Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England: A retrospective cohort study of primary care data

Iain M. Carey; Derek G. Cook; Tess Harris; Stephen DeWilde; Umar A. R. Chaudhry; David P. Strachan

doi:10.1371/journal.pone.0260381

Peer Review History

Original SubmissionAugust 26, 2021
28 Sep 2021 Decision Letter - Shinya Tsuzuki, Editor PONE-D-21-27684Comparison of risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England (March-May 2020) compared to usual all-cause mortality during 2015-2019: a retrospective cohort study of primary care dataPLOS ONE Dear Dr. Carey, 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 12th Oct 2021. 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. 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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 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Several reviewers made a favorable assessment on the manuscript then only a few minor comments should be addressed before publication. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes 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 #1: Yes 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 #1: Yes 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 #1: The excess mortality in England during the first wave of COVID-19 pandemic, compared with the mortality during 2015-19 was studied. Mortality rates in among different population groups for the period from 18th March to 19th May 2020 was compared with similar indicators in 2015 – 2019. It has been shown that the main risk factors were age >80, non-white ethnicity, dementia, learning disability. By contrast, smokers, and patients with a history of cancer or Chronic Obstructive Pulmonary Disease had mortality ratios in 2020 significantly lower than their usual mortality. Reviewer #2: I think that such articles are important and valuable in order to understand the extent of mortality caused by the Covid-19 epidemic. In this respect, this article presents well-designed and versatile data. Reviewer #3: This article provides important insight into changes in all-cause mortality during, and possibly due to, the COVID-19 pandemic in England in early 2020. Specific feedback below: Title: The title of the paper is probably longer and more detailed than necessary and could be contracted. For example, “Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England” might adequately convey the content in a more succinct manner Abstract: The somewhat strange use of active voice in the abstract is off-putting e.g. “Patients had their [...] status extracted” and “Poisson regression modelled” under the methods heading. The author’s intermittently use active “we” and passive voice throughout the rest of the manuscript in the manuscript. Maintaining consistency might improve the overall flow. Methods: Line 88: The acronym “EMIS” needs to be defined Line 98: the authors state they selected a subset of 770 practices providing data to CPRD. It would be useful to note what proportion of all practices participating in CPRD this represents, and how representative these practices are of all practices in CPRD (Noting representativeness of CPRD compared to all general practices is discussed later). Line 105: The authors should provides justification for selecting the age range 30-104 years i.e. why were younger adults or children not included? Results: The meaning of the symbols in Figure 1 probably don’t need to be defined in the text as they are given in the figure legend. Discussion: Given almost 20% of patients did not have ethnicity recorded, it would worth commenting on effect of this missing data on validity of ethnicity estimates. Line 288: Sentence beginning:“For COVID-19, a novel coronavirus” The meaning of this sentence is not clear to me, also COVID-19 is the disease, SARS-CoV-2 is the novel coronavirus. Reviewer #4: This is a very interesting manuscript where the authors use a large electronic primary care database to estimate the impact of risk factors on excess mortality in England during the first wave, compared with the mortality during 2015-19. The manuscript is very well written and utilizes sound statistical methods which are very well described. Here are my two comments for the authors to consider: 1. In the abstract, the authors state that “Our approach illustrates the use of a novel methodology for evaluating a 52 pandemic’s impact without requiring cause-specific mortality data.”. It is not entirely clear to me what is novel in this analysis compared to other methods used in the past. Can the authors be explicit in stating what is novel in their methods? As far as I know, similar analytic approaches have been used for years to estimate excess mortality associated with influenza infection. 2. Could the authors provide a comment/justification for why the considered 5 pre-pandemic years (2015-2019 combined) rather than less, say 2 or 3 most recent year? Was it all necessary if they could have analyzed the data with less? ****** 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: Ali Acar Reviewer #3: Yes:** Christopher Bailie 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/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. 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Revision 1
22 Oct 2021 Author Response Additional Editor Comments: Several reviewers made a favorable assessment on the manuscript then only a few minor comments should be addressed before publication. * We thank all four reviewers for their positive feedback and address the minor comments they raised below. Where the text has changed, we have indicated below. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author * Sections 1 to 4 – No comments necessary ________________________________________ 5. Review Comments to the Author Reviewer #1: The excess mortality in England during the first wave of COVID-19 pandemic, compared with the mortality during 2015-19 was studied. Mortality rates in among different population groups for the period from 18th March to 19th May 2020 was compared with similar indicators in 2015 – 2019. It has been shown that the main risk factors were age >80, non-white ethnicity, dementia, learning disability. By contrast, smokers, and patients with a history of cancer or Chronic Obstructive Pulmonary Disease had mortality ratios in 2020 significantly lower than their usual mortality. Reviewer #2: I think that such articles are important and valuable in order to understand the extent of mortality caused by the Covid-19 epidemic. In this respect, this article presents well-designed and versatile data. Reviewer #3: This article provides important insight into changes in all-cause mortality during, and possibly due to, the COVID-19 pandemic in England in early 2020. Specific feedback below: Title: The title of the paper is probably longer and more detailed than necessary and could be contracted. For example, “Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England” might adequately convey the content in a more succinct manner * We agree the title could be improved by shortening. However, to comply with STROBE we have retained the last section to give a new title of “Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England: a retrospective cohort study of primary care data” Abstract: The somewhat strange use of active voice in the abstract is off-putting e.g. “Patients had their [...] status extracted” and “Poisson regression modelled” under the methods heading. The author’s intermittently use active “we” and passive voice throughout the rest of the manuscript in the manuscript. Maintaining consistency might improve the overall flow. We apologise for this oversight. In the abstract we now say “Medical history, ethnicity, area-based deprivation and vital status data were extracted for an average of 4.8 million patients aged 30-104 years for each year between 18-March and 19-May over a 6-year period (2015-2020). We used Poisson regression to model total mortality adjusting for age and sex, with interactions between each RF and period (pandemic vs. 2015-19). Total pandemic mortality was partitioned into "usual" and "excess" components, assuming 2015-19 rates represented "usual" mortality. The association of each RF with the 2020 "excess" component was derived as the excess mortality ratio (EMR) and compared with the usual mortality ratio (UMR).” Methods: Line 88: The acronym “EMIS” needs to be defined We now say Egton Medical Information Systems Line 98: the authors state they selected a subset of 770 practices providing data to CPRD. It would be useful to note what proportion of all practices participating in CPRD this represents, and how representative these practices are of all practices in CPRD (Noting representativeness of CPRD compared to all general practices is discussed later). The August 2020 extract of CPRD Aurum consisted of 1366 practices in total, so the 770 we chose represents 56%. CPRD updates the extracts on a monthly basis and not all practices provide data to the most recent date. As we chose 1/8/2020 as a cut-off date for practices to be included to allow enough time for death de-registrations to be recorded, a large proportion of practices were excluded as they only had data to June or July 2020 at this time. There doesn’t appear to be any systematic reason why these practices would differ, and the geographical distribution is similar. We do not have details on the patients from the non-770 practices. We think the issue of representativeness is how geographically representative our 770 practices are of all practices rather than the CPRD itself. We already note in the discussion that we have an oversampling of London practices due to the earlier pattern of excess mortality. However, the key aspect is that our analysis uses the same 770 practices for all years to compare mortality within practices. We have added the following sentence to the methods "A total of 770 (56%) practices were identified, with exclusions due to data not available to August 2020 or no linkage available". Line 105: The authors should provides justification for selecting the age range 30-104 years i.e. why were younger adults or children not included? We now say “We further restricted to adults aged between 30 and 104 years old, as there would be little excess mortality in the young as well as incomplete data for many risk factors, and also excluded a small number of patients (<1%) without linkage to IMD.” Results: The meaning of the symbols in Figure 1 probably don’t need to be defined in the text as they are given in the figure legend. We have now removed these Discussion: Given almost 20% of patients did not have ethnicity recorded, it would worth commenting on effect of this missing data on validity of ethnicity estimates. In UK primary care data, ethnicity is more complete in patients more recently registered (Mathur et al, Journal of Public Health 2014 36(4): 684-692), which suggests that the missing group may be overrepresented by long-term registered patients. However, the group will also likely contain a significant portion of healthier patients, who are not being regularly seen at their practice and having their ethnicity recorded. For each annual cohort, we only used information recorded up to that point in time. This means that the missing % for ethnicity was largely stable in each annual cohort, and as a result one could assume that the (unknown) ethnicity mix among the missing was broadly similar between 2015-9 and 2020. Therefore, our estimates represent the risk of mortality for patients being recorded with ethnicity X in 2020 vs. the risk for patients being recorded with the same ethnicity X in 2015-9. When this classification was “missing”, the excess mortality associated with this was less than 1 (Figure 1, Table 2) compared to the white baseline group. Thus, the estimates we produced for recorded non-white groups (vs. recorded white) may be conservative if anything, and are unlikely to have been exaggerated. We have added this sentence to the discussion “While approximately 20% of the patients in the study had no ethnicity recorded, this group had no excess mortality (EMR <1), suggesting our estimates for non-white ethnicities were unlikely to be exaggerated.” Line 288: Sentence beginning: “For COVID-19, a novel coronavirus” The meaning of this sentence is not clear to me, also COVID-19 is the disease, SARS-CoV-2 is the novel coronavirus. We have simplified sentence to “For COVID-19, first identified by Chinese authorities in January 2020, initial international comparisons have favoured this approach[1,19] over simply counting COVID-19 deaths, due to the heterogeneity in how each country classified deaths from COVID-19”. Reviewer #4: This is a very interesting manuscript where the authors use a large electronic primary care database to estimate the impact of risk factors on excess mortality in England during the first wave, compared with the mortality during 2015-19. The manuscript is very well written and utilizes sound statistical methods which are very well described. Here are my two comments for the authors to consider: 1. In the abstract, the authors state that “Our approach illustrates the use of a novel methodology for evaluating a 52 pandemic’s impact without requiring cause-specific mortality data.”. It is not entirely clear to me what is novel in this analysis compared to other methods used in the past. Can the authors be explicit in stating what is novel in their methods? As far as I know, similar analytic approaches have been used for years to estimate excess mortality associated with influenza infection. We agree the brief sentence in the abstract failed to make an adequate case; that our study is of individual risk factors in relation to excess mortality which is novel. We have changed the abstract sentence to “Our approach illustrates a novel methodology for evaluating a pandemic’s impact by individual risk factor, without requiring cause-specific mortality data” We have also added an additional sentence in the discussion, with a new reference (Davies et al., Nature Communications 2021 12(1): 3755) which also studied excess mortality, but only looked at community, not individual factors, using an ecological approach. “In England, this approach has been used to study the impact of community factors on excess mortality[20] in an ecological analysis. By analysing individual risk factors for excess mortality, and also by presenting the excess mortality ratios in the context of the usual mortality ratios, we think the methodology we have developed for studying the impact of individual risk factors on excess mortality and identifying the true pandemic effect (interaction) for each risk factor. It provides a template that can be generalised across the COVID-19 pandemic, as well as to other causes of excess mortality such as influenza, and will be less susceptible to ecologic bias.” 2. Could the authors provide a comment/justification for why the considered 5 pre-pandemic years (2015-2019 combined) rather than less, say 2 or 3 most recent year? Was it all necessary if they could have analyzed the data with less? Using 5 years for the reference period is commonly used when assessing excess mortality (e.g., Davies et al., Nature Communications 2021 12(1): 3755) and would produce more precise estimates than using 2 or 3 years. Attachments Attachment Submitted filename: Response to Reviewers.docx* https://doi.org/10.1371/journal.pone.0260381.r002
3 Nov 2021 Decision Letter - Shinya Tsuzuki, Editor PONE-D-21-27684R1Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England : a retrospective cohort study of primary care dataPLOS ONE Dear Dr. Carey, 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 9th November 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Shinya Tsuzuki, MD, MSc 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. Additional Editor Comments: Please modify the manuscript according to the reviewer's comments before publipcation. [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 #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #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: Previous comments have been adequately addressed. The Authors may wish to re-revise changes to the two sentences from lines 291-296 beginning "By analysing individual risk factors...", as their meaning is currently unclear. ****** 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.0260381.r003
Revision 2
4 Nov 2021 Author Response We apologise for the minor punctuation error where a full stop had not been marked for deletion. The corrected sentence now reads “By analysing individual risk factors for excess mortality, and also by presenting the excess mortality ratios in the context of the usual mortality ratios, we think the methodology we have developed for studying the impact of individual risk factors on excess mortality and identifying the true pandemic effect (interaction) for each risk factor provides a template that can be generalised across the COVID-19 pandemic, as well as to other causes of excess mortality such as influenza, and will be less susceptible to ecologic bias” Attachments Attachment Submitted filename: Response to Reviewers R2.docx https://doi.org/10.1371/journal.pone.0260381.r004
9 Nov 2021 Decision Letter - Shinya Tsuzuki, Editor Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England : a retrospective cohort study of primary care data PONE-D-21-27684R2 Dear Dr. Carey, 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, Shinya Tsuzuki, MD, MSc Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0260381.r005
Formally Accepted
1 Dec 2021 Acceptance Letter - Shinya Tsuzuki, Editor PONE-D-21-27684R2 Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England : a retrospective cohort study of primary care data Dear Dr. Carey: 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. Shinya Tsuzuki Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0260381.r006

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