Reducing the effect of immortal time bias affects the analysis of prevention of delirium by suvorexant in critically ill patients: A retrospective cohort study

Junji Shiotsuka; Shigehiko Uchino; Yusuke Sasabuchi; Tomoyuki Masuyama; Alan Kawarai Lefor; Masamitsu Sanui

doi:10.1371/journal.pone.0277916

Peer Review History

Original SubmissionAugust 3, 2022
5 Oct 2022 Decision Letter - Konlawij Trongtrakul, Editor PONE-D-22-21193Reducing the effect of immortal time bias affects the analysis of prevention of delirium by suvorexant: A retrospective cohort studyPLOS ONE Dear Dr. Masuyama, 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: Your manuscript has been rigorously reviewed. Please consider editing and justification point-by-point according to the reviewer's recommendations. ============================== Please submit your revised manuscript by Nov 18 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. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. Additional Editor Comments: - Please provide why using 72 hours of ICU admission or before the development of delirium as the suvorexant group in immortal time bias analysis. - Additionally, several issues need to be corrected or clarified as per the reviewer's recommendations as follows: [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: Partly ******** 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 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: This is quite interesting study regarding the effect of suvorexant for delirium prevention in ICU. The study is well designed and good methodology. However. I still have some questions regarding this study. 1. This study is quite difficult to understand. It is probably be their terminology. " the immortal time bias" "anytime before" " within 72 hr" 2. The author should described which program they use for statistical analysis? The authors should add " p value < 0.05 is considered statistically significant. 2. Regarding the result of study. Table 1. the authors described there was statistically significant different between types of surgical procedures in patients with and without suvorexant. However, they should describe which type of surgery was different. Table 2. Co administered medication; Patients in suvorexant received significantly higher tramadol, haloperidol, ramelteon. They did not explain why? The outcome: Delirium. The authors demonstrated both OR and HR. I think the authors had better report only RR or HR. If they demonstrated both they should explain the different between RR and HR Reviewer #2: Reducing the effect of immortal time bias affects the analysis of prevention of delirium by suvorexant: A retrospective cohort study Comments This is an interesting study in term of the study design to lessen the immortal time bias for the effect of suvorexant on the occurrence of delirium. Even the favorable outcomes of suvorexant on the incidence of delirium was addressed in previous studies but some limitations regarding the time of suvorexant administration was not clearly identified. I am impressed for the concept of this study; however, the retrospective cohort design has resulted in several limitation for interpretation of the outcomes. Given that, the imbalance in baseline characteristics between control and exposed groups would be the main concern. Several comments need to be delineated. • Title : - I recommend to add “ in critically ill patients” at the end of the title • Introduction: - Please add reference for the sentence in line 67,69,76 - Line 77 “summarized” (past tense) - Line 97, please provide the rationale for using the time frame “within 72 h” , any other previous studies mentioned about the onset of delirium in Japanese ICUs? • Methods: -If delirium had occurred several time during ICU stay, the investigator would collect only the first time? - Although it was mentioned in the limitation, the author should give more information regarding the general indications and the dosage of suvorexant because suvorexant is not available in many countries. Any other indication than insomnia? Who have ordered? Intensivist? Psychiatrist? Geriatrician? This issue might interfere with the outcomes. - Please provide the data regarding the accuracy of CAM-ICU (sens & spec) in practice because there were studies reported lower accuracy for CAM-ICU in practice. - Did you have any data about the types of delirium (hypo,hyper,mixed) and other non-pharmacologic intervention (ABCDEF bundles) for prevention of delirium? Because non-pharmacologic intervention showed more effectively in prevention of delirium in ICU than pharmacologic prevention. Did you control for this intervention between groups? - Please provide information about sample size calculation • Results: -There was significantly different in baseline characteristics between 2 groups in both analyses. This issue should be mentioned in limitation section. Patients in suvorexant showed higher number of surgical patients especially post cardiac surgery that seem to be less severity than control group. -The onset of delirium was only 0.8 day in control group? Was it hypo or hyperactive delirium? If it was hypoactive delirium, it might result from the anesthesia -related effect? - Could you explain whether ramelteon wasn’t adjusted in both analyses? Ramelteon is a melatonin receptor agonist that might improve sleep quality and decrease delirium in ICUs (even still inconclusive) - Please provide the title of all figures • Discussion: - Please add detail in limitation section as mentioned above - Limitations, consider word “first” because second, third,… were not mentioned? Please re-check English grammar ****** 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: ONUMA CHAIWAT ******** [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. Attachments Attachment Submitted filename: PONE-D-22-2119_REVIEWER.docx https://doi.org/10.1371/journal.pone.0277916.r001
Revision 1
16 Oct 2022 Author Response Editor Comments: - Please provide why using 72 hours of ICU admission or before the development of delirium as the suvorexant group in immortal time bias analysis. We added an explanation to explain the rationale of within “72 hours of ICU admission”. This important consideration is based on existing literature and published results. There are no set “standards” for this determination. Please see lines 125 to 127. Comments to the Author Reviewer #1: This is quite interesting study regarding the effect of suvorexant for delirium prevention in ICU. The study is well designed and good methodology. However. I still have some questions regarding this study. 1. This study is quite difficult to understand. It is probably be their terminology. " the immortal time bias" "anytime before" " within 72 hr" We apologize for any difficulties in understanding. We have revised the beginning of the abstract where these terms were not used consistently with the rest of the paper. The term “immortal time bias”, we believe, is a standard term. We believe that we have used it correctly throughout the paper. In the Methods section, we explain the two types of analysis, the “any time before” analysis and the “within 72h” analysis, in the expanded “Data Analysis” section which clearly explains that 2 analyses were performed on the same patient cohort, and each analysis compared a suvorexant group with a control group. Please see lines 180 – 188. 2. The author should described which program they use for statistical analysis? The authors should add " p value < 0.05 is considered statistically significant. We added these descriptions. Please see lines 167 – 168. 2. Regarding the result of study. Table 1. the authors described there was statistically significant different between types of surgical procedures in patients with and without suvorexant. However, they should describe which type of surgery was different. We calculated the chi-squared analysis for each operative procedure and added the p-value to the table. Please see Table 1 and S1 Table. Table 2. Co administered medication; Patients in suvorexant received significantly higher tramadol, haloperidol, ramelteon. They did not explain why? Because we could not control each physician’s medical practice due to the retrospective design, we can not explain the reason for these differences. We acknowledge the differences as a limitation and describe this in the revised discussion section. Please see line 383 – 389. The outcome: Delirium. The authors demonstrated both OR and HR. I think the authors had better report only RR or HR. If they demonstrated both they should explain the different between RR and HR We eliminated the RR and kept HR in the table. Please see Table 2 and S2 table. Reviewer #2: Reducing the effect of immortal time bias affects the analysis of prevention of delirium by suvorexant: A retrospective cohort study Comments This is an interesting study in term of the study design to lessen the immortal time bias for the effect of suvorexant on the occurrence of delirium. Even the favorable outcomes of suvorexant on the incidence of delirium was addressed in previous studies but some limitations regarding the time of suvorexant administration was not clearly identified. I am impressed for the concept of this study; however, the retrospective cohort design has resulted in several limitation for interpretation of the outcomes. Given that, the imbalance in baseline characteristics between control and exposed groups would be the main concern. Several comments need to be delineated. • Title : - I recommend to add “ in critically ill patients” at the end of the title We added “in critically ill patients” to the title. Please see line 2. • Introduction: - Please add reference for the sentence in line 67,69,76 - Line 77 “summarized” (past tense) - Line 97, please provide the rationale for using the time frame “within 72 h” , any other previous studies mentioned about the onset of delirium in Japanese ICUs? We added the references to the lines as Reviewer #2 kindly pointed out. Please see lines 58, 59 and 67 (because of an addition for other reviewer’s comment, the line number was changed). The rationale for 72hr is explained in lines 125-127, and we responded to a similar comment above from the editor. • Methods: -If delirium had occurred several time during ICU stay, the investigator would collect only the first time? As this was research for prevention and previous studies also investigated the “binary” outcome of delirium, we did not take into consideration multiple events of delirium. Yes, data was collected only for the first time. We added an explanation in lines 133 – 138. - Although it was mentioned in the limitation, the author should give more information regarding the general indications and the dosage of suvorexant because suvorexant is not available in many countries. Any other indication than insomnia? Who have ordered? Intensivist? Psychiatrist? Geriatrician? This issue might interfere with the outcomes. As for the indication and doses, we added the information to the Background section. Please see line 64 – 65. As for the person who decides the prescription, this was added to the methods section. Please see line 128 – 130. - Please provide the data regarding the accuracy of CAM-ICU (sens & spec) in practice because there were studies reported lower accuracy for CAM-ICU in practice. We added information regarding CAM-ICU to the revised discussion section. Please see lines 393 – 402. - Did you have any data about the types of delirium (hypo,hyper,mixed) and other non-pharmacologic intervention (ABCDEF bundles) for prevention of delirium? Because non-pharmacologic intervention showed more effectively in prevention of delirium in ICU than pharmacologic prevention. Did you control for this intervention between groups? As for the types of delirium, the definition of delirium in this study was based on CAM-ICU, and, therefore, we do not have data about the types of delirium. Please see line 132 – 133 and line 371 – 372. As for the non-pharmacological prevention, we added information. Please see lines 130 – 132. - Please provide information about sample size calculation Please see lines 170 – 173 in the new section “Sample Size Determination”. • Results: -There was significantly different in baseline characteristics between 2 groups in both analyses. This issue should be mentioned in limitation section. Patients in suvorexant showed higher number of surgical patients especially post cardiac surgery that seem to be less severity than control group. We added this information to the limitation section. Please see line 389 – 393. -The onset of delirium was only 0.8 day in control group? Was it hypo or hyperactive delirium? If it was hypoactive delirium, it might result from the anesthesia -related effect? As we mentioned earlier, we cannot know if this difference caused by the types of delirium. However, we added the possible reason and explanation to the revised Discussion section. Please see line 371 – 375. - Could you explain whether ramelteon wasn’t adjusted in both analyses? Ramelteon is a melatonin receptor agonist that might improve sleep quality and decrease delirium in ICUs (even still inconclusive) We initially thought that most administration of ramelteon was made with suvorexant, there was no need to adjust for it. We reanalyzed with ramelteon and found a small difference. Please see tables 3a and 3b. However, we apologize to the editors and reviewers with regard to the mis-transcription of the data to table 3b. The hazard ratio of emergency admission was smaller than the real number. The HR became larger in this revision, which is not due to the adjustment for ramelteon. - Please provide the title of all figures We added titles for each figure to the figure legends. • Discussion: - Please add detail in limitation section as mentioned above Please see above. We have added considerable detail to the limitation section. - Limitations, consider word “first” because second, third,… were not mentioned? We added several limitations and, thus, we changed the description. Please see lines 344 – 371. Please re-check English grammar We greatly appreciate your review and comment. This manuscript was thoroughly reviewed and revised by one of the co-authors, Professor Alan Kawarai Lefor who is a native English speaker and well-published surgical scientist. While there may be an occasional typographic error or stylistic difference, we believe that this manuscript conforms to standard scientific English language usage. We would certainly be willing to address any specific issues that you identify. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0277916.r002
6 Nov 2022 Decision Letter - Konlawij Trongtrakul, Editor Reducing the effect of immortal time bias affects the analysis of prevention of delirium by suvorexant in critically ill patients: A retrospective cohort study PONE-D-22-21193R1 Dear Dr. Masuyama, 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, Konlawij Trongtrakul, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): 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: (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.0277916.r003
Formally Accepted
18 Nov 2022 Acceptance Letter - Konlawij Trongtrakul, Editor PONE-D-22-21193R1 Reducing the effect of immortal time bias affects the analysis of prevention of delirium by suvorexant in critically ill patients: A retrospective cohort study Dear Dr. Masuyama: 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 Associate Professor Konlawij Trongtrakul Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0277916.r004

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