Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: An exploratory post-hoc investigation

Richard A. Parker; Catriona Keerie; Christopher J. Weir; Atul Anand; Nicholas L. Mills

doi:10.1371/journal.pone.0271027

Peer Review History

Original SubmissionNovember 15, 2021
9 Feb 2022 Decision Letter - Salvatore De Rosa, Editor PONE-D-21-36318Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: an exploratory post-hoc investigationPLOS ONE Dear Dr. Parker, 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 Mar 26 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Salvatore De Rosa 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. [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 ******** 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: No Reviewer #2: No ****** 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 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: Several post-hoc statistical models were fitted for the primary outcomes of length of hospital stay and safety events. Models were adjusted for exposure time and incorporated spline fitting and a random effect for the time effect. The methods used were direct inclusion, regression adjustment for propensity score, and weighting, as well as a data augmentation approach. The new statistical models confirmed the results of the pre-specified trial analysis where the event rate was low: 0.36%. Minor revision: Table 1: In the “Primary analysis” specify the type of statistical model used for the analysis. Reviewer #2: Parker and colleagues should be congratulated for their efforts carrying out this important analysis. In their current paper, they investigate in very carefully robust analysis the reasons for the divergent results that were reported in the HiSTORIC trial. The current paper helps understand the results of the HiSTORIC trial more, and can assist researches with the design and implementation of future stepped-wedge cluster randomised trials. Parker and colleagues have confirmed the results of the pre-specified trial analysis and have validate their complexity. Several major comments: 1. Although the design and the execution of the current analysis are very elegant, the additive scientific value is not well presented. The conclusion at the end of the manuscript is very long and should be shortened and more focused. 2. Overall the discussion and the conclusion are very long and it's hard to follow. Would highly recommend to be more focused. 3. In the discussion the authors discuss several potential reasons for the differences between certain results under separate headings. I would recommend to choose two or three that the authors believe are the most important ones, expand on them, and mention the rest briefly. It's difficult for a non-statistician to understand which reason affected the diversity the most. Minor comments: 1. Limitation. Each study including the current one is prone to several limitations. I would highly recommend mention the limitation of the current study: post hoc; selective population etc.. 2. Figure labels for the ratio and the CI should be added. 3. The Results section contains many explanations for the findings. These should be moved to the discussion. The Result section should report findings only and not their interpretations or explanations. ****** 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:** Arwa Younis [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.0271027.r001
Revision 1
3 Mar 2022 Author Response We would like to thank the associate editor and reviewers for their constructive comments, which we are pleased to address in the revised version of the manuscript. We give a point-by-point response to the associate editor and reviewers’ comments below: 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. Thank you for your comment. We have now modified the manuscript so that it meets the PLOS ONE style requirements. 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. Participant consent was not sought for our study and this was approved by the NHS Scotland Public Benefit And Privacy Panel For Health And Social Care (NHSS HSC-PBPP) committee. We have now clarified this in the methods section (page 5): “We received approval to use routinely collected National Health Service (NHS) data for research without the need for individual patient consent. This approval was granted by the NHS National Services Scotland Privacy Advisory Committee (PAC), now called the NHS Scotland Public Benefit And Privacy Panel For Health And Social Care (NHSS HSC-PBPP).” Reviewers' comments: Reviewer #1: Several post-hoc statistical models were fitted for the primary outcomes of length of hospital stay and safety events. Models were adjusted for exposure time and incorporated spline fitting and a random effect for the time effect. The methods used were direct inclusion, regression adjustment for propensity score, and weighting, as well as a data augmentation approach. The new statistical models confirmed the results of the pre-specified trial analysis where the event rate was low: 0.36%. Minor revision: Table 1: In the “Primary analysis” specify the type of statistical model used for the analysis. Thank you for your comment. We have now specified that we used mixed effects models in the first row (below the headings) of Table 1. We have also clarified this in Table 2. Reviewer #2: Parker and colleagues should be congratulated for their efforts carrying out this important analysis. In their current paper, they investigate in very carefully robust analysis the reasons for the divergent results that were reported in the HiSTORIC trial. The current paper helps understand the results of the HiSTORIC trial more, and can assist researches with the design and implementation of future stepped-wedge cluster randomised trials. Parker and colleagues have confirmed the results of the pre-specified trial analysis and have validate their complexity. Thank you very much for these comments! Several major comments: 1. Although the design and the execution of the current analysis are very elegant, the additive scientific value is not well presented. The conclusion at the end of the manuscript is very long and should be shortened and more focused. Thank you for your comment. We have now made the conclusions section more focussed and have reduced its length by 117 words. 2. Overall the discussion and the conclusion are very long and it's hard to follow. Would highly recommend to be more focused. Thank you for your comment. We agree, and have removed a substantial amount of material from the discussion section, including our long list of recommendations, which we felt was overly repetitive and not very focussed. As a whole, the length of these sections has reduced by almost 400 words, despite us adding in more material in response to your other helpful comments regarding including “explanations from the results section” and also including a strengths and limitations sections. We have made substantial changes to the discussion and conclusions sections so that they are now more focussed and easier to read. 3. In the discussion the authors discuss several potential reasons for the differences between certain results under separate headings. I would recommend to choose two or three that the authors believe are the most important ones, expand on them, and mention the rest briefly. It's difficult for a non-statistician to understand which reason affected the diversity the most. Our changes (mentioned above in response to point 2) have helped to address these concerns and have made the discussion section more focussed. In particular, we have reduced the number of headings we are using in the discussion section. Our main conclusions regarding the reason for differences between results are highlighted in the Conclusions section (as well as covered in the section entitled “Horizontal versus vertical bias”). In the conclusions section we write: “we think a combination of issues jointly contributed to the divergent results: sparse event data, low number of sites, short randomisation phase, and non-adherence to the planned intervention schedule.”, and then go on to expand briefly on the key issues of sparse event data (in combination with low number of sites) and strong influence of data near the crossover points. Minor comments: 1. Limitation. Each study including the current one is prone to several limitations. I would highly recommend mention the limitation of the current study: post hoc; selective population etc.. Thank you for your comment. We agree, and have now added a limitations section to the Discussion. In addition, we feel that the HISTORIC trial had important strengths that we need to acknowledge, and so we have also mentioned these in a “strengths” section. 2. Figure labels for the ratio and the CI should be added. Thank you for your comment. We have now added the clarifying information (“geometric mean ratio” and “95% confidence intervals”) to the figure labels. 3. The Results section contains many explanations for the findings. These should be moved to the discussion. The Result section should report findings only and not their interpretations or explanations. Thank you for your comment. We have moved explanations for the findings contained in the results section to the Discussion section (particularly the last two paragraphs of the results section). Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0271027.r002
6 Apr 2022 Decision Letter - Salvatore De Rosa, Editor PONE-D-21-36318R1Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: an exploratory post-hoc investigationPLOS ONE Dear Dr. Parker, 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. In particular, the external Reviewer #1 has additional minor requests. Please, make sure to address all residual criticism. Please submit your revised manuscript by May 21 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Salvatore De Rosa 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: (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 #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: No ****** 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 ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The results and conclusions from a relatively new study design are now more succinctly and clearly summarized. Minor Revision: State the underlying covariance structures used in the mixed effects models and the criteria for selecting them. ****** 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 [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.0271027.r003
Revision 2
24 May 2022 Author Response We would like to thank the reviewer for their comment, which we are pleased to address in the revised version of the manuscript. Reviewer #1: The results and conclusions from a relatively new study design are now more succinctly and clearly summarized. Minor Revision: State the underlying covariance structures used in the mixed effects models and the criteria for selecting them. Thank you for your comment. We have now specified in the paper that a “compound symmetry variance-covariance structure was assumed” for the linear mixed effects models (page 6). We have also added a limitation to the limitations section of the discussion section (pages 17-18): “Furthermore, the statistical models were fitted using the lme4 package [9] in R software [24], which makes the assumption of a simple correlation structure of compound symmetry for linear mixed effects models (i.e. no autocorrelation in model residuals). Although we attempted to fit models assuming autoregressive or general (unstructured) correlation using the nlme package [31], the models would not fit, presumably for the same reason as for the GEE model: the within-cluster sizes were too large. Nevertheless, we believe that compound symmetry is a reasonable assumption given that independent individuals attending emergency departments within each site may be expected to be approximately equally correlated (or uncorrelated) with each other conditional on the fixed effects including season and time of presentation. Indeed, a few of the models fitted include sophisticated modelling of the time trend (e.g. via splines), which we think makes the compound symmetry assumption even more plausible because residual autocorrelation due to incomplete modelling of the time trend is less likely.” We confirm that a reference to the “nlme” package has now been added to our reference list (number [31]). Attachments Attachment Submitted filename: Responses to reviewer R2.docx https://doi.org/10.1371/journal.pone.0271027.r004
23 Jun 2022 Decision Letter - Salvatore De Rosa, Editor Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: an exploratory post-hoc investigation PONE-D-21-36318R2 Dear Dr. Parker, 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, Salvatore De Rosa Academic Editor PLOS ONE 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 ******** 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (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 #1: (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 #1: (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 #1: (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 #1: No ******** https://doi.org/10.1371/journal.pone.0271027.r005
Formally Accepted
24 Jun 2022 Acceptance Letter - Salvatore De Rosa, Editor PONE-D-21-36318R2 Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: an exploratory post-hoc investigation Dear Dr. Parker: 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. Salvatore De Rosa Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0271027.r006

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