Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: Retrospective analyses of three large healthcare databases in the US

Ajit A. Londhe; Chantal E. Holy; James Weaver; Sergio Fonseca; Angelina Villasis; Daniel Fife

doi:10.1371/journal.pone.0255887

Peer Review History

Original SubmissionFebruary 8, 2021
21 May 2021 Decision Letter - Ping-Hsun Wu, Editor PONE-D-21-04320 Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: retrospective analyses of three large healthcare databases in the US PLOS ONE Dear Dr. Chantal E Holy, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jun 25 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. 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Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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: No ****** 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: Summary This study evaluated the potential association between fluoroquinolones (FQ), other common antibiotics (amoxicillin, azithromycin, trimethoprim), and febrile illness with the risk of aortic aneurysm or aortic dissection (AA/AD) using a self-controlled case-series design in three large US claims databases. The aim was to examine potential confounding in prior observational studies. Several issues listed below warrant further revision to improve study quality. Comments 1. The authors calculated event occurrence before and after the first FQ exposure and estimated the incidence rate ratio (IRR) before the first FQ exposure to demonstrate there may be potential confounding for the association between FQ and AA/AD (Table 2 and Figure 2). However, the timeline scales mentioned in the methods (e.g., within “60 days” before and after the first FQ exposure) and shown in the results (e.g., within “150 days” before and after the first FQ exposure in Figure 2) were not consistent, which may make the audience a little bit confusing. It will be better to have consistent timeline scales in the method and result sections. 2. The authors estimated calibrated p values for FQ, febrile illness not treated with antibiotics, amoxicillin, azithromycin, trimethoprim/sulfamethoxazole, and 38 negative exposure controls to demonstrate there may be bias or systematic errors for the association between FQ and AA/AD. However, for the general audience, it is not easy or intuitive to understand why the measure of calibrated p values can indicate potential bias. It will be better to have more detailed explanation for the difference between calibrated p values and traditional p values and why calibrated p values can suggest potential bias in the methods section. 3. The authors mentioned they estimated IRR for FQ, febrile illness not treated with antibiotics, amoxicillin, azithromycin, and trimethoprim/sulfamethoxazole, followed by calibration of p values for 38 negative exposure controls and so called pre-exposure and timeline analyses. However, the results did not show up as this order, which made the article difficult to read and follow-up. It will be better to re-arrange the order of the findings (including main text, figures, and tables) in the result sections. 4. It will be better to indicate “Appendix table 1, Appendix table 2, and etc.” in the main text and in the supplemental materials, which will be better for the audience to find corresponding results. ****** 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 [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.0255887.r001
Revision 1
9 Jul 2021 Author Response Response to Reviewers Additional Editor Comments: A more detailed explanation between calibrated p values and traditional p values is needed for the reader to understand their differences. Besides, it will be better to re-arrange the order of the findings in the result sections as the reviewer's suggestion. A paragraph explaining the negative control approach, and references to the p-value calibration work, had been added in the introduction: “Another key limitation of prior analyses is the possibility of systemic bias. Residual bias can occur in all large retrospective database analyses after confounding control has been implemented and this bias can skew results in even the best designed studies. Approaches to identify residual bias often include the use of negative controls – exposures known to not cause the outcome of interest. The distribution of effects obtained from analyzing a large number of negative controls can be utilized to create a so-called calibrated p-value, one that, based on the data that we are actually using – rather than a priori statistical considerations – reflects the probability that the observed effect would be seen by chance. (11-13) For example, if the negative controls are not centered on the null value or are more scattered than expected, the calibrated p value would take this into account. Further details are added in the discussion section.” The authors calculated event occurrence before and after the first FQ exposure and estimated the incidence rate ratio (IRR) before the first FQ exposure to demonstrate there may be potential confounding for the association between FQ and AA/AD (Table 2 and Figure 2). However, the timeline scales mentioned in the methods (e.g., within “60 days” before and after the first FQ exposure) and shown in the results (e.g., within “150 days” before and after the first FQ exposure in Figure 2) were not consistent, which may make the audience a little bit confusing. It will be better to have consistent timeline scales in the method and result sections. Figure 2 was modified to include only the 60-day pre- and post-exposure time period, to be consistent with the at-risk definitions described in the methods. 2. The authors estimated calibrated p values for FQ, febrile illness not treated with antibiotics, amoxicillin, azithromycin, trimethoprim/sulfamethoxazole, and 38 negative exposure controls to demonstrate there may be bias or systematic errors for the association between FQ and AA/AD. However, for the general audience, it is not easy or intuitive to understand why the measure of calibrated p values can indicate potential bias. It will be better to have more detailed explanation for the difference between calibrated p values and traditional p values and why calibrated p values can suggest potential bias in the methods section. A paragraph explaining the methodology was added in the introduction (See above). In addition, greater discussion of our approach, and the rationale thereof, was added in the Discussion section: “In our study and as shown in Figure 1, the relative risks obtained from using negative controls were not centered around the null, as would be expected in a study with no residual bias. Negative control estimates were instead centered between 1 and 2, suggesting a moderate, positive systemic error. In Figures 1A-1C: the dashed lines represent thresholds of significance using non-calibrated p value: any estimate below the dashed lines, in a study with no residual bias, would be considered significant. In contrast, the estimates in the solid orange area have calibrated p < 0.05. Using non-calibrated p values, 8 out of 38 negative controls would have yielded significant risk estimates for AAD in OPTUMEXTDOD versus 2 out of 38 using calibrated p values. Calibrating p value was therefore essential to control for systemic error in our databases. “ 3. The authors mentioned they estimated IRR for FQ, febrile illness not treated with antibiotics, amoxicillin, azithromycin, and trimethoprim/sulfamethoxazole, followed by calibration of p values for 38 negative exposure controls and so called pre-exposure and timeline analyses. However, the results did not show up as this order, which made the article difficult to read and follow-up. It will be better to re-arrange the order of the findings (including main text, figures, and tables) in the result sections. The findings were reorganized accordingly. 4. It will be better to indicate “Appendix table 1, Appendix table 2, and etc.” in the main text and in the supplemental materials, which will be better for the audience to find corresponding results. Appendix Tables were relabeled accordingly. Attachments Attachment Submitted filename: AA Reviewer Comments PLOS One RESPONSE FINAL.docx https://doi.org/10.1371/journal.pone.0255887.r002
27 Jul 2021 Decision Letter - Ping-Hsun Wu, Editor Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: retrospective analyses of three large healthcare databases in the US PONE-D-21-04320R1 Dear Dr. Chantal E Holy, 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, Ping-Hsun Wu, M.D. PhD. Academic Editor PLOS ONE Additional Editor Comments (optional): All comments had been revised accordingly. This paper is suitable for publication. 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 ******** 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: 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 ****** 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: In general, the authors responded the comments from the reviewers. However, it will be better to provide corresponding page number and line number in the main text for each response (e.g., calibrated P value), which facilitates the reviewers to confirm the questions raised have been well addressed. ****** 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.0255887.r003
Formally Accepted
6 Aug 2021 Acceptance Letter - Ping-Hsun Wu, Editor PONE-D-21-04320R1 Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: retrospective analyses of three large healthcare databases in the US Dear Dr. Holy: 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. Ping-Hsun Wu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255887.r004

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