PONE-D-24-00537Uncertainty quantification and sensitivity analysis of neuron models with ion concentration dynamicsPLOS ONE

Dear Dr. Signorelli,

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 Mar 20 2024 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,

Alexey Kuznetsov

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse.

3. 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.

Additional Editor Comments:

First, reviewers have raised concerns on model calibration. Therefore, the choice of parameter values requires better justification.

Second, reviewers found multiple typos and convoluted spots. Therefore, the manuscript is required to be corrected and carefully proofread by a proficient English speaker.

Additionally, the manuscript would improve if the discussion was written for a more general audience.

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

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: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

**********

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

**********

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: This paper carried out uncertainty quantification analysis for a six-compartment neuron model incorporating ion concentration dynamics from a comprehensive viewpoint. The topic is interesting and important, and the English language is clear. I think the paper can be accepted after a minor revision.

The following two points should be improved.

I. I am wondering how the dynamical parameters and the non-dynamical parameters are taken in Table 1 and Table 2. The authors should add necessary demonstration or citation.

II. The authors should reexamine their whole context to eliminate the possibles errors. For example, in the abstract, the sentence "To mitigate computational cost, we employ surrogate modeling techniques, optimized using efficient numerical integration techniques." contains grammatical error due to "optimized using efficient numerical integration techniques". For another example, the sentence "Our sensitivity analysis not only sheds some light on the critical parameters influencing our model’s outputs, their interdependencies, and which ones demand precise estimation to mitigate uncertainty in the results" seems strange due to " and which.....", please see Line 638-640.

Reviewer #2: This paper investigates the effect of uncertain parameters on an electrodiffusive neuron-extracellular-gli (edNEG) neuron model through the use of uncertainty quantification (UQ) and sensitivity analysis (SA). The authors focus on the effect of uncertainties in a selected set of dynamic model parameters and examined the effects on the model under two different conditions, physiological and pathological. This paper discusses several common challenges for uncertainty quantification of neuron models with ion concentration dynamics and is a good showcase for how to approach these challenges within the field of neuroscience.

The main strength of the paper is the case study and discussion of the encountered challenges. This serves as a showcase for how common challenges related to UQ and SA of neuron models may be addressed, contributing to wider adoption of uncertainty quantification within neuroscience.

There are a few minor issues that preferably could be addressed to improve the article, but no major issues that fundamentally affect the work and conclusions.

The main issue that would strengthen the paper if it was improved is to generalize the discussions related to how the different challenges were solved, making it easier for others to apply them, as the authors mention they want the article to offer guidelines for others to follow.

One example is the section on “Numerical implementation and validation” of the edNEG model (line 165), which details how the edNEG model was optimized in order to perform UQ and SA. The specific optimizations needed are of course highly dependent on the specific model and could be the topic of multiple focused papers, however it would be useful to have more information why these specific changes were made and the thought process behind them, as that will help guide others. It would also be useful if the text could mention some general considerations that others can make. For example, why was the choice of a timestep of 10ms selected? What other timesteps did the authors consider to use and why were they discarded?

The same applies elsewhere, it would for example be useful to know why the selected quantities of interest were chosen for examination in the physiological and pathological cases (line 298-305). If the reader is provided with insight as to why these quantities of interest were the most relevant for this case study, it may be easier for them to make similar considerations for their own use case. There might also be other places where broader perspectives could enhance the article, perhaps for the Factor fixing section (line 231)?

Specific comments:

1. The first sentence of the abstract makes me interpret the paper to focus on inventing new computational or algorithmic approaches for more efficient UQ and SA. It would be beneficial with a rephrasing that shows the main strength of the paper, namely as a case study for how common challenges with UQ and SA in neuroscience can be approached and solved.

2. 53-54: “ To fully exploit the potential of surrogate modeling, it is essential to adopt efficient numerical integration techniques”. Would this not be even more essential if other methods than surrogate modeling were used, for example quasi-Monte Carlo methods?

3. 82-83: “Additionally, evaluating sensitivity indices for a time-dependent output (i.e., one for each time point) is computationally demanding,”. I am just curious, is this computationally demanding when compared to the computational cost of running the model evaluations?

4. 85-86: “we introduce a comprehensive and computationally efficient approach for conducting UQ and GSA on neuron models with ion concentration dynamic”. This sentence gives the same impression as in the abstract (1.). Perhaps rephrasing it would make the content of the paper more clear?

5. 99 - 100: “This efficiency demonstrates the feasibility of conducting sensitivity analysis on complex neuroscience models”. It would be beneficial to know the runtime for UQ and SA of the model with and without the performance improvements, since most readers likely do not know the performance of the unoptimized model and subsequently if the (rather impressive) speedup is necessary.

6. 178-179: The code is readable and freely available with instructions for how to run it, which is very good! My one suggestion would be to also archive the code on zenodo (https://zenodo.org/). That would give the code a DOI to cite and track it with and provide redundancy in case github repositories get deleted.

7. 248: Was there a reason an uncertainty of 15% was used in the factor fixing analysis, while for examining the dynamic parameters {0, 1, 5, 10} was used?

8. 258: “these variables were carefully selected”: It would be nice with a reference to where in the paper this ends up being expanded upon (see comment on main issue).

9. 261-266: “Implementation details”. To my understanding, this calculates the Sobol indices using quasi-Monte Carlo methods? Why are not surrogate models used, as that is mentioned earlier to be imperative for computational efficiency? It would also make the text more clear if the authors mention that the goal is to calculate the Sobol indices.

10. 319-320: “Outputs were generated by drawing a Monte Carlo sample of size 104 from the parameter distribution”. To my understanding, this sentence refers to how many samples were used for finding the 5th and 95th percentiles? (the nr_pc_mc_samplest argument?). If so, it might be more clear to say 5th and 95th percentiles instead of outputs, and I would put it after the next sentence “To enhance computational efficiency,” as that is the more important information in this context.

11. 323: “Rosenblatt transformation for dependent parameter”, the Rosenblatt transformation is not necessary unless there are dependencies in the input parameters, which seems to not be the case in the manuscript?

12. 350: It is a bit unclear to me how the total order Sobol indices for each group was found in the factor fixing analysis, is it the sum of the Sobol indices for all uncertain parameters in each group?

13. Fig 3, Fig 5, Fig 6, and Fig 8 could all benefit from having subtitles added to the subplots. The plots are readable, but that would make it easier and faster to interpret them.

**********

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: Yes: Simen Tennøe

**********

[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.]

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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Uncertainty quantification and sensitivity analysis of neuron models with ion concentration dynamics

PONE-D-24-00537R1

Dear Dr. Signorelli,

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. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Alexey Kuznetsov

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 #2: 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 #2: Yes

**********

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

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 #2: 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 #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 #2: All my comments have been addressed and I am happy to recommend the paper being accepted. The authors have done a solid job.

**********

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 #2: Yes: Simen Tennøe

**********