PONE-D-24-15473Digital measurement of ocular microtremor in Parkinson’s Disease: Protocol to assess reliability and clinical validation.

Dear Dr. Stuart,

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“This study is based at the Physiotherapy Innovation Laboratory (Website: www.pi-lab.co.uk, Twitter: @Physio_In_Lab) and has been funded by a Northumbria University PhD studentship in collaboration with Head Diagnostics Ltd. (Dublin, Ireland). Dr Samuel Stuart is supported, in part, by a Parkinson’s Foundation Post-doctoral Fellowship for Basic  Scientists (PF-FBS-1898-18-21) and a Clinical Research Award (PF-CRA-2073). Private Physiotherapy Educational Foundation funding also supported this research (PPEF – #368; PI: Stuart).”

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“This study is based at the Physiotherapy Innovation Laboratory (Website: www.pi-lab.co.uk, Twitter: @Physio_In_Lab) and has been funded by a Northumbria University PhD studentship in collaboration with Head Diagnostics Ltd. (Dublin, Ireland). Dr Samuel Stuart is supported, in part, by a Parkinson’s Foundation Post-doctoral Fellowship for Basic  Scientists (PF-FBS-1898-18-21) and a Clinical Research Award (PF-CRA-2073). Private Physiotherapy Educational Foundation funding also supported this research (PPEF – #368; PI: Stuart).”

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“This study is based at the Physiotherapy Innovation Laboratory (Website: www.pi-lab.co.uk, Twitter: @Physio_In_Lab) and has been funded by a Northumbria University PhD studentship in collaboration with Head Diagnostics Ltd. (Dublin, Ireland). Dr Samuel Stuart is supported, in part, by a Parkinson’s Foundation Post-doctoral Fellowship for Basic  Scientists (PF-FBS-1898-18-21) and a Clinical Research Award (PF-CRA-2073). Private Physiotherapy Educational Foundation funding also supported this research (PPEF – #368; PI: Stuart).”

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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

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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

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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

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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: No

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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: 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: This is a very well conceptualized and constructed protocol. All necessary components are included and adequately detailed. This protocol is IRB approved and has been registered on clinicaltrials.gov. I have no reservations in recommending this protocol for publication at this time.

Reviewer #2: • Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing of the stated hypotheses?

Yes, with the following caveats:

The protocol indicates that patients will be recruited when they first present at clinic with suspected PD. Those that are confirmed as PD go into the PD group, those that get some other diagnosis (or are healthy) go into the ‘not PD’ group. Superficially this makes good sense, at it allows the researchers to compare two groups at the point of diagnosis. However, the non-PD group will be extremely heterogeneous and may include people with no illness at all, people with non-PD motor disorders and people with other illnesses that could compromise their eye-movements such as stroke or Alzheimer’s disease. I think this could be a potential problem for interpretation, especially if the study finds no group differences.

The justification for the sample size is not very convincing. The purpose of the power analysis is establish the sample necessary to observe a statistically significant difference between the two groups. Given there is prior evidence that OMT differs in PD and controls I would expect to see a formal power analysis to support the sample of 30, irrespective of whether or not the authors wish to draw conclusions about the clinical value of the test.

Why is only the PD group getting a 2nd assessment in the home? It seems necessary to test reliability in both groups in the home to make a valid conclusion about the reliability of iTremor, especially as people homes are much more variable than the lab, so it would not be very surprising to see at least some variation in scores when testing moves from controlled lab environments to homes.

How will usability and acceptability be assessed? The authors mention reporting descriptions of usability and acceptability but not how this date will be collected (e.g. is it based on the researchers reflection? Will patients be asked? will metrics like the time it takes to perform the test be measured?)

Minor comments

Introduction

Line 81-83 : sentence doesn’t make sense. I think because the authors don’t explain what ability is being referred to in line 81.

Line 84: the authors argue that that main problem for using eye-movements to diagnose PD is that some patients don’t understand the instructions on some tasks. They allude to the antisaccade task, but are not explicit. I didn’t quite follow this line of argument, as earlier in the para it is argued that prosaccades are in fact the most best for predicting decline. I would also be surprised if non-dementing PD patients had problems understanding antisaccade or memory guided saccade tasks (at least, no more so than similarly aged controls). The issue of medication is more problematic, but of course if a patient is already on medication isn’t it likely they have been diagnosed with PD, so the use of eye-movement data for diagnosis is no longer necessary? (whereas it it might still be useful for progression monitoring)

Line 304-306: the text suggests patients will be told to abstain from taking their meds, then a week later the team will visit. I assume this not the plan, so this phrasing needs to be tightened up

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Reviewer #1: Yes: Erin E. Robertson

Reviewer #2: No

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Digital measurement of ocular microtremor in Parkinson’s Disease: Protocol for a pilot study to assess reliability and clinical validation.

PONE-D-24-15473R1

Dear Dr. Stuart,

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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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,

Karsten Witt

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Dr. Stuart,

Thank you for the submitted revision of your paper entitled “Digital measurement of ocular microtremor in Parkinson's Disease: Protocol for a pilot study to assess reliability and clinical validation”.

I am pleased to accept the paper in the revised version, I have received the positive evaluation from the reviewers. The review process took some time because I was not able to find suitable reviewers right away, so I apologize for the delay.

Best regards

Karsten Witt

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

**********

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: 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

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 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

**********

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: 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: The revisions these authors have made has resulted in a stronger protocol, more clearly defined protocol. I have no reservation in recommending this manuscript for publication.

Reviewer #2: The authors responses have convincingly addressed the issues raised in my first review. The study should be a worthwhile contribution.

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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

Reviewer #2: No

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