PCOMPBIOL-D-25-02375

Assessing the Importance of Sex and Disease-Specific Anatomy in Electrophysiology and Mechanical Simulations with a Newly Developed Public Virtual Cohort of Four-Chamber Heart Models

PLOS Computational Biology

Dear Dr. Solis-Lemus,

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Daniela Valdez-Jasso, Ph.D.

Academic Editor

PLOS Computational Biology

Dimitrios Vavylonis

Section Editor

PLOS Computational Biology

Additional Editor Comments:

The reviewers acknowledged the relevance of the study and expressed interest in the manuscript; however, reviewers raised concerns regarding the lack of validation and aspects of the statistical analysis, which should be addressed in a revised version.

Journal Requirements:

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.

1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: Jose Alonso Solis-Lemus, Cristoph Augustin, Rosie K. Barrows, Cesare Corrado, Nishant Lahoti, Natalie Montarello, Steven A. Niederer, Pras Pathmanathan, Gernot Plank, Abdul Qayyum, Shahrohk Rahmani, Ronak Rajani, Cristobal Rodero, Caroline Roney, Marina Strocchi, Hao Xu, and Alistair Young. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: Please see the attached comments.

Reviewer #2: review is also attached.

The paper presents a cohort of patient-specific virtual models of human hearts suitable for numerical simulations. Starting from medical images, the geometry of the heart is reconstructed via a multi-step process, in which the data are segmented and labeled, and successively, the mesh is created by interfacing with a third-party software (CGAL). The produced dataset is balanced in terms of sex and includes patients with heart disease.

A few clarifications can improve the quality of the manuscript:

1) Are the reconstructed meshes referred to the same timepoint of the cardiac cycle? What is the internal pressure at that instant? Otherwise, how are the models aligned to perform and compare the simulations?

2) Which type of finite elements are supported by the mesh-generator?

3) Have the authors checked the quality of the generated meshes, for instance, by computing the determinant of the Jacobian of the geometrical map? (or the element distortion)

4) Have the authors assessed the quality of the reconstructed geometry compared to the clinical images?

5) Do the users have the possibility of controlling and adapting the mesh by varying the density in specific (user-defined) regions?

Several references are not correctly formatted with respect to the page size; I guess this will be solved during the production stage.

Reviewer #3: The manuscript by Solis-Lemus, Barrows, and co-workers outlines a methodology to generate and anatomical models of patient-specific hearts to assess sex-based differences in healthy and failing hearts. The paper presents results that there are sex-related differences in the mechical and electrophysiological responses to simulation that arises from the anatomical differences alone. This work contributes to the current need in personalized medicine for cardiovascular diseases. However, there are significant issues with the manuscript that need to be addressed prior to publication:

Major Issues

1) The last two paragraph of the introduction section are too long. I would say the very last paragraph is not needed. The second to last paragraph has too much methodology for an intro. For example, sample size numbers don't really belong here. Also, these two paragraphs jump tenses too much.

2) The main issue with the paper is lack of proper validation. There is comparison of lung volumes and ephys between groups, but there is no validation back to patient data. While in the future, the idea of in silico clinical trials is very important, this paper seems to exhibit most of the weaknesses that are the barrier to entry of this technology.

3) There should be a way to get at an estimate for the QRS duration without having to model the full torso. This is really needed to allow the work to be validated against physiological data.

4) Fig 5 is not informative. All I can see are columns of images that to my eye look completely identical. If the reader is supposed to see differences they need to be properly blown up and pointed out. Alternatively, move this to the supplemental if it is not essential.

5) Looking at the data in Fig 6, this does not look like a proper validation. There are plenty of blue (control) dots outside the gray band. And plenty or red dots inside the gray band. If this is to be taken as validation it is very qualitative. Maybe providing distributions from MRI studies?

6) Section 5.3 - given the point above, this was not a convincing argument.

7) Line 233 states that the UK Biobank defines the reference ventricle volumes. It is unclear whether this

definition that was based on only Caucasians is an appropriate standard for the patient demographics in

this study. The paper provided by the link is only Caucasians which seems to be problematic given the stated scope of this paper.

Minor Issues

- In figure 7b, it is quite difficult to distinguish which line of comparison corresponds to which parameter.

- Lines 350-352, is this referencing figure 7a? It is unclear whether "HF females showed the greatest

relative differences" is in comparison to HF males or to control females.

- The acronym CM&S is not necessary and makes it harder to read the paper. Just use the words.

- citation numbers are used as nouns, which makes reading the paper awkward. This would work if the citation style included author names, but reading "[13] did this" is very strange.

- line 261 HF has strange spacing

While the paper addresses an important aspect of furthering the techniques to create in silico clinical trials, there are major issues with validation that follows the same pattern as the barriers in this field.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Attachments

Attachment

Submitted filename: renamed_98ef9.docx

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Submitted filename: PCOMPBIOL-D-25-02375_rev.pdf

Dear Dr Solis-Lemus,

We are pleased to inform you that your manuscript 'Assessing the Importance of Sex and Disease-Specific Anatomy in Electrophysiology and Mechanical Simulations with a Newly Developed Public Virtual Cohort of Four-Chamber Heart Models' 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. In addition, please consider following the recommendation of Reviewer 3, who has suggested moving Figure 5 to Supplemental Data.

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,

Daniela Valdez-Jasso, Ph.D.

Academic Editor

PLOS Computational Biology

Dimitrios Vavylonis

Section 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 #2: nothing to add

Reviewer #3: I still feel that there is no need for Fig. 5 in the main body of the paper, but otherwise the authors have addressed all of my concerns.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: None

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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 #2: No

Reviewer #3: No