Outcomes and clinical implications of intranasal insulin on cognition in humans: A systematic review and meta-analysis

Sally Wu; Nicolette Stogios; Margaret Hahn; Janani Navagnanavel; Zahra Emami; Araba Chintoh; Philip Gerretsen; Ariel Graff-Guerrero; Tarek K. Rajji; Gary Remington; Sri Mahavir Agarwal

doi:10.1371/journal.pone.0286887

Peer Review History

Original SubmissionMarch 3, 2023
3 Mar 2023 Author Response Attachments Attachment Submitted filename: Rebuttal Letter.docx https://doi.org/10.1371/journal.pone.0286887.r001
16 Apr 2023 Decision Letter - Belgin Sever, Editor PONE-D-23-05529Outcomes and Clinical Implications of Intranasal Insulin on Cognition in Humans: A Systematic Review and Meta-AnalysisPLOS ONE Dear Dr. Agarwal, 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 May 31 2023 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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Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. 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: Yes Reviewer #2: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: 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: 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: Would like initially to congratulate the authors on performing hard work in preparing this manuscript after their review and analysis of many of the screened studies. This would be considered a well done manuscript for future references. Reviewer #2: Reviewer statement: The manuscript entitled “Outcomes and Clinical Implications of Intranasal Insulin on Cognition in Humans: A systematic review and metanalysis” aims the application of metanalysis technics to test the association of intranasal insulation and cognition. The manuscript carries some methodological flaws that need to be addressed before being accepted for publication. Main suggestions: 1- The version I received had the actual manuscript text duplicated. Something went wrong during the manuscript final editing. 2- The grammar and phrase constructions used in the manuscripts need to be revised. 3- The definition of the global cognition phenotype is not clear. The authors pooled data from different studies, each one with their own unique set of measured cognitive traits. The authors need to show the set of cognitive traits shared among the individual studies and how those study-specific traits were meta-analyzed. 4- The authors never considered the effect of simple covariates such as sex and age on each individual study. The individual studies are focused on different phenotypes with completely different cohorts. This heterogeneity and not considering the effect of sex and age could be a major source of bias that would be even more pronounced when doing a metanalysis. 5- The authors merged studies focused on mental health disorders, AD and metabolic disorders (lines 177 to 196) without considering that the underlying conditions may have an effect on the “global cognition”. This lack of rigor can lead to many experimental artifacts. 6- The authors didn’t explain the assumptions if the Cochrane Risk of Bias tool and didn’t even include a scientific reference for it. 7- The authors never even discussed the heterogeneity statistics I2 on each individual metanalysis. Low I2 statistics hinders the interpretation of any metanalysis. 8- There is a lot of confusion between the terms metanalysis and pooled analysis during the reading. Terms such as pooled population metanalysis are very misleading. 9- The authors need to further develop their introduction and their discussion sections. They need to incorporate similar studies using the same metanalytic approaches even for other focal phenotypes. 10- There is a lot of confusion between the definition of tables and a figure. Figure 2 and 3, as an example, are tables and not figures. The authors need to split tables and figures and discussed The authors didn’t include labels to any “figure” or supplementary “figures”. The interpretation is challenging without the proper labels. 11- The authors referred (line 236) the supplementary figure 9 that didn’t exist in the supplementary materials. ****** 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: 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.0286887.r002
Revision 1
11 May 2023 Author Response The version I received had the actual manuscript text duplicated. Something went wrong during the manuscript final editing. There are two versions of the manuscript. The latter version has tracked changes with our updated systematic search performed on February 11, 2023, as requested by the journal. The manuscript and analyses were then updated accordingly. Per journal protocols, a tracked and clean version of the manuscript were uploaded upon resubmission. The grammar and phrase constructions used in the manuscripts need to be revised. Thank you for your comment. We have gone through the manuscript and proofread to ensure that there are no grammatical and phrase construction errors. The definition of the global cognition phenotype is not clear. The authors pooled data from different studies, each one with their own unique set of measured cognitive traits. The authors need to show the set of cognitive traits shared among the individual studies and how those study-specific traits were meta-analyzed. Supplementary Table 3 outlines the different cognitive domains that were measured across studies as well as the various cognitive measures used to assess each domain. For each included study in the quantitative meta-analysis, an effect size for global cognition was calculated by averaging the effect size of individual cognitive domains. The effect size for global cognition for each study was then entered into another meta-analysis to obtain a pooled effect of global cognition across all studies in each patient population. We have updated and included this explanation in our Methods section to further elaborate our definition of global cognition. The authors never considered the effect of simple covariates such as sex and age on each individual study. The individual studies are focused on different phenotypes with completely different cohorts. This heterogeneity and not considering the effect of sex and age could be a major source of bias that would be even more pronounced when doing a metanalysis. Based on the reviewer’s comment, we ran subgroup analyses based on sex, age, and dose of INI. Within patient populations, age wasn’t a heterogenous variable. Subgroup analysis could be conducted for patients with AD/MCI as all patients were 55 years or older. Furthermore, subgroup analysis could not be conducted due to the limited number in the mental health and metabolic disorder groups. Please see section 3.5 for the updated results. The authors merged studies focused on mental health disorders, AD and metabolic disorders (lines 177 to 196) without considering that the underlying conditions may have an effect on the “global cognition”. This lack of rigor can lead to many experimental artifacts. Thank you for your comment. We agree with the reviewer that this is a heterogenous population and removed the overall pooled effect size in Figure 3. We reported on the outcomes individually, though they are displayed in one figure for organization purposes. The authors didn’t explain the assumptions if the Cochrane Risk of Bias tool and didn’t even include a scientific reference for it. Thank you for bringing this to our attention. We have added the reference for the Cochrane Risk of Bias tool as well as the different domains it addresses. The authors never even discussed the heterogeneity statistics I2 on each individual metanalysis. Low I2 statistics hinders the interpretation of any metanalysis. Thank you for your comment. We have addressed the heterogeneity I2 statistics in our limitation sections. We also discuss potential sources of heterogeneity throughout our discussion based on each patient population. There is a lot of confusion between the terms metanalysis and pooled analysis during the reading. Terms such as pooled population metanalysis are very misleading. Thank you for bringing this to our attention. We have updated our results section using the proper nomenclature for a meta-analysis. The authors need to further develop their introduction and their discussion sections. They need to incorporate similar studies using the same metanalytic approaches even for other focal phenotypes. Thank you for your suggestion. We have further elaborated on the study that we referenced for the same meta-analytic approach. There is a lot of confusion between the definition of tables and a figure. Figure 2 and 3, as an example, are tables and not figures. The authors need to split tables and figures and discussed The authors didn’t include labels to any “figure” or supplementary “figures”. The interpretation is challenging without the proper labels. As per requested by PLOS One, the figure captions are included in the manuscript and the figures followed the references at the end. To note, Figure 2 and 3 are forest plots that were exported by RevMan. Forest plots are a graphical representation of the findings of multiple studies, thus we listed them as figures and not tables. All figures and tables are correctly labeled in our supplementary file. The authors referred (line 236) the supplementary figure 9 that didn’t exist in the supplementary materials. Thank you for bringing this to our attention. We had mislabeled the last few figures. We have updated the supplementary file with additional subgroup analyses and updated the figure label accordingly. Attachments Attachment Submitted filename: Rebuttal Letter April 2023.docx https://doi.org/10.1371/journal.pone.0286887.r003
25 May 2023 Decision Letter - Belgin Sever, Editor Outcomes and Clinical Implications of Intranasal Insulin on Cognition in Humans: A Systematic Review and Meta-Analysis PONE-D-23-05529R1 Dear Dr. Agarwal, 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, Belgin Sever, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0286887.r004
Formally Accepted
2 Jun 2023 Acceptance Letter - Belgin Sever, Editor PONE-D-23-05529R1 Outcomes and Clinical Implications of Intranasal Insulin on Cognition in Humans: A Systematic Review and Meta-Analysis Dear Dr. Agarwal: 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 Assoc. Prof. Dr. Belgin Sever Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0286887.r005

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