Dear Dr Wing,

Thank you for submitting your manuscript entitled "Effectiveness of E-based Cognitive Behavioral Therapy for Insomnia on Preventing Major Depressive Disorder in Youth with Insomnia and Subclinical Depression: A Randomized Clinical Trial" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Aug 27 2024 11:59PM. Please do let us know if you need more time.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Syba

Syba Sunny, MBBS, MRes, FRCPath

Associate Editor

PLOS Medicine

ssunny@plos.org

Dear Dr Wing,

Many thanks for submitting your manuscript "Effectiveness of E-based Cognitive Behavioral Therapy for Insomnia on Preventing Major Depressive Disorder in Youth with Insomnia and Subclinical Depression: A Randomized Clinical Trial" (PMEDICINE-D-24-02778R1) to PLOS Medicine. The paper has been reviewed by subject experts and a statistician; their comments are included below and can also be accessed here: [LINK]

As you will see, whilst there was an appreciation of the value of the work presented, the reviewers raised a number of concerns, including discrepancies between what was written in the manuscript and the protocol documentation provided. However, after discussing the paper with the editorial team and an academic editor with relevant expertise, I'm pleased to invite you to revise the paper in response to the reviewers' and editors’ comments. We plan to send the revised paper to some or all of the original reviewers, and we cannot provide any guarantees at this stage regarding publication.

When you upload your revision, please include a point-by-point response that addresses all of the reviewer and editorial points, indicating the changes made in the manuscript and either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please also be sure to check the general editorial comments at the end of this letter and include these in your point-by-point response. When you resubmit your paper, please include a clean version of the paper as the main article file and a version with changes tracked as a marked-up manuscript. It may also be helpful to check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper.

We ask that you submit your revision by Nov 12 2024 11:59PM. However, if this deadline is not feasible, please contact me by email, and we can discuss a suitable alternative.

Don't hesitate to contact me directly with any questions (ssunny@plos.org).

Best regards,

Syba

Syba Sunny, MBBS, MRes, FRCPath

Associate Editor

PLOS Medicine

ssunny@plos.org

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Comments from the academic editor:

The academic editor was supportive of inviting you to revise your paper. He agreed with the reviewer comments and asked that you give special attention to the comments of Reviewer 3 and the diagnostic issue.

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Comments from the reviewers:

Reviewer #1: The paper reports on a trial of an app-based insomnia intervention to prevent depression in young people with insomnia symptoms. I was not a reviewer of the original version of the manuscript and have not been provided with details of the previous review round, so I apologize for any overlap with previous comments. Overall the trial is clearly reported and the outcomes further establish the importance of reducing insomnia symptoms for the prevention of mental ill health. To my knowledge, no previous study has robustly tested whether treatment of insomnia symptoms can prevent depression in a young adult sample.

1. The term "e-based" is not commonly used in the literature and not clearly defined. Electronic interventions are broader than digital interventions or internet interventions, which include smartphone applications (apps). A more precise term should be used throughout.

2. Page 4: "...emergence of sleep and mental health problem[s]" (should be plural)

3. Page 4: "...translate the modifiable risk factors for depression into [an] effective preventive strategy."

4. Page 5: It appears that insomnia disorder was only assessed using the ISI, with no clinical confirmation. Perhaps the term "insomnia disorder" should be replaced by "significant insomnia symptoms" or "probable insomnia disorder". This also seems inconsistent with the trial registration, which indicates that ICD-10 criteria were to be used to assess insomnia disorder.

5. Page 5: "in addition to any pharmacological treatments" - should this be "irrespective of any pharmacological treatments"?

6. Page 5: "The study was conducted and reported in accordance with the CONSORT Guidelines." - CONSORT guidelines are only for the reporting of trials, not a recipe for conducting trials.

7. Page 5: "Informed consents were obtained... consents from their parents" - consent should be singular (unless there were multiple consents provided for different aspects of the trial - if so, this should be described).

8. Page 6: Were the interventions delivered in Chinese? Was any co-design or user testing conducted before the trial?

9. Page 6 / Table S1: How much sleep hygiene content was included in the control condition? The authors are likely aware that sleep hygiene can be an active intervention (e.g., https://doi.org/10.1093/fampra/cmx122). Perhaps this might explain the (smaller) improvements in insomnia in the control condition.

10. Page 8: It is not clear why the sensitivity analysis (LOCF) used a less rigorous methodology than the primary analysis, as LOCF assumes MCAR instead of MAR.

11. Page 9: "attended the 6-month assessments" - the method suggests that assessments were self-completed (was this online?) but the term "attended" suggests they were done in-person at a specified location - please clarify.

12. No adverse events were reported. This seems surprising - did none of the control condition participants report deterioration of symptoms or any other negative experience that might have been related to the intervention? Perhaps the wording of the question about adverse events set a high threshold - some explanation would be helpful.

13. The discussion (p15) reports on impacts on functional impairments - it seems this is based on daytime fatigue. It is not clear that this measure can appropriately be described as assessing functional impairments.

14. The discussion attributes the low attrition to reminders. However, previous similar trials also used automated reminders (e.g., 11). I wonder if the higher adherence might be partly explained by cultural differences in expectations around completion of trial activities, given this trial seems to be the first of its kind conducted outside of Western nations? More could also be made of this outcome - that the effectiveness of addressing insomnia symptoms seems to extend beyond US/Europe/Australia.

15. It is interesting that the intervention had much more modest effects on anxiety (which is also closely tied to insomnia) than on depression. No interpretation of this finding is provided.

16. The limitation around use of the MINI might be strengthened. The measure had modest psychometric performance in the single validation study that was conducted against clinical interviews (in 1998) and I am not aware of any cultural adaptation of the inventory for Chinese-speaking populations.

17. Another limitation of the study that should be noted is that a clear majority of the participants were young adults (18-25) rather than adolescents. There may be development differences in the role of insomnia in adolescents vs young adults, but the adolescent sample in this trial (n=20) was insufficient to examine this possibility and the findings may not generalize to adolescents (under 18 years of age).

Reviewer #2: This paper reports the main results of a randomised controlled trial of an e-based CBT on preventing MDD in youth with insomnia. Overall, I found the paper very clear and easy to follow. The results were consistent across a range of outcomes which strengthen the likelihood of intervention benefits. Most of my comments are relatively minor and are listed below.

Major / general comments:

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1) The outcome hierarchy is not entirely clear to me. According to the protocol, outcomes were classified as follows:

* Primary outcomes (x4): ⁕ Remission rate of insomnia disorder conformed by ICD-10 Classification of Mental and Behavioral Disorders, ⁕ Change of insomnia symptoms measured by ISI ⁕ Occurrence of MDD conformed by MINI and ⁕ Change of depressive symptoms measured by PHQ-9

* Secondary outcomes (x2): ⁕ Incidence of suicidality which includes plans and attempts as measured by MINI and ⁕ Change of anxiety symptoms measured by GAD-7

* Other outcomes (x10): ⁕ Incidence of suicidal ideation measured by BSSI, ⁕ Change of daytime symptoms measured by MFI, ⁕ Change of sleep-related thoughts and behaviours measured by DBAS-16, ⁕ Change of circadian rhythms measured by 7-Day Daily Sleep Diary and MEQ, and ⁕ Change of sleep parameters including time in bed (TIB), total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE) measured by 7-Day Daily Sleep Diary

While all these outcomes appear to be reported in the manuscript, time to MDD onset has been selected as the primary outcome with PHQ9 and ISI as secondary outcomes. Please justify this change/choice.

2) The primary outcome is time to MDD onset (i.e. a survival outcome); however, assessments only occurred at discrete visits (6 and 12 months). Based on the discrete timing of the assessment, I would expect censoring and the recording of event times to occur only at the time of visits but the Kaplan-Meier plot suggests that event times were recorded continuously which surprises me. Was the actual date of MDD onset recorded (e.g. using a diary)? Please clarify in the response and manuscript.

3) The attached protocol and SAP are in a Word document which does not contain any contextual information e.g. title page, date or footnote. If available, please share a full version of the protocol (and SAP) e.g. in PDF format.

Minor / specific comments:

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4) The sample size calculation assumes a HR of 0.5. This is a fairly large effect, -at least for someone new to this field such as me -; however, there is no justification for the choice of effect size in the manuscript. Please add.

5) "Remission rates of insomnia were analysed using a weighted generalized estimating equations model". It is not clear to me why a "weighted" version of GEEs was used. Please clarify the purpose and weighting approach.

6) When reporting the results of new onset MDD, the authors indicate that 10% and 18% of participants developed new onset in the intervention and control groups respectively. In the same paragraph, they report the one-year incidence of MDD estimated from the cumulative incidence curves. These numbers (12% and 21%) are different from the proportions at one year (10% and 18%). The differences are presumably due to censoring when using cumulative incidence curves. Please confirm/clarify.

7) Adjusted analyses of new onset MDD were conducted after adding multiple covariates (including prior history of MDD, educational level, family income, comorbid medical illnesses and use of sleep-promoting medication). Please clarify whether this adjusted analysis was pre-specified and how the covariates were selected. Were other adjusted analyses performed?

8) In the results section 3.3.1 (remission rates - bottom of page 12), please clarify what is meant by "weighted" in "the *weighted* percentage of remitters". Please also clarify what is mean by "controlling missing data" in "after controlling for strata variables and *missing data*". Does this mean that missing data was imputed? And if so, how? I would expect the primary analysis of remission rates over time to be based on all available data with no imputation; however, it is not clear to me that this was the approach used (except in sensitivity analyses).

9) Table 2. Please add the number of participants with available data at each timepoint for each arm and outcome when reporting the mean and SE by visit.

10) Please consider including plots of PHQ-9 and ISI (and potentially PHQ-8) scores showing the mean and SE by treatment for each visit to supplement Table 2. These plots could be part of the supplementary appendix. The same could be done for other outcomes presented in S5 Table.

-Laurent Billot

Reviewer #3: The authors investigated the effects of digital insomnia cognitive behavioral therapy on the occurrence of major depression in adolescents through a randomized, double-blind clinical trial. As a result of the 12-month follow-up, the prevalence of insomnia and the incidence of major depression in the group receiving digital insomnia cognitive behavioral therapy were significantly lower than those in the control group.

The strength of this study is that it was conducted while controlling various variables well. This study is meaningful in that there is a lack of studies that control variables that affect the results well. Another strength is that the compliance of the study participants was evaluated and presented.

However, it is a significant problem that the duration of insomnia as a study participant was not applied as the diagnostic criterion for insomnia adopted by DSM-IV and ICSD-3 since 2013, "3 months." In addition, previous studies on insomnia and depression have shown that persistent insomnia affects relapse rather than onset of depression (Persistent Sleep Disturbance: A Risk Factor for Recurrent Depression in Community-Dwelling Older Adults, http://dx.doi.org/10.5665/sleep.3128). It is an important issue whether the variables evaluated by the authors measure relapse or first onset of depression. In addition, the authors should have considered the history of depression when randomizing. Third, the authors should mention the mechanism of operation of the digital cognitive behavioral therapy for insomnia. Information should be provided on whether the therapist delivers the prescription through the Internet based on the entered sleep diary or by an artificial intelligence model, what mechanism is used to prescribe the sleep schedule provided to the study participants, and whether cognitive therapy also addresses depression or only insomnia. It is necessary to describe the aforementioned issues as limitations. Finally, the authors have already mentioned the limitations, such as the difficulty in maintaining double-blindness and the fact that the recurrence of depression was assessed over the phone, which are important issues to consider when interpreting the study results.

Any attachments provided with reviews can be seen via the following link: [LINK]

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Comments and requests from the editorial team:

(Note: not all will apply to your paper, but please check each item carefully)

* We note that the reviewers picked up on discrepancies between the study protocol that was submitted and the information provided in the main text of the manuscript. For example, it does not appear that the diagnosis of insomnia was made as planned. Please clarify and explain all discrepancies between the paper and protocol. If the outcomes were not prespecified in the protocol, please define them in the Methods (Outcomes section) as post hoc and explain why they were added. Post hoc comparisons should be presented as hypothesis generating rather than conclusive.

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Dear Dr. Wing,

Thank you very much for re-submitting your manuscript "Effectiveness of App-based Cognitive Behavioral Therapy for Insomnia on Preventing Major Depressive Disorder in Youth with Insomnia and Subclinical Depression: A Randomized Clinical Trial" (PMEDICINE-D-24-02778R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by the reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Dec 20 2024 11:59PM.   

Sincerely,

Rebecca Kirk

On behalf of:

Syba Sunny, MBBS, MRes, FRCPath

Senior Editor 

PLOS Medicine

plosmedicine.org

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Requests from Editors:

GENERAL EDITORIAL REQEUSTS

* At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Ideally each sub-heading should contain 2-3 single sentence, concise bullet points containing the most salient points from your study. In the final bullet point of ‘What Do These Findings Mean?’ Please include the main limitations of the study in non-technical language.

Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary. "

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* Please provide titles and legends for all figures (including those in Supporting Information files).

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* The sample size listed in the submitted manuscript and the trial registry differ. Please explain the discrepancy.

Comments from Reviewers:

Reviewer #1: I thank the authors for their comprehensive responses to my comments. I have no additional concerns.

-- Phil Batterham

Reviewer #2: All my previous comments have been adequately adressed. Thank you.

-Laurent Billot

Reviewer #3: The authors have fully explained and revised the manuscript in response to the reviewers' questions and comments.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr Wing, 

On behalf of my colleagues and the Academic Editor, Mark Tomlinson, I am pleased to inform you that we have agreed to publish your manuscript "Effectiveness of App-based Cognitive Behavioral Therapy for Insomnia on Preventing Major Depressive Disorder in Youth with Insomnia and Subclinical Depression: A Randomized Clinical Trial" (PMEDICINE-D-24-02778R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Rebecca Kirk

On behalf of:

Syba Sunny, MBBS, MRes, FRCPath 

Senior Editor 

PLOS Medicine