PONE-D-22-02931Reliability of multi-site UK Biobank MRI brain phenotypes for the assessment of neuropsychiatric complications of SARS-CoV-2 infection: the COVID-CNS travelling heads studyPLOS ONE

Dear Dr. Duff,

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" This research is supported by the COVID-19 Clinical Neuroscience Study (COVID-CNS)(covidcns.org), an Medical Research Council/UK Research and Innovation (www.ukri.org) funded grant: MR/V03605X/1. Data acquisition was additionally supported by the National Institute of Health Research (NIHR) (www.nihr.ac.uk), Cambridge Biomedical Research Centre (Mental Health theme) (cambridgebrc.nihr.ac.uk/research/mental-health) and by Addenbrooke’s Charitable Trust (www.act4addenbrookes.org.uk). LG, PJ and ED are supported by the NIHR Oxford Health Biomedical Research Centre (BRC) (oxfordhealthbrc.nihr.ac.uk) ETB is supported by a NIHR Senior Investigator award. TO is Reliability of multi-modal MRI-derived brain phenotypes for multi-site assessment of neuropsychiatric complications of SARS-CoV-2 infection Duff et al., January 2022, submission to PLOS ONE supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust (wellcome.org) and the Royal Society (royalsociety.org) (Grant Number 220204/Z/20/Z). This research was funded in part by the Wellcome Trust [203139/Z/16/Z, 202788/Z/16/Z and 215573/Z/19/Z]. For the purpose of open access, the author has applied a CC-BY public opyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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"This work was partly funded by the UKRI COVID-CNS consortium (covidcns.org). Data acquisition was additionally supported by the National Institute of Health Research (NIHR) (www.nihr.ac.uk), Cambridge Biomedical Research Centre (Mental Health theme) (cambridgebrc.nihr.ac.uk/research/mental-health) and by Addenbrooke’s Charitable Trust (www.act4addenbrookes.org.uk). 

LG, PJ and ED are supported by the NIHR Oxford Health Biomedical Research Centre (BRC) (oxfordhealthbrc.nihr.ac.uk). ETB is supported by a NIHR Senior Investigator award. TO is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust (wellcome.org) and the Royal Society (royalsociety.org) (Grant Number 220204/Z/20/Z).

This research was funded in part by the Wellcome Trust [203139/Z/16/Z, 202788/Z/16/Z and 215573/Z/19/Z]. For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. 

This research is supported by the COVID-19 Clinical Neuroscience Study (COVID-CNS), an Medical Research Council/UK Research and Innovation (www.ukri.org) funded grant: MR/V03605X/1. 

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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: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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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: Yes

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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: Yes

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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: In this manuscript the reliability of features extracted from multi-modal MRIs were evaluated across different sites and scanners, by scanning 8 participants at 4 UK sites: 3 using Siemens

PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King’s

College London). It gave confidence that large, multi-site MRI datasets can be

collected reliably at different sites across the diverse range of MRI modalities and IDPs

that could be mechanistically informative in COVID brain research. This work is important to give guidelines on how to handle the cross-site/cross-scanner data heterogeneity of various MRI phenotypes.

The major limitation of the paper is the small sample size---only 8 participants were considered. With such a small sample size, the statistical analysis should be more rigid. It seems like I cannot find the confidence intervals in tables or Figures of the ICCs. Have some confounding factors removed from the IDP similar to what UK Biobank did, such as motion parameters from rest fMRI, ICV from brain regional volume etc.? The authors needed to describe in details. The author should better provide more demographic information about the 8 participants, for example, are they British, percentages of males/females? Could the authors show the scatterplots of UKBiobank reliabilities versus your IDP reliabilities for both the cases of all scanners and siemens only? They should be highly correlated if they are correct. As the sample size is too small, the author may use more non-parametric statistical test instead of those test with Gaussian assumptions.

Minor issues are listed in the following.

1) In page 19, for fMRI traits, why there are 3464 IDPs? could the author explain. Similarly for dMRI, the author considered FA, MO, MD, ICVF, ISOVF, ODI, and there may probably be (48+27)*6 but why there are 675 IDPs?

2) to correct some typos. For example, for standard deviation, the author uses "sd" somewhere while uses "SD" in other places.

3) There are four rows in Figure 6. Does the subfigures in row 3 belong to Figure 6 C) or Figure 6 B)? Please make it clear.

Reviewer #2: This paper presents a multi-modal MRI protocol to reliably scan post-COVID patients across different sites. More than 2,000 IDPs were obtained by processing the acquired T1w, T2w, dMRI, rs-fMRI, sw-MRI, and ASL images. Between-site reliability of these IDPs were tested using intra-class correlations (ICC) and compared against the test-retest reliability of the same IDPs in scans from UK Biobank. The results for sites with same scanner manufacturer are more reliable compared to the one with different scanner manufacturer. Thus, reliability of the proposed multi-modal MRI protocol is limited to same type of scanner, which may not guarantee comparable data acquired using different scanner types.

I have following questions:

1. The authors mentioned that 1,073 IDPs were obtained from T1w and T2-FLAIR scans. Can they list few IDPs that were obtained? And what are the metrics of subcortical segmentation?

2. For post-acquisition processing of structural MRIs, why a standardized distortion correction method not applied to scans from Siemens and GE scanners?

3. “To avoid dependence on site-specific T1w data, we used T1w data from all sites to define generic masks for estimation of mean grey matter CBF and ATT.” How are these generic masks obtained? Are multi-site T1w data spatially normalized to a common space to get mask?

4. Are dMRI data collected with single phase encoding?

5. How are the weighted-mean summaries of diffusion parameters for each tract computed?

6. Can the reliability of IDPs be improved using post-acquisition harmonization?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-02931R1Reliability of multi-site UK Biobank MRI brain phenotypes for the assessment of neuropsychiatric complications of SARS-CoV-2 infection: the COVID-CNS travelling heads studyPLOS ONE

Dear Dr. Duff,

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 Aug 27 2022 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 rebuttal 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,

Pew-Thian Yap

Academic Editor

PLOS ONE

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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. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. 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: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. 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: 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: Yes

**********

6. 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: The author has fully addressed my comments, and I think the analysis now is rigid. One of my minor concern is the resolution/quality of many of your figures are low, for example, Figure 2~6. I cannot see clearly the axis labels/fonts/numbers in many places of the figures. Please improve the figure resolution and increase those font sizes.

Reviewer #2: (No Response)

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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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Reliability of multi-site UK Biobank MRI brain phenotypes for the assessment of neuropsychiatric complications of SARS-CoV-2 infection: the COVID-CNS travelling heads study

PONE-D-22-02931R2

Dear Dr. Duff,

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.

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Kind regards,

Pew-Thian Yap

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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