-->PONE-D-25-53607-->-->Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial-->-->PLOS One

Dear Dr. Wong,

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.

==============================

Dear Authors,

Thank you for submitting your manuscript entitled

“Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial” (PONE-D-25-53607) to PLOS ONE.

Your manuscript has now been reviewed by three independent reviewers. All reviewers agree that the study addresses an important and timely clinical question and that the overall randomized controlled design is appropriate. The trial is well motivated, registered, and supported by ethical approval, and the focus on Cantonese-speaking people with aphasia addresses an underrepresented population in the literature.

However, while Reviewers 1 and 2 raise primarily clarificatory and reporting-related issues, Reviewer 3 identifies several substantive methodological and procedural concerns that require resolution before the protocol can be considered suitable for publication. After careful consideration of all reviews, I have therefore decided that the manuscript requires Major Revision.

Below, I summarise the key issues that must be addressed in a revised version.

Major issues requiring attention

1. Randomization and allocation concealment
   The protocol must provide a clear and explicit description of allocation concealment procedures, including who generates the randomization sequence, who enrolls participants, and who assigns interventions. Please also clarify whether stratified or minimization procedures will be used to balance key prognostic variables across the three arms, or justify why this is not planned.
2. Primary outcome definition and scoring procedures
   The primary outcome requires more precise operationalization. Please clarify criteria for correct script production, handling of partial responses, self-corrections, and semantic substitutions.
   In addition, scoring procedures must be specified in greater detail, including the number of raters, blinding procedures, rater training, adjudication rules, and justification or validation of the adapted scoring approach (e.g., NORLA-6 adaptation).
3. Reliability and double scoring
   The current plan for double scoring a limited proportion of recordings requires strengthening. Please increase and pre-specify the proportion of recordings to be double scored, define acceptable reliability thresholds, and outline procedures if reliability falls below target.
4. Sample size calculation and assumptions
   Please provide a fully transparent account of the sample size calculation, including justification for the assumed effect size, statistical test framework (e.g., LME vs. repeated-measures ANOVA), assumptions regarding correlations among repeated measures, and how power relates to specific planned comparisons. Attrition assumptions should also be clarified.
5. Statistical analysis plan (pre-specification)
   The statistical analysis plan requires further pre-specification, including the planned mixed-effects model structure, handling of baseline measures and covariates, treatment of missing data, sensitivity analyses, and approach to multiple comparisons. Planned subgroup or moderator analyses should be clearly identified as confirmatory or exploratory.
6. Blinding and bias mitigation
   Please clarify how assessor blinding will be maintained and monitored, and how potential expectancy effects related to unblinded treatment providers will be mitigated.
7. Treatment fidelity and therapist training
   Additional details are required regarding therapist training, treatment manuals, fidelity monitoring procedures, and corrective actions for protocol deviations.
8. Safety monitoring and adverse events
   The protocol should specify procedures for monitoring and reporting adverse events (including VR-related symptoms), criteria for discontinuation, and the structure of safety oversight (e.g., DSMB or equivalent justification).
9. Eligibility criteria and generalizability
   Please clarify inclusion and exclusion criteria (including aphasia severity and motor speech disorders) and discuss how VR tolerance-based exclusions may affect generalizability.

Additional comments

In addition to the major points above, please address the minor and editorial comments from all reviewers, including clarifying timelines, outcome measurement details, data-sharing plans, adherence to reporting guidelines (e.g., SPIRIT), and language clarity.

Revision instructions

Please submit a detailed, point-by-point response to all reviewer comments, clearly indicating how each issue has been addressed. Revised text should be clearly identifiable.

Please note that failure to adequately address the major methodological and procedural concerns outlined above may preclude further consideration of the manuscript.

We appreciate the potential contribution of this protocol and look forward to receiving a carefully revised version.

Sincerely,

Jan Christopher Cwik

==============================

Please submit your revised manuscript by Mar 27 2026 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.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Jan Christopher Cwik, Prof. Dr. Dr.

Academic Editor

PLOS One

Journal Requirements:

-->1. When submitting your revision, we need you to address these additional requirements.-->--> -->-->Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at -->-->https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and -->-->https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf-->--> -->-->2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. -->--> -->-->When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.-->--> -->-->3. Thank you for stating the following in the Acknowledgments Section of your manuscript: -->-->We are grateful to the following organizations for their support in subject recruitment in the funding application: AKA Social Service, The Hong Kong Polytechnic University Speech Therapy Unit, The Hong Kong Stroke Association, The Neighbourhood Advice-action Council NT West Community Rehabilitation Day Centre.-->--> -->-->We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. -->-->Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: -->-->Wong received the General Research Fund from Hong Kong Research Grants Council for the project (Project number: 15602024).-->-->https://www.ugc.edu.hk/eng/rgc/funding_opport/grf/-->-->The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript -->--> -->-->Please include your amended statements within your cover letter; we will change the online submission form on your behalf.-->--> -->-->4. Please note that your Data Availability Statement is currently missing the repository name and/or the DOI/accession number of each dataset and a direct link to access each database. If your manuscript is accepted for publication, you will be asked to provide these details on a very short timeline. We therefore suggest that you provide this information now, though we will not hold up the peer review process if you are unable.-->--> -->-->5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.-->--> -->-->6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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 requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

Reviewer #3: Yes

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-->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

Reviewer #2: No

Reviewer #3: Yes

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-->6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: For sample size calculation, what test was used, t-test? Was a repeated measure method considered?

Descriptive statistics can be added to the statistical analysis plan.

Was baseline considered as a covariate in the LME? Change from baseline can be used as the dependent variable.

P value adjustment needs to be clearly written.

Reviewer #2: The study is well-grounded, and the authors demonstrate a solid understanding of the subject matter and relevant literature. The work addresses an important need to strengthen the validity of studies conducted using virtual reality (VR).

However, several points warrant reconsideration:

Protocol Design and Covariates: The study design does not account for covariates such as age, severity, and time since stroke, and the power calculation was performed without considering these factors. Additionally, these covariates are not planned to be balanced between groups. This represents a significant limitation that could reduce the validity of the results.

Population Specificity: The study focuses on Cantonese-speaking participants. While this is appropriate from a study design perspective, it should be clearly acknowledged as a limitation in the manuscript.

Subjective Assessments: Some subjective evaluations are conducted by a single author. It may be advisable for multiple evaluators to perform these assessments independently, followed by a joint review of scores, to improve reliability.

General Writing and Clarity: The manuscript has issues with overall fluency, and certain sections contain grammatical errors. A thorough revision of the text is recommended to improve readability and clarity.

Overall, the study has strong potential, but addressing the points above would enhance its rigor and the clarity of its presentation.

Reviewer #3: - Well-motivated, timely three-arm RCT (VR vs non-VR computerized script training vs no-treatment) targeting an important clinical question for Cantonese-speaking PWA. Trial is registered (NCT06722092), ethics approved (PolyU IRB), and data/code sharing on OSF is declared. The basic design and choice of script training are appropriate; however, several methodological, safety, and analysis details require clarification or strengthening before the protocol is acceptable.

Major issues (expanded)

1. Randomization and allocation concealment

- Provide explicit allocation concealment procedures: who generates and stores the sequence, who enrolls participants, and who performs assignments. Describe physical/technical safeguards (e.g., opaque sealed envelopes, central web-based randomization).

- Consider stratified randomization or minimization on key prognostic variables (baseline AQ/aphasia severity, time since stroke, age) to prevent imbalance across three arms.

2. Primary outcome definition, scoring, and rater procedures

- Fully operationalize the primary outcome: precise criteria for “correct” script production (treatment of semantic substitutions, paraphasias, partial utterances, prompts), timing window, and handling of self-corrections.

- Provide details on scoring procedures: blinded independent raters, number of raters per recording, training, and adjudication rules.

- The NORLA-6 adaptation and counting “semantically acceptable” productions as correct require justification or validation evidence (pilot reliability/validity). If novel, include plan to validate scoring (inter-rater reliability targets, pilot ICCs).

3. Reliability and proportion of double scoring

- Ten percent double-scoring is low. Increase to at least 20–25% of recordings, sampled across arms, timepoints, and script types. Pre-specify acceptable ICC thresholds and procedures if reliability is below threshold (retraining, rescoring).

4. Sample size calculation and assumptions

- Report full sample-size inputs: effect size origin and justification for d=0.74, assumed correlation among repeated measures, number of repeated measures, alpha adjustment for multiple pairwise comparisons (if applicable), and statistical test basis (LME vs repeated measures ANOVA). Clarify whether power is for VR vs non-VR, VR vs control, or all comparisons.

- Explain how the 20% attrition was applied and whether recruitment targets account for missing-at-random vs differential dropout across arms.

5. Statistical analysis plan (pre-specify)

- Provide detailed LME specification: random intercepts and/or slopes, whether time is categorical or continuous, covariance structure, fixed effects (arm, time, arm*time), planned covariates (age, baseline AQ, education) and rationale.

- State handling of missing data (ML via LME, multiple imputation), sensitivity analyses, and assumptions to be tested.

- Predefine primary contrasts and multiple comparison correction approach (hierarchical testing vs Bonferroni). Specify planned subgroup/moderator analyses (aphasia type, severity) and whether they are exploratory.

6. Blinding and bias mitigation

- Describe concrete steps to maintain assessor blinding (separate staff, standardized scripts to avoid revealing arm, blinding checks), and plan to assess and report blinding success.

- Clarify that therapy deliverers cannot be blinded and how expectancy effects will be mitigated (standardized instructions, scripted feedback).

7. Treatment fidelity and therapist training

- Provide details on manuals, training sessions for therapists/assistants, fidelity checklists, frequency of fidelity audits, and predefined corrective actions if deviations occur. Specify who monitors fidelity (independent reviewer) and their criteria.

8. Safety monitoring and adverse events

- Specify adverse-event monitoring procedures: which events are tracked (cybersickness, headache, dizziness, emotional distress), how often assessed, reporting timelines, criteria for temporary/permanent discontinuation, and who adjudicates events.

- State whether a DSMB or safety oversight committee will be convened; if not, justify and outline alternative safety oversight.

9. Inclusion/exclusion and generalizability

- Excluding anyone intolerant to a 10-minute VR exposure introduces selection bias toward those tolerating VR; discuss implications for generalizability and how findings will be interpreted relative to broader PWA populations.

- Clarify lower AQ limit (severe aphasia allowed?) and operational criteria for excluding “moderate to severe” motor speech disorders.

Minor issues and reporting suggestions

1. Sample and timeline consistency

- Reconcile inconsistent recruitment/start dates (May vs Aug 15, 2025) and provide final clear timeline. Provide updated, high-resolution SPIRIT figure

2. Outcome measurement details

- For CANELT z-scores and other transformed measures, specify normative data sources and transformation procedures.

- Clarify use of averaged baseline (two pre-treatment assessments) vs single baseline value in analyses.

3. Data sharing and reproducibility

- Good to see OSF links. Specify exactly which materials will be shared (de-identified audio, transcripts, scoring sheets, analysis code), timing of release, and de-identification steps for audio files.

4. Reporting and adherence to guidelines

- Ensure completed SPIRIT checklist and adherence to CONSORT extension for non-pharmacologic trials and ROMA recommendations are demonstrated in the final protocol.

5. Figure/table quality and minor edits

- Improve figure resolution and correct small typographical repetitions in submission metadata.

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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

Reviewer #3: Yes:lars clemmensen

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Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial

PONE-D-25-53607R1

Dear Dr. Wong,

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. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

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,

Jan Christopher Cwik, Prof. Dr. Dr.

Academic Editor

PLOS One

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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #1: 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?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Yes

**********

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

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: 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 requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 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.

(Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: All my concerns are addressed.

**********

-->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

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