Exploration of alive-and-ventilator free days as an outcome measure for clinical trials of Resuscitative interventions

Ari Moskowitz; Xianhong Xie; Michelle Ng Gong; Henry E. Wang; Luke Andrea; Yungtai Lo; Mimi Kim; for the Hospital Airway Resuscitation Trial Investigators

doi:10.1371/journal.pone.0308033

Peer Review History

Original SubmissionFebruary 29, 2024
8 May 2024 Decision Letter - Sebastian Schnaubelt, Editor PONE-D-24-07606Exploration of Alive-and-Ventilator Free Days as an Outcome Measure for Clinical Trials of Resuscitative InterventionsPLOS ONE Dear Dr. Moskowitz, 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 22 2024 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. 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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: No Reviewer #2: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: I Don't Know ****** 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 study describes alive-and-ventilator free days (AVFD) as outcome parameter for cardiac arrest trials. The authors try to compare the results of different definitions of AVFD with different results of simulation studies and also with results of an already completed trial. However, the description of some very important points were inadequate or confusing for me. I came away with too many questions to be able to recommend this paper without major revision. - Please revise the Methods section, especially the part describing the simulation of results. I am not sure in which way the results of the observational cohort, the bootstrapped samples from PART and the PART study influenced the simulation. - I am very confused of Figure 1 - as this is the observational cohort, what do you mean with intervention and placebo? Try to improve the graphic in general to illustrate the results in a better way. - In an paper about CPR outcome the Utstein style should be mentioned. - Please also include in the definition of AVFD what is considered as ventilator. Is a patient for example with NIV ventilator free? Is there a consensus on this in the research community? Reviewer #2: The authors of the present study describe the possible benefits of the composite outcome of alive-and-ventilator-free days in resuscitation trials. They assess different definitions of AVFD as well as different methods for comparison in simulated data. Finally, the evaluated methods are presented on actual data of a completed trial. However, some points are unclear and confusing to me: • I do not fully understand the use of the Two-Part modelling framework. As mentioned on page 15 lines 141-146 the first part assesses death/survival or ROSC/death/survival, however these metrics cannot be inferred by the composite AVFD endpoint alone (as you mention yourself on page 13 lines 105-110). Utilizing additional data by one analysis only renders comparability questionable. o If a composite endpoint for the three levels ROSC/death/survival is desired why didn`t you impose penalty on both unfavorable outcomes (e.g. no ROSC =-2, death after ROSC=-1)? • Regarding the interpretation of the statistical results it should be noted that the AVFD in the observational cohort clearly does not follow a normal distribution. Did you generate normally distributed AVFD values in the simulation process? If not, what did the used distributions look like? • Despite the primary focus on the simulation results, the underlying patient collective should be described in a formal and transparent manner to enable assessment of applicability in different cohorts. • Because of the primary focus on simulated data, the sampling/simulation process should be described in more detail in my opinion. • Graphics: Please use a different type of format or higher resolution for the graphics. Interpretability in the current form is limited. • Regarding Table 1: o Please add a description of the presented values. It is not clear to me if the AVFD days are presented as mean+SD or median+IQR for example. o Additionally, the presentation differs between the columns. Please ensure uniform presentation. • Regarding Table 2: o Please add a description of the presented values. It is not clear to me for example what the values in the LT and ETI column in the first row mean? (I presume mean days+SD?) o It do not understand the meaning of “Mean proportion of AVFD out of 30 days among survivors: ###%”. This metric is not used or described before. o Furthermore, the format of the table makes it rather hard to read. ****** 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: Yes: Christoph Veigl Reviewer #2: 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.0308033.r001
Revision 1
7 Jun 2024 Author Response Response to Reviewers Reviewer #1 (R1): This study describes alive-and-ventilator free days (AVFD) as outcome parameter for cardiac arrest trials. The authors try to compare the results of different definitions of AVFD with different results of simulation studies and also with results of an already completed trial. However, the descriptions of some very important points were inadequate or confusing for me. I came away with too many questions to be able to recommend this paper without major revision. Authors (A): We thank the Reviewer for their comments and have made Major Revisions to the manuscript as suggested by the Reviewers. R1: Please revise the Methods section, especially the part describing the simulation of results. I am not sure in which way the results of the observational cohort, the bootstrapped samples from PART and the PART study influenced the simulation. A: We agree that the flow of analyses described in the manuscript may be challenging for a reader to follow. We have substantially revised the Methods section to more clearly show the specific steps taken in the simulation studies. As now indicated in the section on study rationale and overall approach, two separate simulations were performed: “model-based simulations” in which data are simulated from an underlying statistical model with parameters informed by results from an observational IHCA cohort, and a second set of “bootstrap” simulations where the simulated data were drawn with replacement from the PART trial data. This approach was taken so as to provide the reader with simulation results when using an in-hospital cardiac arrest AVFD distribution as well as an out-of-hospital cardiac arrest AVFD distribution. R1: I am very confused of Figure 1 - as this is the observational cohort, what do you mean with intervention and placebo? Try to improve the graphic in general to illustrate the results in a better way. A: Thank you for this important observation. The Figure 1 attached with the manuscript was incorrect and has been revised in the resubmission. Further, the Figure has been updated for clarity as suggested. R1: In an paper about CPR outcome the Utstein style should be mentioned. A: This has been noted as suggested. R1: Please also include in the definition of AVFD what is considered as ventilator. Is a patient for example with NIV ventilator free? Is there a consensus on this in the research community? A: This is an important point for the more general PLOS One audience. Ventilation for the purpose of AVFD calculation refers to the administration of positive pressure through an endotracheal or tracheostomy tube. Non-invasive ventilation would not lead to a ventilator day. There is consensus on this definition in the critical care research community. Reviewer #2 (R2): The authors of the present study describe the possible benefits of the composite outcome of alive-and-ventilator-free days in resuscitation trials. They assess different definitions of AVFD as well as different methods for comparison in simulated data. Finally, the evaluated methods are presented on actual data of a completed trial. A: Thank you for your thoughtful review. R2: I do not fully understand the use of the Two-Part modelling framework. As mentioned on page 15 lines 141-146 the first part assesses death/survival or ROSC/death/survival, however these metrics cannot be inferred by the composite AVFD endpoint alone (as you mention yourself on page 13 lines 105-110). Utilizing additional data by one analysis only renders comparability questionable. A: Thank you for this comment and we apologize that our prior description of the Two-Part method was unclear. We have revised the paper to provide more justification for using the two-part modeling framework to analyze the composite AVFD outcome; we emphasize that modeling in two parts the intervention effect on ROSC/death/survival and the effect on ventilator days among survivors offers greater flexibility and can yield more insights about the relationship between the intervention and individual components of AVFD than standard methods. This is especially true when the effects are in opposite directions across AVFD components, as in Scenario 3 in our simulations (positive effect on reducing risk of ROSC but negative effect on ventilator free days among survivors). We showed that in this case, power to detect an overall intervention effect is greater with the two-part method than with the more restrictive proportional odds model that assumes the intervention effect is the same across all levels of AVFD. With a compositive outcome like AVFD, it is important to consider approaches that allow for greater flexibility in modeling the treatment effect across categories of the outcome. Various types of two-part models exist and have been applied in a number of different fields (PMID 28890906). R2: If a composite endpoint for the three levels ROSC/death/survival is desired why didn`t you impose penalty on both unfavorable outcomes (e.g. no ROSC =-2, death after ROSC=-1)? A: This is a very important point and the Reviewer is correct that additional levels for other unfavorable outcomes could have been added. We elected to only study one alternative approach to the AVFD definition to maintain simplicity and because there is precedence from published, high-impact trials for assigning a -1 to a less favorable outcome when analyzing AVFD. We have added these considerations to the Discussion section. R2: Regarding the interpretation of the statistical results it should be noted that the AVFD in the observational cohort clearly does not follow a normal distribution. Did you generate normally distributed AVFD values in the simulation process? If not, what did the used distributions look like? A: The Reviewer is correct that AVFD does not follow a normal distribution and this has now been noted in the manuscript. In addition, as described in the revised methods section of the paper, the model-based simulated data was generated in two parts to reflect the non-normality of the AVFD data: first, a multinomial logistic regression model was used to randomly generate for each subject their status with respect to failure to achieve ROSC/death after ROSC/survival. For the survivors, a beta-binomial regression model was then used to randomly generate the number of alive and vent free days. The beta-binomial model was selected to model AVFD among survivors since it yielded the best fit to our IHCA observational data that showed a non-normal distribution with an excess number of values at both ends of the distribution. Given the lack of normality in the AVFD distribution, non-parametric analysis approaches to analyze the AVFD data were considered as part of this study and indeed the findings suggest that use of parametric tests such as a t-test would yield less statistical power. Figure 1 has also been substantially revised to reflect the underlying distribution of the data. Additional details about how the data were simulated are provided in the data supplement. R2: Despite the primary focus on the simulation results, the underlying patient collective should be described in a formal and transparent manner to enable assessment of applicability in different cohorts. A: This is an important point. We have added details regarding the observation cohort in Supplemental Table 1. The details of the PART cohort can be found in the original trial publication. This has been noted in the manuscript. R2: Because of the primary focus on simulated data, the sampling/simulation process should be described in more detail in my opinion. A: We agree with the Reviewer and have added an extended, technical description of the sampling and simulation process in the Data Supplement. R2: Graphics: Please use a different type of format or higher resolution for the graphics. Interpretability in the current form is limited. A: The labeling and resolution of the figures has been improved as suggested. R2: Regarding Table 1: o Please add a description of the presented values. It is not clear to me if the AVFD days are presented as mean+SD or median+IQR for example. o Additionally, the presentation differs between the columns. Please ensure uniform presentation. A: These changes have been made as suggested. R2: Regarding Table 2: o Please add a description of the presented values. It is not clear to me for example what the values in the LT and ETI column in the first row mean? (I presume mean days+SD?) o It do not understand the meaning of “Mean proportion of AVFD out of 30 days among survivors: ###%”. This metric is not used or described before. o Furthermore, the format of the table makes it rather hard to read. A: We agree with the Reviewers assessment and the Table has been modified as suggested. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0308033.r002
17 Jul 2024 Decision Letter - Sebastian Schnaubelt, Editor Exploration of Alive-and-Ventilator Free Days as an Outcome Measure for Clinical Trials of Resuscitative Interventions PONE-D-24-07606R1 Dear Dr. Moskowitz, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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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: (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: Thank you for addressing all our comments. Please also add the programs and softwares you used to conduct the study Reviewer #2: (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: Yes: Christoph Veigl Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0308033.r003
Formally Accepted
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