Dear Dr Ii,

Thank you very much for submitting your manuscript 'Hybrid modeling of whole-scale cerebrovasculature based on personalized morphometry and mathematical algorithm' for review by PLOS Computational Biology. Your manuscript has been fully evaluated by the PLOS Computational Biology editorial team and in this case also by independent peer reviewers. The reviewers appreciated the attention to an important problem, but raised some substantial concerns about the manuscript as it currently stands. While your manuscript cannot be accepted in its present form, we are willing to consider a revised version in which the issues raised by the reviewers have been adequately addressed. We cannot, of course, promise publication at that time.

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

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Sincerely,

Daniel A Beard

Deputy Editor

PLOS Computational Biology

Daniel Beard

Deputy Editor

PLOS Computational Biology

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: See attached file

Reviewer #2: The review is uploaded as an attachment.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

Reviewer #2: No: Either these data have not been made available or I haven't been able to find them.

It is stated that: "All relevant data are within the manuscript and its Supporting Information files."

These are only pdf files and contain no data, unless the data is simply considered irrelevant here.

This concerns both large-scale datasets such as imaging CT and MRI pre- or post-processed data or reconstructed volumes, and summary statistics.

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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.

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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

Attachments

Attachment

Submitted filename: PLoSCompBIoCerebralNetworksLi.pdf

Attachment

Submitted filename: Review.pdf

Dear Dr Ii,

Thank you very much for submitting your manuscript "Modeling of multiscale human cerebrovasculature: a hybrid approach using image-based geometry and mathematical algorithm" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Daniel A Beard

Deputy Editor

PLOS Computational Biology

Daniel Beard

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Authors have significantly improved the manuscript, the manuscript has a number of good components, but it still lacks a clear description of the study presented. As far as I see the main message in this manuscript is Figure 5 illustrating that it is possible to reconstruct the cerebrovascular network, in which the large vessels are informed by imaging data while the smaller vessels are generated using approximation techniques.

I think this paper should be presented as a method paper discussing how best to approximate the small vessels not captured by the imaging data.

To convey this story I suggest to include the following changes:

Abstract: Remove the first paragraph - start by noting that cerebral vasculature is complex and with standard imaging techniques it is difficult to segment all vessels in the network, and that this study proposes a method to obtain these networks by explicitly segmenting the large vessels combined with approximation techniques for small vessels. The next few sentences should address how the method proposed here is validated, and what are its limitations.

Introduction: Relate the method proposed here to other segmentation studies extracting networks from imaging data. Motivate what you intent to do with the segmented network - compute flow, couple it with a model for cerebral autoregulation, etc etc. But this would be future work as it is not included in the current study.

Methods: I do not like the word "modeling" as this is really "network reconstruction". I suggest to take out the word modeling instead generating a title e.g. "Network Generation". Moreover, I suggest removing the first paragraph page 4 lines (88-102)

Close to figure 2 - add more details describing how the image was segmented and the network generated for the large vessels. Include a description of how the vessels in the network are extracted from the image and connected. Also describe what quantities are stored , e.g. vessel length, vessel diameter?

Page 4:Rename the section on "preparation for mathematical modeling" the title does not describe what is "modelleld"

I think the authors are describing that the next step needed to generate a network is to extract the volume (space) in which the network lies. Therefore, use a title e.g. Extracting Brain Volume (or volume enclosed by the network).

Page 5: Delete section "Inputs to mathematical modeling"

Page 5: Change title "Mathematical model for mesocale vasculature" to "Construction of mesocale part of the network" or something like that.

Page 5: Here you discuss "potential features" focus on addressing features included in this study, e.g. you do not show any flow computations so remove lines 167-168

Page 5: Title "Definition of vascular pathways and structures" change this to generation of vascular pathways and structures.

Page 7: Authors discuss how the vessel radii are evaluated by studying flow in the network, but no simulations are provided showing the flow. Either take the flow discussion out or show flow calculations.

Page 10: Should the title of this section be "Network Validation" or something along these lines. For each evaluation type compare predicted network to data. Currently this section reads as you are calculating several metrics, but I don't see how they are related to data.

Page 11: Separate the results (showing the generated networks and how they compare to data) and discussion addressing how the technique presented here compare with other studies.

See e.g. the study by Meijs et al. Scientific Reports 2017 DOI:10.1038/s41598-017-15617-w

or

Reviewer #2: I would like to thank the authors, who made a substantial effort to improve their paper and to respond to the reviewers' comments.

Indeed, most of the revisions and significant issues raised appear to have been reasonably addressed.

However, I encourage the authors to carefully review the manuscript again, as I have identified a number of minor errors (typographical, spelling or grammatical) that would require attention, especially in the added paragraphs.

Also, even though it may seem like a detail, I would like to point out one formulation issue that caught my attention, as it appears several times in the manuscript, including in the title: "multiscale model(ing) of human cerebrovasculature" would be more correct than "model(ing) of multiscale human cerebrovasculature", in my opinion.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

Reviewer #2: Yes

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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

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions, please see http://journals.plos.org/compbiol/s/submission-guidelines#loc-materials-and-methods

Dear Dr Ii,

We are pleased to inform you that your manuscript 'Multiscale modeling of human cerebrovasculature: a hybrid approach using image-based geometry and a mathematical algorithm' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Daniel A Beard

Deputy Editor

PLOS Computational Biology

Daniel Beard

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: No further comments

**********

Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

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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