-->PCOMPBIOL-D-25-02107

Transportation flows and outbreak origins in epidemic spread: Insights from agent-based modeling

PLOS Computational Biology

Dear Dr. Klochkov,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology'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 Mar 07 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 ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter

We look forward to receiving your revised manuscript.

Kind regards,

Shi Zhao

Academic Editor

PLOS Computational Biology

Denise Kühnert

Section Editor

PLOS Computational Biology

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: Konstantin A. Klochkov, Elena N. Ilina, Ivan E. Kozlov, and Alexander I. Manolov. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

The list of CRediT author contributions may be found here: https://journals.plos.org/ploscompbiol/s/authorship#loc-author-contributions

2) Please upload all main figures as separate Figure files in .tif or .eps format. For more information about how to convert and format your figure files please see our guidelines:

https://journals.plos.org/ploscompbiol/s/figures

3) Some material included in your submission may be copyrighted. According to PLOSu2019s copyright policy, authors who use figures or other material (e.g., graphics, clipart, maps) from another author or copyright holder must demonstrate or obtain permission to publish this material under the Creative Commons Attribution 4.0 International (CC BY 4.0) License used by PLOS journals. Please closely review the details of PLOSu2019s copyright requirements here: PLOS Licenses and Copyright. If you need to request permissions from a copyright holder, you may use PLOS's Copyright Content Permission form.

Please respond directly to this email and provide any known details concerning your material's license terms and permissions required for reuse, even if you have not yet obtained copyright permissions or are unsure of your material's copyright compatibility. Once you have responded and addressed all other outstanding technical requirements, you may resubmit your manuscript within Editorial Manager.

Potential Copyright Issues:

i) Figures 1A, 2A, 2B, and 3A. Please confirm whether you drew the images / clip-art within the figure panels by hand. If you did not draw the images, please provide (a) a link to the source of the images or icons and their license / terms of use; or (b) written permission from the copyright holder to publish the images or icons under our CC BY 4.0 license. Alternatively, you may replace the images with open source alternatives. See these open source resources you may use to replace images / clip-art:

- https://commons.wikimedia.org

- https://openclipart.org/.

4) Please amend your detailed Financial Disclosure statement. This is published with the article. It must therefore be completed in full sentences and contain the exact wording you wish to be published.

1) State the initials, alongside each funding source, of each author to receive each grant. For example: "This work was supported by the National Institutes of Health (####### to AM; ###### to CJ) and the National Science Foundation (###### to AM)."

2) State what role the funders took in the study. If the funders had no role in your study, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

3) If any authors received a salary from any of your funders, please state which authors and which funders..

If you did not receive any funding for this study, please simply state: u201cThe authors received no specific funding for this work.u201d

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: It is meaningful to investigate how mobility influence disease spreading and ABM is appropriate. However, the rules of transmission dynamics in this study is not clear enough.

The reviewer has some questions and suggestions as follows:

1. I think mobility and transportation flow are in different scopes. Please check the difference between these terms. The definition of inbound and outbound flows are not clear as well. It is suggested to rename your title.

Introduction:

2. The existing structure has listed relevant evidence of different epidemics and shown the connection between mobility and disease spreading. However, this part is too redundant. How about different methodologies that help investigate how mobility influence disease spreading? Overall, please state the research gap of developing an agent-based transCovasim model in this study.

Methods:

3. Please state your transCovasim model by introducing three components 1) agent; 2) environment; 3) interaction rules, which is widely used in the filed of ABM. Please add a technical framework of ABM.

4. the rule of transmission dynamics of deases should be better explained in the transCovasim model. Have you considered the heterougeneity brought by mobility through different transportation modes? If no, why you select ABM as your method.

Design of the experiments:

5. This study has three scenarios: 1) two-city transport model with equal/unequal agent counts; 2) hub-and-satellite transport model and 3) detecting the outbreak’s origin in the hub-satellite model. Please state the reason why you designed these experiments.

Results:

6. how about the validation of your model?

7. how did you design restriction strategies?

Reviewer #2: This paper presents and analyses transCovasim, an extension of the Covasim agent-based model of COVID-19. Whereas Covasim models a single population, this extension enables the authors to study mixing between two identical populations, unequal populations, and a hub-and-spoke configuration. Results show how population sizes and migration flows affect disease burden, and indicate how interventions could mitigate/delay the peak and total burden.

Overall, the manuscript is clear and well written. The results are a bit dense and detailed, and some readers may get lost in the details of origin and neighbor nodes. The figures support the main results presented by the authors.

I have a few technical questions for author consideration:

--> Dynamic rescaling. Covasim has a `rescale` parameter that is set to True by default. This parameter configures dynamic rescaling. In Covasim, there is only one population, and all agents have the same scaling factor. With dynamic rescaling, the effective scale of agents increases over time. Conceptually, this process represents "zooming out" from an initial small seed area to the full population being simulated.

The implementation here is quite clever. While Covasim runs a single process, the authors have extended the MultiSim capabilities using multiprocessing "barrier" and "lock" to synchronize. However, with this modification, there are multiple instances of the simulation running in lockstep, but each instance may have a different population scaling factor. An agent migrating from one city to the next may have a different scale factor.

The scale factor increases following seeding, but quickly stabilizes at a maximum value -- so it might be a non-issue. Please check, and consider rerunning the simulation experiments with rescaling disabled.

--> I wonder about population sizes. Each node starts with a specified population size, but the number of agents in each city will change dynamically as migration unfolds (unless balanced?).

• If not balanced, consider adding a supplementary figure showing how the population in each city changes throughout the course of a simulation.

• Worth checking that the upper limit of population is not reached.

• Additionally, it might be worth letting between-city mobility (population sizes) reach steady state before seeding infection.

• Finally, ensure that key statistics like incidence and prevalence are calculated correctly with dynamic city sizes.

--> The mixing structure within each city is in fact quite detailed in these simulations. I did not realize this until looking at the source code. The populations are built using the SynthPops package configured for Seattle (for which rich microdata are available). It might be worth a sentence or two in the methods section describing that agents have static home/school/work/community connections that are not affected by between-city migration.

--> The approach to moving agents between cities, each running in a separate simulation, is already quite novel! I might suggest that the authors describe that agents are physically moved, not the a rewiring of the network. This pattern could be reused by others, so highlighting code availability and key changes from Covasim would be welcome.

--> In the hub-and-spoke source identification, are symmetries holding back results. Because all satellite communities are equal in size and connectivity to Moscow, it would seem challenging to identify the source. Would the source be more identifiable if node sizes and/or connection weights were heterogeneous?

Overall, I find this work interesting and potentially useful if oriented towards a "next pandemic" or disease X. The conclusions support interventions affecting population mobility. In practice, my understanding is that mobility restrictions have demonstrated mixed impact. The literature review focuses attention to the early outbreak in China and other simulation papers, but a few more examples here to illustrate where such interventions have worked/failed may help readers connect this work to practical policy.

**********

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 #1: Yes

Reviewer #2: Yes

**********

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 resubmission:

While revising your submission, we strongly recommend that you use PLOS’s NAAS tool (https://ngplosjournals.pagemajik.ai/artanalysis) to test your figure files. NAAS can convert your figure files to the TIFF file type and meet basic requirements (such as print size, resolution), or provide you with a report on issues that do not meet our requirements and that NAAS cannot fix.-->

After uploading your figures to PLOS’s NAAS tool - https://ngplosjournals.pagemajik.ai/artanalysis, NAAS will process the files provided and display the results in the "Uploaded Files" section of the page as the processing is complete. If the uploaded figures meet our requirements (or NAAS is able to fix the files to meet our requirements), the figure will be marked as "fixed" above. If NAAS is unable to fix the files, a red "failed" label will appear above. When NAAS has confirmed that the figure files meet our requirements, please download the file via the download option, and include these NAAS processed figure files when submitting your revised manuscript.

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

PCOMPBIOL-D-25-02107R1

Human mobility and outbreak origins in epidemic spread: Insights from agent-based modeling

PLOS Computational Biology

Dear Dr. Klochkov,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology'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 Jun 15 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 ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Shi Zhao

Academic Editor

PLOS Computational Biology

Denise Kühnert

Section Editor

PLOS Computational Biology

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 amend your detailed Financial Disclosure statement. This is published with the article. It must therefore be completed in full sentences and contain the exact wording you wish to be published.

1) State the initials, alongside each funding source, of each author to receive each grant. For example: "This work was supported by the National Institutes of Health (####### to AM; ###### to CJ) and the National Science Foundation (###### to AM).".

If you did not receive any funding for this study, please simply state: u201cThe authors received no specific funding for this work.u201d

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: The authors have addressed most of my concerns in this revision.

However, I am still worried about model heterogeneity.

Line 301-310：Several limitations mentioned here are all related to model heterogeneity, but they are described less specific. Could you please elaborate on the heterogeneity issues brought by different situations that you mentioned here, and add future research directions or plans to better list appropriate solutions?

**********

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 #1: Yes

**********

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

Figure resubmission:

-->While revising your submission, we strongly recommend that you use PLOS’s NAAS tool (https://ngplosjournals.pagemajik.ai/artanalysis) to test your figure files. NAAS can convert your figure files to the TIFF file type and meet basic requirements (such as print size, resolution), or provide you with a report on issues that do not meet our requirements and that NAAS cannot fix.-->

After uploading your figures to PLOS’s NAAS tool - https://ngplosjournals.pagemajik.ai/artanalysis, NAAS will process the files provided and display the results in the "Uploaded Files" section of the page as the processing is complete. If the uploaded figures meet our requirements (or NAAS is able to fix the files to meet our requirements), the figure will be marked as "fixed" above. If NAAS is unable to fix the files, a red "failed" label will appear above. When NAAS has confirmed that the figure files meet our requirements, please download the file via the download option, and include these NAAS processed figure files when submitting your revised manuscript.

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Mr. Klochkov,

We are pleased to inform you that your manuscript 'Human mobility and outbreak origins in epidemic spread: Insights from agent-based modeling' 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,

Shi Zhao

Academic Editor

PLOS Computational Biology

Denise Kühnert

Section Editor

PLOS Computational Biology

***********************************************************