SARS-CoV-2 infection and cardiovascular or pulmonary complications in ambulatory care: A risk assessment based on routine data

Siranush Karapetyan; Antonius Schneider; Klaus Linde; Ewan Donnachie; Alexander Hapfelmeier

doi:10.1371/journal.pone.0258914

Peer Review History

Original SubmissionJune 21, 2021
20 Jul 2021 Decision Letter - Huei-Kai Huang, Editor PONE-D-21-20330 SARS-CoV-2 infection and cardiovascular or pulmonary complications in ambulatory care: a risk assessment based on routine data PLOS ONE Dear Dr. Karapetyan, 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 Sep 03 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, Huei-Kai Huang, 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. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. 3. 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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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: Yes ****** 5. Review Comments to the Author Reviewer #1: Karapetyan and colleagues initial an interesting study to investigate the factors and building model for COVID-19 and following complications using Germany PCR database. The result showed good accuracy, they provided technical information detailly. However, I have some questions about the study design and the source material. (1) Was authors investigate the source of study populations? For example, some patient felt uncomfortable so they decided to take PCR test by themselves, others could be notice or required by government. In my point of view, there were quite different in the risk of SARS-CoV-2 infection, if this factor is available and meaningful for model building, I would happy to see revised result, and please describe some related regulation briefly to help reader understand Germany’s policy. (2) According to your study setting, residence area was categorized to urbanization level and including in the model. Urbanization was an interesting factor, also, provide some information of people’s probability to working, communication, interaction with other people. But my question is, an area, its local COVID-19 prevalence, maybe more important than the urbanization. Could you consider this factor in your analysis? (3) Finally, in Results line 186, there was written “For the analysis of defined complications the cohort of test-positives was reduced to 46 071 participants with available data for the first quarter after the index quarter of PCR test”. What is it mean about “available”? Please address in detail. Reviewer #2: In this study, the authors used ambulatory claims data to determine possible risk factors for (1) COVID infection, using a test-negative design (2) cardiovascular or pulmonary complications in patients with positive COVID tests, using a cohort design. The authors also developed a rule to predict the risk of cardiovascular or pulmonary complications among those with positive COVID tests. Overall, this is a well-designed study that answers important clinical questions using available data. I only have some minor points for the authors to consider: 1. In the model mentioned in page 11 (line 208-217), do the P values account for multiple comparison and the usage of stepwise regression? If not, it can be serious inflated and should not be used to argue that the interaction terms are statistically significant (so a separate risk factor model should be constructed for test-positives). Since the authors are essentially testing the relative fit between models with and without interaction terms, maybe it would more sound to calculate the likelihood ratio between the two models and use bootstrap to test for its significance. 2. In a test-negative design, it is optimal that the symptoms prompting the patients to undergo testing are similar between test-positives and test-negative, so as to prevent certain risk groups showing different patterns of probabilities of receiving tests, which then introduces bias. For example, if obese patients are more alert to anosmia than others because they know they're at higher risk of complications once infected by COVID, then the testing rate of test-positive obese patients would be higher than others, leading to the conclusion of "higher risk of infection" when the test-negative design is applied. The authors may discuss more on possible scenarios that violate the assumptions of test-negative designs. 3. In the second paragraph of the discussion section, the author attributed the attenuation or inversion of risk to the behavioral adjustment. In a test-negative design, this argument is only valid if the behavioral adjustment decreases the COVID (those who would be test-positive) infection rate more than common cold (those who would be test-negative). Do behavior adjustments demonstrate differential protective effects against COVID vs common cold? 4. Are all patients tested symptomatic, or are there screening tests for asymptomatic patients? If the latter is the case, differential screening rate among different risk groups may also introduce bias. 5. The authors mentioned that the recording of negative test results was optional for physicians (line 304). This could introduce bias if the behavior of selective recording differs between patient groups. For example, the physician is more willing to record the negative tests of a smoking patient than a non-smoking patient, smoking would be falsely considered as a protective factor. 6. The predictive model had adequate performance in the internal validation. However, the generalizability of the model should be assessed by external validation. The authors may list this as one of the limitations of the study. 7. In the discussion section line 284, PPV = 13.3% may seem low to readers. Maybe the authors can reiterate the prevelance of complications (~4%) to demonstrate why this PPV is acceptable. ****** 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:** Ming-Chieh Shih [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.0258914.r001
Revision 1
10 Aug 2021 Author Response Rebuttal Letter Dear Editor, dear Reviewers, Thank you for reviewing our manuscript and for your helpful comments and suggestions for improvement. In the following, we address these point by point (line references refer to the version of the tracked changes). 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 R: Thank you for the templates. We hope to meet the Journal style requirements by updating the following parts: • In the author names we have moved the commas to the end. • We have now updated figure citations (e.g. „Figure 1“ is now „Fig 1“, titles are bold) and figure files naming (e.g. „Figure 1.tiff“ is now „Fig1.tif“). • We have formatted table citations (titles are now bold). • We have now updated Supporting Information citations in the text and listed Supporting Information captions at the end of the manuscript in a section titled “Supporting information”. In addition, we uploaded Supporting Information files separately. • We have updated the font size for the headings. 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. R: The data are pseudonymized (the data are not technically anonymized because the source data with identifying information are held by the Bavarian Association of Statutory Health Insurance Physicians). We hope to meet your requirements by reformulating ethics statement: „The underlying data for this study are pseudonymized and the study was approved by the Ethics Commission of the Technical University of Munich (Ethikkommission der Technischen Universität München) (approval No 673/20 S-EB).“ In addition, we addressed details regarding participant consent in the Methods section, specifically that no further participant consent was required because the analyses were based on secondary billing data and were conducted in accordance with the German guideline "Good Practice in Secondary Data Analysis." (see lines 79-81) 3. 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. R: We updated Data Availability statement to reflect Journal requirements: „The data are held by the Bavarian Association of Statutory Health Insurance Physicians (BASHIP) and availability is restricted by a contractual agreement. The data are therefore not publically available due to data protection regulations, but may be obtained from the authors upon reasonable request and with the consent of the BASHIP (versorgungsforschung@kvb.de).“ Reviewers' comments: Reviewer's Responses to Questions Comments to the Author R: Questions without reviewer comments (1.-4. and 6.) and notes have been removed to improve readability. 5. Review Comments to the Author Reviewer #1: Karapetyan and colleagues initial an interesting study to investigate the factors and building model for COVID-19 and following complications using Germany PCR database. The result showed good accuracy, they provided technical information detailly. However, I have some questions about the study design and the source material. R: Thank you for your review and the valuable comments. (1) Was authors investigate the source of study populations? For example, some patient felt uncomfortable so they decided to take PCR test by themselves, others could be notice or required by government. In my point of view, there were quite different in the risk of SARS-CoV-2 infection, if this factor is available and meaningful for model building, I would happy to see revised result, and please describe some related regulation briefly to help reader understand Germany’s policy. R: Thank you for your note. We also think it would be interesting to include this factor in the models. However, the distinction between codes describing the reason for taking the PCR test did not exist at the beginning of the pandemic; it was introduced during the third quarter in 2020 and, unfortunately, was not used consistently by physicians after introduction, as we have seen in our data, so we could not include this factor in the model. We do now describe Germany’s testing strategy in the methods section (see lines 72-75). (2) According to your study setting, residence area was categorized to urbanization level and including in the model. Urbanization was an interesting factor, also, provide some information of people’s probability to working, communication, interaction with other people. But my question is, an area, its local COVID-19 prevalence, maybe more important than the urbanization. Could you consider this factor in your analysis? R: Thank you for this valuable point. We indeed did not consider this factor in our analysis. However, our objective was not to follow infection chains or to describe hotspots, but to adjust our analyses to the more general effects of different settlement and health care supply densities. We added this to the methods section and now we write: „To adjust for different settlment and health care supply densities we included a measure of urbanization …“ (see lines 106-107). (3) Finally, in Results line 186, there was written “For the analysis of defined complications the cohort of test-positives was reduced to 46 071 participants with available data for the first quarter after the index quarter of PCR test”. What is it mean about “available”? Please address in detail. R: Thank you for addressing this. We hope to make this clear by reformulating the sentence (see line 194). Reviewer #2: In this study, the authors used ambulatory claims data to determine possible risk factors for (1) COVID infection, using a test-negative design (2) cardiovascular or pulmonary complications in patients with positive COVID tests, using a cohort design. The authors also developed a rule to predict the risk of cardiovascular or pulmonary complications among those with positive COVID tests. Overall, this is a well-designed study that answers important clinical questions using available data. I only have some minor points for the authors to consider: R: Thank you for your review and the supportive comments. 1. In the model mentioned in page 11 (line 208-217), do the P values account for multiple comparison and the usage of stepwise regression? If not, it can be serious inflated and should not be used to argue that the interaction terms are statistically significant (so a separate risk factor model should be constructed for test-positives). Since the authors are essentially testing the relative fit between models with and without interaction terms, maybe it would more sound to calculate the likelihood ratio between the two models and use bootstrap to test for its significance. R: Thank you very much for raising this important point. The mentioned P values indeed do not account for multiple comparison, however we choose the model based on Akaike’s Information Criterion (AIC). We now removed the P values and pointed out that we compared the models based on a descriptive likelohood-ratio test. In the methods section we now write: “Goodness-of-fit of these nested models was compared by a descriptive likelihood-ratio test without formal adjustment for AIC-based model selection.” (see lines 140-141) Further, in the results section we write now: “… a multivariable regression model with forward stepwise variable selection by AIC included interaction effects between the PCR test result and the investigated risk factors …” (see lines 218-223). We hope this will clear up any confusion. 2. In a test-negative design, it is optimal that the symptoms prompting the patients to undergo testing are similar between test-positives and test-negative, so as to prevent certain risk groups showing different patterns of probabilities of receiving tests, which then introduces bias. For example, if obese patients are more alert to anosmia than others because they know they're at higher risk of complications once infected by COVID, then the testing rate of test-positive obese patients would be higher than others, leading to the conclusion of "higher risk of infection" when the test-negative design is applied. The authors may discuss more on possible scenarios that violate the assumptions of test-negative designs. R: Thank you for raising this important point. We discussed it in the limitations detailed in the discussion section (see lines 314-317). 3. In the second paragraph of the discussion section, the author attributed the attenuation or inversion of risk to the behavioral adjustment. In a test-negative design, this argument is only valid if the behavioral adjustment decreases the COVID (those who would be test-positive) infection rate more than common cold (those who would be test-negative). Do behavior adjustments demonstrate differential protective effects against COVID vs common cold? R: We agree with the point that the argument would be valid if behavioral adjustment is more successful in reducing risk for COVID-19 than risk for other infections. However, this is only true in a setting where only symptomatic participants are tested. Because we also have asymptomatic participants in our cohort, i.e. within the test-positives and within the test-negatives, we cannot directly state that. We therefore now write: „The latter might be explained with possible behavioural adjustment in the patients belonging to respective vulnerable subgroups, however, this assumption might be impaired as the cohort of tested participants also includes asymptomatic participants.” (see lines 268-269) 4. Are all patients tested symptomatic, or are there screening tests for asymptomatic patients? If the latter is the case, differential screening rate among different risk groups may also introduce bias. R: There have also been PCR tests for asymptomatic patients, e.g. for travelers, asymptomatic individuals in health care or other vulnerable sectors, contacts (with criteria of exposure or disposition) etc. This can indeed introduce bias to the assessment of total risks. However, we assume that the assessment of relative risks is unaffected. Therefore, the association between risk factors and the outcome, the estimated odds ratios, should be unbiased. 5. The authors mentioned that the recording of negative test results was optional for physicians (line 304). This could introduce bias if the behavior of selective recording differs between patient groups. For example, the physician is more willing to record the negative tests of a smoking patient than a non-smoking patient, smoking would be falsely considered as a protective factor. R: Thank you very much for this valuable point. We added it to the limitations detailed in the discussion section (see lines 320-322). 6. The predictive model had adequate performance in the internal validation. However, the generalizability of the model should be assessed by external validation. The authors may list this as one of the limitations of the study. R: We agree with this point and add this now as one of the limitations of our study (see lines 306-307). 7. In the discussion section line 284, PPV = 13.3% may seem low to readers. Maybe the authors can reiterate the prevelance of complications (~4%) to demonstrate why this PPV is acceptable. R: Thank you for your suggestion. We now explain this in the discussion section (see lines 295-297). 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. R: We uploaded our figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool to ensure that our figures meet PLOS requirements. We have updated our figures accordingly. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0258914.r002
23 Aug 2021 Decision Letter - Huei-Kai Huang, Editor PONE-D-21-20330R1 SARS-CoV-2 infection and cardiovascular or pulmonary complications in ambulatory care: a risk assessment based on routine data PLOS ONE Dear Dr. Karapetyan, 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. ACADEMIC EDITOR: Please mention and discuss your assumption in the Discussion section (please refer to the reviewer comment). Please submit your revised manuscript by Oct 07 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, Huei-Kai Huang, 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 #1: Yes Reviewer #2: 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 #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: 4. Are all patients tested symptomatic, or are there screening tests for asymptomatic patients? If the latter is the case, differential screening rate among different risk groups may also introduce bias. R: There have also been PCR tests for asymptomatic patients, e.g. for travelers, asymptomatic individuals in health care or other vulnerable sectors, contacts (with criteria of exposure or disposition) etc. This can indeed introduce bias to the assessment of total risks. However, we assume that the assessment of relative risks is unaffected. Therefore, the association between risk factors and the outcome, the estimated odds ratios, should be unbiased. The authors may consider mentioning the assumptions they made in the manuscript. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes:** Ming-Chieh Shih [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.0258914.r003
Revision 2
24 Sep 2021 Author Response Rebuttal Letter Dear Editor, dear Reviewers, Thank you very much for considering our manuscript as potentially acceptable for publication in PLoS One. We incorporated all of the comments into the revised version and attached a point by point response to all comments (line references refer to the version of the tracked changes). We would be pleased to see the actual version published in PLoS One. ACADEMIC EDITOR: Please mention and discuss your assumption in the Discussion section (please refer to the reviewer comment). R: Thank you for your suggestion. We have discussed our assumptions in the Discussion section as proposed from the Reviewer (see lines 335-339). 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. R: Thank you for your note. We have checked our reference list. All articles are still available and none have been retracted. We have noted that the article by Ioannisids J. (2020) has now been published in Bulletin of the World Health Organization and have changed the reference accordingly: • Ioannidis JPA. The infection fatality rate of COVID-19 inferred from seroprevalence data. medRxiv. 2020;2020.05.13.20101253 � Ioannidis, J. P. Infection fatality rate of COVID-19 inferred from seroprevalence data. Bull World Health Organ. 2021;99(1), 19. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 6. Review Comments to the Author Reviewer #2: 4. Are all patients tested symptomatic, or are there screening tests for asymptomatic patients? If the latter is the case, differential screening rate among different risk groups may also introduce bias. R: There have also been PCR tests for asymptomatic patients, e.g. for travelers, asymptomatic individuals in health care or other vulnerable sectors, contacts (with criteria of exposure or disposition) etc. This can indeed introduce bias to the assessment of total risks. However, we assume that the assessment of relative risks is unaffected. Therefore, the association between risk factors and the outcome, the estimated odds ratios, should be unbiased. The authors may consider mentioning the assumptions they made in the manuscript. R: Thank you for this valuable suggestion. We have now reformulated our explanation and now write in the methods section: “During the evaluation period from February to the end of September 2020 (i.e., first to third quarter 2020), patients suspected to suffer from COVID-19 infection received naso-pharyngeal swabs for PCR testing in general practice. According to the national testing strategy, participants without symptoms could also be tested in general practice, for example travelers from risk areas, staff in health care or other vulnerable sectors, and contacts of infected persons. However, these cases were to be billed separately by the Ministry and were thus not documented as claims data.” (see lines 75-81). We have also discussed this in the limitations detailed in the discussion section, where we write: “Beyond that, the possibility of asymptomatic participants in a cohort can presumably introduce bias. However, tests of asymptomatic patients were to be billed separately by the government and consequently not documated as claims data for the BASHIP. Therefore, the association between risk factors and the outcome, the estimated odds ratios, should be unbiased in this respect.” (see lines 335-339). In addition, we have corrected one formulation: “… this assumption might be impaired as the cohort of tested participants may also include asymptomatic participants.” (see lines 279-280). We are sorry for the confusing wording before and hope this clears up any confusion. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0258914.r004
8 Oct 2021 Decision Letter - Huei-Kai Huang, Editor SARS-CoV-2 infection and cardiovascular or pulmonary complications in ambulatory care: a risk assessment based on routine data PONE-D-21-20330R2 Dear Dr. Karapetyan, 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, Huei-Kai Huang, M.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0258914.r005
Formally Accepted
13 Oct 2021 Acceptance Letter - Huei-Kai Huang, Editor PONE-D-21-20330R2 SARS-CoV-2 infection and cardiovascular or pulmonary complications in ambulatory care: a risk assessment based on routine data Dear Dr. Karapetyan: 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. Huei-Kai Huang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0258914.r006

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