Dear Dr. Rousseaux,

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Mohammad Mofatteh, PhD, MPH, MSc, PGCert, BSc (Hons), MB BCh (c)

Academic Editor

PLOS ONE

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Additional Editor Comments :

Please provide a detailed point-by-point response along with updated version of the manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Partly

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?-->?>

Reviewer #1: No

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

PLOS ONE

Reviewer #1: Yes

Reviewer #2: Yes

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Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: This manuscript is essentially a study protocol to conduct a longitudinal randomized controlled trial (RCT) for comparing the effectiveness of "VRH (virtual reality + hypnosis" versus "standard of care" for improving the quality of life during stem cell transplantation during hematologic treatments. The study was registered in clinicaltrials.gov, with a valid NCT number, and approved by the respective Ethics/IRB board. While the objectives and timeliness of this project appear sound and convincing, some comments appear below, following CONSORT guidelines and statistical perspectives:

(a) In Section 3, subsection 3.3, the "Randomization and Blinding" should appear as a separate subsection, with a clear focus. Details on randomization is needed (just saying computer-generated numbers doesn't suffice). In order to achieve equal participation in 2 groups, often block randomization is conducted, with some pre-decided block size. Why was that not proposed?

(b) Similarly, in Subsection 3.3, "sample size/power" should appear as a separate subsection. Although a repeated measures MANOVA will be used, it's not clear what "primary response" was used to compute the sample size? Infact, the primary response variables were mentioned much later in the manuscript.

(c) Statistical/Quantitative Analysis:

(c1) Here, it is mentioned that a MANOVA will be conducted, which is heavily based on Gaussian assumptions of the response variable. Alternatives, such as the nonparametric MANOVAs should be mentioned. Now, it is not clear what kind of nonparametric MANOVA the authors like to propose (such as, PERMANOVA, multivariate Kruskal-Wallis, etc).

(c2) Even before doing MANOVA, it's not clear why the authors initially don't like to compare the 2 groups at separate points (via 2-group t-tests/Wilcoxon rank sum tests), separately for each response variable, and then conduct a repeated measures ANOVA (and, if needed, a nonparametric counterpart) to test the group differences, separately for each response, now factoring in all time-points together. Then, they should move into the MANOVA analysis, considering multiple responses together. h

(c3) A Bonferroni correction can be too harsh; I would suggest using FDR (False Discovery rate).

(c4) It's appealing to mention the name of the software to be used to conduct the analysis.

(d) Conclusions/Discussion: This section should mention that the expected results from this study are only valid for this sample of patients recruited at a single-center hospital, and should allude to future trials with larger sample sizes and at other geographical locations to assess the effectiveness of the VRH intervention.

Reviewer #2: This is an exciting protocol that will hopefully result in a meaningful study. The N of 60 is plenty large for the goals, but I recommend a solid recruitment and headset management plan.

Some considerations in regards to the exclusion criteria: You may want to exclude patients with head wounds who can not safely wear a headset, exclude patients with a history of seizures induced by flashing lights, and exclude patients with a history of cybersickness.

I would also revisit your plan for only 2 time points for the intervention (1 week after transplant and 2 weeks thereafter). Why not prescribe this as a weekly or even daily meditation practice and assess effects further out? just two session doesn't seem nearly enough.

You mention using the Quest Pro, but your diagrams show a Quest 3. I would opt for the Quest 3 as the pro is no longer manufactured and costs much more with little benefit unless you are considering eye tracking.

Finally - consider also using the System usability Scale and Multimodal Presence Scale for your measurements after the initial session.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes: Asher Marks, MD

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Using Virtual Reality Hypnosis During Stem Cell Transplant for Patients in Hematology: A Protocol for a Randomized Study

PONE-D-25-12703R1

Dear Dr. Rousseaux,

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.

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Kind regards,

Made Satya Nugraha Gautama, RN, M.Sc.,M.N.Sc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: The authors were able to address my previous comments with great satisfaction. I have no further comments.

Reviewer #2: Thank you for the thorough and thoughtful responses to initial review. Good luck with the project and I look forward to reading more about it in the future.

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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

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