the study, 30% cases lost to follow-up may affect the distribution of the pathogen of the disease, making the results less reliable. So, suggest to analysis the basic situation of the lost. Response: thank you for this comment. We highlighted this limitation of the study at the end of our discussion. (line 454-455) In addition, we compared the age structure of our study population to the overall population in the district tested positive for SARS-CoV-2 to identify potential underrepresentation of age groups. (line 129-131; line 194-197) 4. Regarding to the risk factor analysis, it is more appropriate for the authors to conduct univariate analysis firstly to find meaningful variate and then do multiple logistic regression. Response: we appreciate the reviewer’s comment and have revised the appropriate methods section to indicate that we had done a univariate analysis first. The section should be clearer now. (Line 139-143) 5. The authors should notice that all COVID-19 including are required to hospital for isolation in China. Response: we are thankful for this information and have acknowledged this. This is not the case in Germany. 6. Line 212-213, page 19, please check the number of percent and its corresponding type of patients. It is inconsistent with the figure presented in Table 2 Response: we appreciate that the reviewer pointed this out. We have identified the mistake and included appropriate changes but could not find inconsistencies on page 19. Reviewer 4: 1. Discussion Data regarding BMI index is missing in the study and it has also been related to worse outcomes in other large community-based cohort study (Gao M, Piernas C, Astbury NM, Hippisley-Cox J, O'Rahilly S, Aveyard P, Jebb SA. Associations between body-mass index and COVID-19 severity in 6•9 million people in England: a prospective, community-based, cohort study. Lancet Diabetes Endocrinol. 2021 Apr 28:S2213-8587(21)00089-9). Please, add this comment to the discussion section. Response: thank you for this helpful comment! Unfortunately, the data collected on weight in our study was not reliable, which led us to exclude the information. However, we added this risk factor to our discussion (line 417-424). 2. Supplementary material Please translate the questionnaire into English Response: we appreciate the reviewer’s feedback and have added supplement tables that depict the assessed variables of the questionnaire. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0255513.r002
16 Jun 2021 Decision Letter - Tai-Heng Chen, Editor PONE-D-21-06695R1 Description and analysis of representative COVID-19 cases – a retrospective cohort study PLOS ONE Dear Dr. Denkinger, 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 Jul 31 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. 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, Tai-Heng Chen, M.D. 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. 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 #3: (No Response) ******** 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #3: In my opinion, cohort study means classification is made according to exposure factor, generally one factor. For example, if we want to study the association between smoking (exposure factor) and lung cancer (outcome variable), the study population are classified as smoking group and non-smoking group according to their smoking history status. And then follow them, observe whether they develop lung cancer or not after a period of times. Usually, only one exposure factor is used as the classified variable. Conversely, the outcome variables may be more than one. In the above mentioned example, aside from lung cancer, the outcome variables may be hypertention, stroke or others. Here, we calculate the relative ration (RR) rather than the odds ratio (OR) to show the degree of association between the two factors (here is smoking and lung cancer). So, if the author declared that they used a cohort study, please explain what the exposure variable and outcome variable were in their study. ****** 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 #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. https://doi.org/10.1371/journal.pone.0255513.r003
Revision 2
5 Jul 2021 Author Response Journal Comments to the Author 1. 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. Response: We have checked our references and ensured only appropriate references were included. We did not include retracted publications. We revised two preprint references because both studies had undergone peer-review and were published in journals. The first reference titled “A demographic scaling model for estimating the total number of COVID-19 infections” by Bohk-Ewald et al. was published in the International Journal of Epidemiology. The second one named “Prevalence of SARS-CoV-2 Infection in Residents of a Large Homeless Shelter in Boston” by Baggett et al was published in JAMA. Reviewer 3 Comments to the Author 1. In my opinion, cohort study means classification is made according to exposure factor, generally one factor. For example, if we want to study the association between smoking (exposure factor) and lung cancer (outcome variable), the study population are classified as smoking group and non-smoking group according to their smoking history status. And then follow them, observe whether they develop lung cancer or not after a period of times. Usually, only one exposure factor is used as the classified variable. Conversely, the outcome variables may be more than one. In the above mentioned example, aside from lung cancer, the outcome variables may be hypertention, stroke or others. Here, we calculate the relative ration (RR) rather than the odds ratio (OR) to show the degree of association between the two factors (here is smoking and lung cancer). So, if the author declared that they used a cohort study, please explain what the exposure variable and outcome variable were in their study. Response: We appreciate the reviewer’s feedback and generally agree with the raised points and assessment. Coherent with the design of a cross-sectional study, our study was constructed to show correlations between an exposure and outcome variable. Due to the retrospective design, data for both were collected at the same time and the Odds ratio was calculated based on a logistic regression model. Nonetheless, we still are of the opinion that this study could also be described as a cohort study due to the reasons mentioned below. In their textbook on medical statistics, Aviva and Sabin define a (retrospective) cohort study as follows: “A cohort study takes a group of individuals and usually follows them forward in time, the aim being to study whether exposure to a particular aetiological factor will affect the incidence of a disease outcome in the future. If so, the factor is generally known as a risk factor for the disease outcome. […] Although most cohort studies are prospective, historical cohorts are occasionally used: these are identified retrospectively and relevant information relating to outcomes and exposures of interest up to the present day ascertained using medical records and memory.” (Petrie, Aviva, and Caroline Sabin. Medical Statistics at a Glance, John Wiley & Sons, Incorporated, 2009. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/ub-heidelberg/detail.action?docID=1561073. Created from ub-heidelberg on 2021-06-24 15:30:09.) We believe that this definition of a historical or retrospective cohort applies to our study because a defined group (in this case patients who tested positive for SARS-CoV-2) was followed backwards in time to identify whether the exposure of an aetiological factor (i.e. age, sex heart disease, lung disease, diabetes, smoking history, living with children) had an effect on the defined outcome (i.e. hospitalization, severity of disease). Instead of classifying by exposure variables (i.e. age, sex heart disease, lung disease, diabetes, smoking history, living with children) as usually done in cohort studies, we decided to classify the population by the outcome variable (hospitalization and no hospitalization) due to the relatively large number of variables considered in the analysis. This in our opinion allowed a better and more structured way of presenting our results to the reader without defying the essence of a cohort study. Because of the complex demographic of our study population, we needed to adjust for confounding factors. To do so, we created a logistic regression model for our (binary) exposure variables and therefore, present the results as odds ratios. Even though we, alongside other reviewers, believed to have fulfilled the criteria for a retrospective cohort study, we acknowledge that our study also meets criteria for a cross-sectional study design. If deemed necessary by the editor, we will change the title and methods to cross-sectional instead of cohort. Attachments Attachment Submitted filename: Response to reviewers_R2.docx https://doi.org/10.1371/journal.pone.0255513.r004
19 Jul 2021 Decision Letter - Tai-Heng Chen, Editor Description and analysis of representative COVID-19 cases – a retrospective cohort study PONE-D-21-06695R2 Dear Dr. Denkinger, 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, Tai-Heng Chen, M.D. Academic Editor PLOS ONE 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 #3: (No Response) ******** 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 #3: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: (No Response) ****** 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 #3: (No Response) ****** 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 #3: (No Response) ****** 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 #3: (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 #3: No https://doi.org/10.1371/journal.pone.0255513.r005
Formally Accepted
23 Jul 2021 Acceptance Letter - Tai-Heng Chen, Editor PONE-D-21-06695R2 Description and analysis of representative COVID-19 cases – a retrospective cohort study Dear Dr. Denkinger: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Tai-Heng Chen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255513.r006

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