-->PONE-D-25-59562-->-->A-eye: Automated 3D MRI Segmentation and Morphometric Feature Extraction for Eye and Orbit Atlas Construction-->-->PLOS One

Dear Dr. Barranco,

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.

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

ACADEMIC EDITOR: Despite the critical comments from both reviewers, I have decided to recommend MAJOR REVISION in light of the merits in this manuscript. I hereby request the authors to address the reviewers criticisms and concerns to the greatest extent possible.

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

Please submit your revised manuscript by Mar 26 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:-->

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We look forward to receiving your revised manuscript.

Kind regards,

Ziyu Qi, M.D., Ph.D.

Academic Editor

PLOS One

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This work was supported by the Gelbert Foundation, whose contribution is gratefully acknowledged. We acknowledge access to the facilities and expertise of the CIBM Center for Biomedical Imaging, a Swiss research center of excellence founded and supported by CHUV, UNIL, EPFL, UNIGE and HUG, and the HES-SO University of Applied Sciences and Arts Western Switzerland. HK is supported by the Swiss National Science Foundation, grant (215641, PI: MBC). This study was partially supported by funding received from the Swiss National Science Foundation, grant (220433, PI: BF).

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JB - Gelbert Foundation

HK - Swiss National Science Foundation grant number 215641

YJ - Swiss National Science Foundation grant number 220433

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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: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: No

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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: No

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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: Thank you for the opportunity to review this novel work. The study presents the first large-scale eye atlas with multi-structure segmentation and sex-stratified analysis. The manuscript demonstrates strong novelty, transparent data practices, and generally appropriate statistical analyses.

I have attached a detailed report, but several points require clarification or further evidence to fully support the conclusions:

1. Validation and generalization of the atlas to left eyes.

2. Quantitative validation and inter-rater reliability of the eye-specific QC protocol.

3. Analysis of axial length extraction failures, especially in pathological eyes.

4. Reporting correlation statistics for BMI versus eye structure volumes.

5. Clarification of cohort ethnic composition and cross-ethnic generalizability.

6. Justification of nnU-Net architecture choices, including patch size and data augmentation.

7. Precision, confidence intervals, and test-retest reliability of volumetry measurements.

8. Interpretation and thresholding of atlas probability maps.

9. Limitations due to single-rater manual segmentations and their impact on performance.

Addressing these points will strengthen the manuscript and enhance confidence in the atlas’s robustness and applicability.

Reviewer #2: While the topic and dataset scale are commendable, the manuscript contains critical methodological flaws thus the decision is to be rejected.

1. Critically Small Training Set With No External Validation. The model was trained on only 31 subjects. No external validation on independent data (different scanner, field strength, or population) was performed. The generalizability claims are therefore entirely unsupported. The authors evaluate a 10-class 3D segmentation with 31 training cases and a 43-case test set, and performance claims are then extended to a 1,000+ subject cohort and atlas construction. This is an unusually small training set for the complexity of the task and raises a high risk of dataset-specific learning.

2. Right-Eye-Only Design Severely Limits Utility. Right-eye-only labelling and atlas construction severely limit the usefulness and generalizability of the proposed framework. Left-eye generalization is merely hypothesized but never tested, despite known subtle orbital asymmetries.

3. Single-Rater Ground Truth Makes All Metrics Uninterpretable. All annotations were produced by one junior ophthalmologist (1 year of experience) and reviewed by a senior expert. Without independent multi-rater annotations, there is no inter-rater variability baseline. This fundamentally undermines every quantitative claim in the paper.

4. Unvalidated Atlas Inherits Systematic Model Errors. Atlas label generation is based on projecting automated nnU-Net segmentations and majority voting. This means the atlas will inherit systematic model errors (e.g., weaker performance in extraconal fat/rectus muscles, laterality mix-ups, missing lens segmentations). Yet, the manuscript provides no convincing atlas-validation framework (e.g., manual-label evaluation in atlas space, registration-quality/sharpness metrics, or uncertainty quantification tied to label fidelity). Without that, the atlas cannot be considered a reliable reference standard.

5. Axial Length Estimation Shows Systematic Bias. The manuscript uses an MRI-specific definition of AL (posterior corneal surface to posterior globe boundary with orbital fat) rather than standard clinical optical biometry AL, but does not discuss implications for clinical interpretability or comparability across modalities/devices.

6. BMI and Sex-Difference Analyses Are Statistically Flawed. The BMI–volume analysis uses simple Huber regression without adjusting for age, height, or head size, all established confounders. No p-values for regression coefficients or power analyses are reported. Similarly, sex differences in volumetry (Table 3) are claimed without any formal statistical test, effect sizes, or adjustment for body size. These analyses would not pass basic statistical review.

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-->6. 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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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Attachments

Attachment

Submitted filename: PONE-D-25-59562.docx

-->PONE-D-25-59562R1-->-->A-eye: Automated 3D MRI Segmentation and Morphometric Feature Extraction for Eye and Orbit Atlas Construction-->-->PLOS One

Dear Dr. Barranco,

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 Jul 09 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.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Ziyu Qi, M.D., Ph.D.

Academic Editor

PLOS One

Journal Requirements:

1. 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.

2. 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.

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

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

**********

-->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

**********

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

Reviewer #1: 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

**********

-->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. 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: Check with language and grammer. For me I am happy with the response given by authors and I don't have much comment to state as I am satisfied with the authors response.

**********

-->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

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

A-eye: Automated 3D MRI Segmentation and Morphometric Feature Extraction for Eye and Orbit Atlas Construction

PONE-D-25-59562R2

Dear Dr. Barranco,

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,

Ziyu Qi, M.D., Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

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

**********

-->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

**********

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

Reviewer #1: 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

**********

-->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. 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: Authors should ensure that all information, data, and conclusions are accurately supported by the appropriate references. As reviewers, it is not practical to verify every statement with each cited reference. Therefore, the authors are requested to carefully review and confirm the accuracy of all citations and references throughout the manuscript before publication.

**********

-->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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