[Vp-integration-subgroup] [Vp-reproduce-subgroup] Paper review and revision check list

Thu Jan 13 18:50:29 PST 2022

Sorry, I was not clear enough: no response is required for Reviewer 2, as they have endorsed the manuscript. A response to Reviewer 1 is overdue, however; see the email below.

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________________________________
From: Jacob Barhak <jacob.barhak at gmail.com>
Sent: Thursday, January 13, 2022 8:14 PM
To: Torres, Marcella <mtorres at richmond.edu>
Cc: Rahuman Sheriff <sheriff at ebi.ac.uk>; vp-reproduce-subgroup at lists.simtk.org <vp-reproduce-subgroup at lists.simtk.org>; vp-integration-subgroup at lists.simtk.org <vp-integration-subgroup at lists.simtk.org>; John Gennari <gennari at uw.edu>; Faeder, James R <faeder at pitt.edu>
Subject: Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list

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Thanks Marcella, Thanks Gilberto,

Since the second reviewer did not respond, I think we have more time - we did respond in time however.

The figures were provided by Alex and Sheriff - they seem pretty good resolution to me, yet if we want increased resolution, they will have to generate those again from the same software that generated thm originally - Basically the images have to be at least 300 dpi and export it as pdf and extract it as tiff or eps - not jpg.

Section 2.2.2 in the instruction provides information about the image quality:
https://www.frontiersin.org/about/author-guidelines

Hopefully we can have those ready.

However, I do ask that all authors be ready to approve the paper assuming the other reviewer will be positive - we worked on thai for a year and there were many discussions - before this paper gets published I want all authors to be good with the final outcome. We will do this formally like we did before - yet I want everyone to be ready to avoid any delays. Hopefully it will take us less than 3 weeks this time.

                Jacob

On Thu, Jan 13, 2022 at 1:05 PM Torres, Marcella <mtorres at richmond.edu<mailto:mtorres at richmond.edu>> wrote:
Hi again all,

On the 7th I shared comments from Reviewer 1 that we are now late responding to. Is it possible to provide high resolution figures, or no (see below)?

Reviewer 2 has endorsed the manuscript.

[cid:17e561adf9ecb971f161]
Reviewer 1 comment:
 Reviewer 1 | 07 Jan 2022 | 14:36
#3

I would like to thank the authors for having fully addressed my comments. I'm satisfied about the quality the manuscript has been reached in this latest version. Finally, I would only suggest the authors to provide an high quality resolution of both new figures. Thank you.

Marcella Torres, Ph.D.
Director of Mathematical Studies
University of Richmond
Jepson Hall Room 212
221 Richmond Way
Richmond, VA 23173
(804) 289-8081
Pronouns:  she/her

________________________________
From: Vp-reproduce-subgroup <vp-reproduce-subgroup-bounces at lists.simtk.org<mailto:vp-reproduce-subgroup-bounces at lists.simtk.org>> on behalf of Rahuman Sheriff <sheriff at ebi.ac.uk<mailto:sheriff at ebi.ac.uk>>
Sent: Monday, January 10, 2022 3:09 PM
To: Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>>
Cc: vp-reproduce-subgroup at lists.simtk.org<mailto:vp-reproduce-subgroup at lists.simtk.org> <vp-reproduce-subgroup at lists.simtk.org<mailto:vp-reproduce-subgroup at lists.simtk.org>>; vp-integration-subgroup at lists.simtk.org<mailto:vp-integration-subgroup at lists.simtk.org> <vp-integration-subgroup at lists.simtk.org<mailto:vp-integration-subgroup at lists.simtk.org>>; John Gennari <gennari at uw.edu<mailto:gennari at uw.edu>>; Faeder, James R <faeder at pitt.edu<mailto:faeder at pitt.edu>>
Subject: Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list

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Thanks Jakob for submitting the revision and others for the support. Thanks William for editing my response.

Best
Sheriff

On 7 Jan 2022, at 04:52, Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>> wrote:

Thanks Hana, Thanks William, and thanks to Gilberto, Alex, and Sheriff,

With your help and some effort, the revised paper was resubmitted in time - just now.

William, please keep on reminding me about your second affiliation - I kept a comment as a reminder to do this - the submission system did not allow making any changes in Author information - not sure why - if this gets accepted we should ask the editor to add your affiliation manually.

I urge all other authors to look at the changes we made and our response. We will have to approve the manuscript with everyone before it gets published - hopefully we will convince the reviewers this review round.

                    Jacob

On Thu, Jan 6, 2022 at 3:51 PM Dobrovolny, Hana <h.dobrovolny at tcu.edu<mailto:h.dobrovolny at tcu.edu>> wrote:

I've read through the paper and fixed a few grammar mistakes.

Hana

*******************************************************
Dr. Hana Dobrovolny
Associate Professor of Biophysics
Texas Christian University
TCU Box 298840
Fort Worth, TX 76129

phone: (817) 257-6379 fax: (817) 257-7742
email: h.dobrovolny at tcu.edu<mailto:h.dobrovolny at tcu.edu>
*******************************************************

________________________________
From: Vp-integration-subgroup <vp-integration-subgroup-bounces at lists.simtk.org<mailto:vp-integration-subgroup-bounces at lists.simtk.org>> on behalf of Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>>
Sent: January 5, 2022 11:48 PM
To: William Waites; James Glazier
Cc: vp-reproduce-subgroup at lists.simtk.org<mailto:vp-reproduce-subgroup at lists.simtk.org>; vp-integration-subgroup at lists.simtk.org<mailto:vp-integration-subgroup at lists.simtk.org>; John Gennari; Faeder, James R
Subject: Re: [Vp-integration-subgroup] [Vp-reproduce-subgroup] Paper review and revision check list

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Greetings paper contributors,

Gilberto has addressed the final point and added text in the paper and review, thus concluding our response.

I went over the paper from start to finish again and cleaned it up.

There are two last comments in the paper addressed to William Waites and James Glazier - if you can quickly check those, it would help.

If someone else wants to read the paper once more, please do this today - otherwise I will convert the paper and our response to reviewers and submit it to the Journal portal.

If anyone has any objections, now is the time to raise them so we can withdraw rather than submit.

Here is the link to the revised paper:
https://docs.google.com/document/d/1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM/edit?usp=sharing<https://urldefense.com/v3/__https://docs.google.com/document/d/1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM/edit?usp=sharing__;!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0hvK3OmJ8$>

Here is the link to response for reviewers:
https://docs.google.com/document/d/1bO1CDbMMlyyweYayP9rGohPIfgvIhfe14sFchtJMJ-s/edit?usp=sharing<https://urldefense.com/v3/__https://docs.google.com/document/d/1bO1CDbMMlyyweYayP9rGohPIfgvIhfe14sFchtJMJ-s/edit?usp=sharing__;!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0haRkeB0o$>

Hopefully there will be no objections and can submit this tomorrow.

              Jacob

On Tue, Jan 4, 2022 at 11:30 PM Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>> wrote:
Hi Alex, Hi William, Hi Gilberto, and all other contributors.

Alex, William and Gilberto are mentioned since we are the most active contributors.

We have 2 days to finish edits.

William - I attempted to add your suggestions to the paper regarding issue 11. You are free to revise further.

Gilberto - I merged some of your texts, yet it seems you are the only one I saw interested in resolving issue 12 where the reviewer asks to remove the "Model Application and Implementation Barriers" section. Please suggest your corrections as soon as possible. If you cannot do this by tomorrow I will do my best to add a response based on your idea. Yet I really hope you can do this before me.

Please finalize any edits you have - and if anyone has any objection to the text, please raise it within one day since after tomorrow I will start closing down all issues.

I would ask for a  volunteer that will go over the paper once more after its finalized and check for typos and grammar - we do not want the paper to return again due to this issue. Time is tight, so please volunteer fast.

Hopefully we can get it done in time.

                Jacob

On Tue, Jan 4, 2022 at 7:25 AM Alexander Kulesza <alexander.kulesza at novadiscovery.com<mailto:alexander.kulesza at novadiscovery.com>> wrote:
Dear Jacob, dear all,
thanks for endorsing my figure. I'll gladly add this. Please find enclosed the .png.

What you say makes sense and I agree that exaggerating changes is not speeding up approval. Please still consider it as a tool to perform "major" change (ordering of sections is a major change of a paper in my opinion) without changing too much the sections as such. But I agree that this could be tried out should the reviewers insist.

I therefore reverted the table change (disconnecting ist from Figure 1) and suggest the following Figure caption:

"Figure 2: Sketch of difficulties persistent that impede reproducibility, credibility, utility and integration of models, especially in computational biology. An assignment of these difficulties to the four different concepts interpreting them as hurdles is attempted. We would like to point out that this sequential assessment model indicated in the graph is only one of the possibilities a modeler would assess the suitability of available models. In the rest of the paper we therefore address each difficulty separately. "

With that sentence we can discuss the difficulties in any order.

Best
Alexander

On Tue, 4 Jan 2022 at 13:24, Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>> wrote:
Yes Alex,

Your image is much better than mine, please use it instead in the paper and send a link to the image itself in an acceptable image format so I can upload it to the submission system later on.

As for changing the table and order, I am not sure. Although it may be possible. We need to think about it. Yet we really are crunched in time, so I am leaning to say no.

First, because some of the difficulties span more than one category, for example unit standardization affects integration as well as reproducibility, only it appears first at reproducibility, therefore it was placed there in the figure.

Second, if you look at the text there are some transition sentences among sections, that connect them, so swapping those around may just mess things. I am not sure it if will also mess up acronym definitions on the first appearance as well, so shuffling order is not something's I would do unless necessary. And it was not requested by reviewers anyway.

I am also trying to minimize changes and focus only on what was requested rather than change a lot more. Otherwise we may never finish changing things since each one of the 18 of us will have a one last item they MUST have corrected. I personally did not add some recent publications I had, although I added one publication James asked to add in the previous approval round and corrected one that Sheriff mentioned. Yet I really want to avoid opening the paper to significant changes.

 If you start opening corrections beyond what was requested, this will drag on forever since we do have a large list of contributors and each one of us will generate a new idea. So please focus on what was asked unless absolutely necessary.

So I suggest not changing the table, and changing only the figure and keeping order intact. I hope I am projecting the sense of urgency - we had the paper lying around for a couple of weeks during the holiday without much progress, I ask not to escalate things just because a deadline is looming.

If you have extra time on your hands in the next couple of days, I suggest you focus on addressing the last two points in the response that we have not resolved yet. I know Gilberto wanted to fix one of them, yet you are welcome to do it. Those are things requested by the review

Hopefully my arguments make sense.

         Jacob

On Tue, Jan 4, 2022, 06:45 Alexander Kulesza <alexander.kulesza at novadiscovery.com<mailto:alexander.kulesza at novadiscovery.com>> wrote:
Dear all,

I have thought about the additional Figure requested by the reviewer. Jacob your Figure nicely shows the assignment of the difficulties we detail in our central table with the 4 big concepts.

I feel however that the text-heavy figure is a lot o redundancy with the rest of the elements (existing figure & table). Therefore I wanted to throw another suggestion forward (inspired by systematic reviews narrowing down eligible studies/data).

@all please notice that the assignment I would do is a bit different to what is currently done in the paper. The order of sections would have to be altered. Not sure if that is acceptable.
<image.png>
The table with Difficulties (hurdles) and solutions would then be

Difficulty
Potential Solutions

Reproducibility
Models are written in different languages
Common transport specifications such as SBML or CellML, and proper documentation and annotation
Models are hard to locate
Archive web sites such as: BioModels, SimTK, IMAGWiki, and the future modeleXchange
Lack of common platforms for executing models and simulations
Platforms such as BioSimulators, and runBioSimulations
Unit standardization
Standardization efforts, and machine learning solutions such as ClinicalUnitMapping.com<http://ClinicalUnitMapping.com>
Credibility
Models have built-in barriers to Evaluating model credibility
Better modeling practices, documentation, and tests.
Data availability and measurement definitions
Models that merge human interpretation, and newer measurement devices

Missing annotations in models
Adoption of policies such as those COMBINE suggests
Utility
Models are not consistently licensed to allow for reuse
Abandoning some old school open source licenses and promoting licenses that release to public domain
Different scales and modeling paradigms
Standardization effort and centralization tools
Stochastic modeling difficulties
Development of tools that guarantee repeatability and standards to address stochastic simulations
Integration
Model application and implementation barriers
Education of modelers, users, and the public
Modeling requires adaptation towards integration
Tools for composing models such as SBML-Comp, and SemGen

Following this assignment.

Please let me know what you think. I have added this suggestion in track changes mode to the revision draft.

Best
Alexander

On Mon, 3 Jan 2022 at 07:27, Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>> wrote:
Thanks Alex,

You did great by adding the new material that the reviewers actually asked for. This is great - I found myself adding the new FDA document to find out that you already added it - I just voice read it ona  long drive and figured it fits well - it seems you were faster - great.

I merged your edits and I am ok with adding your response to the reviewers - I only had an issue with one example paragraph that you deleted - I left it with a comment - please check if it is possible to keep this example somewhere in the text.

I will assemble a letter that includes all those responses point by point and will try to use your text almost verbatim if possible. You really bring important knowledge with you.

It seems most points have been answered to some level - even a figure was created - although I wish I was a better artist.

I will try to assemble the response letter for everyone within the next few days. And unless there will be objections I will try to pass it by reviewers with a new version. If the new version is accepted, we will do a final approval round before publication.

Many thanks to all those who contributed.

              Jacob

On Sun, Jan 2, 2022 at 7:27 AM Alexander Kulesza <alexander.kulesza at novadiscovery.com<mailto:alexander.kulesza at novadiscovery.com>> wrote:
Dear all,

Happy new year to everyone. I hope that you are all well and safe and have spent a nice holiday season.

I have tried to address

Reviewer 2
Moreover, when the authors mention ASME V&V40 procedure, it could be useful to spend few words about the model credibility pipeline drawn for predictive models in biomedicine, such as the one suggested in "Credibility of in Silico Trial Technologies-A Theoretical Framing", Viceconti, M., Juarez, M.A., Curreli, C., ...Russo, G., Pappalardo, F., IEEE Journal of Biomedical and Health Informatics, 2020, 24(1), pp. 4–13, 8884189.
For this specific aspect, the authors should talk about "specific question of interest" and not "specific purpose" in the paragraph called "Credibility of Models" to follow in such a way a standardised language.

I have worked on the followng document in "track changes" mode:
https://docs.google.com/document/d/1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM/edit<https://urldefense.com/v3/__https://docs.google.com/document/d/1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM/edit__;!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0hrtFQ-XI$>
Actually, I ended up in changing rather drastically the section. I think that all ideas and all text is conserved, but I would very much like to encourage you to read, comment and challenge this revision. Please tell me if that goes to far. No problem to revert to an earlier version if necessary.

I suggest the following formulation in the rebuttal letter:

When trying to better describe the "credibility pipeline" (CoU definition, verification, validation, uncertainty quantification, e.g. as described in Viceconti et al. 2019) or others, we noticed that the section about credibility could be restructured in order to put the reader (not necessarily familiar with regulatory assessment of models) in the position to follow the argumentation.

We now roughly follow the following flow of writing:

 - Every model needs a purpose and credibility is tied to that purpose as well as repeatability and reproducibility
-  Credibility is essential for models that have impact on regulated areas or people's lives which is why regulatory authorities issue guidance
-  The probably most advanced guidance ASME V&V40 suggests a risk-based approach and pipeline to establish credibility of a model. It is overarching and widely applicable
- Regulators and modelers work together (for example in frame of the model informed drug development program MIDD) in order to better understand, better apply and better uptake different kinds of models in regulatory applications
- More work is needed to harmonize, stay up to date and to be more inclusive

We hope that with the rather extensive change of the wording and additional passages as well as citations (see below) we could address the concern of reviewer 2 (and the general remarks of reviewer 1).

" In 2018 the American Society of Mechanical Engineers (ASME) issued an important guidance ASME V&V 40 (ASME, 2018) of how to assess credibility of computational models of medical devices through verification and validation (V&V). The guideline is centered around the definition of the context of use (CoU) of the model which is formulated based on the questions of interest the model will answer. The CoU is then analyzed in terms of the “model risk” - being the influence the model exerts on a decision and the potential consequences these decisions might incur. Commensurate with this model risk the modeler suggests establish the credibility goals, perform verification validation and uncertainty quantification actions and then assess the outcome of this exercise in order to allow judging the acceptability of the model CoU. Key to this guidance is its overarching nature which also allows adoption in other (e.g. drug development) fields irrespective of the model type (Kuemmel  2020, Viceconti 2019)."

We also feel that it is essential to underline the cross-discipline viewpoint of the ASME V&V40 which is further elaborated by the cited paper by formalizing the verification, validation and uncertainty quantification VVUQ pipeline across model types.

We therefore have added the following statement
" In the paper by (Viceconti 2019) the verification, validation and uncertainty quantification (VVUQ) pipeline is streamlined to different types of models. It is, perhaps, the closest to score credibility across model types from mechanistic physics driven models to machine learning models. However, it is still short of including very recent developments such as ensemble models, although it touches upon the topic."

We additionally strengthened our argumentation by citing additional literature

Bai, JPF, Earp, JC, Florian, J, et al. Quantitative systems pharmacology: Landscape analysis of regulatory submissions to the US Food and Drug Administration. CPT Pharmacometrics Syst Pharmacol. 2021; 10: 1479– 1484. doi.org<http://doi.org>:10.1002/psp4.12709

FDA (2021b). Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions. FDA
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-credibility-computational-modeling-and-simulation-medical-device-submissions<https://urldefense.com/v3/__https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-credibility-computational-modeling-and-simulation-medical-device-submissions__;!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0harP7IHc$> [Accessed January 2, 2022]

Galluppi, G.R., Brar, S., Caro, L., Chen, Y., Frey, N., Grimm, H.P., Rudd, D.J., Li, C.-C., Magee, M., Mukherjee, A., Nagao, L., Purohit, V.S., Roy, A., Salem, A.H., Sinha, V., Suleiman, A.A., Taskar, K.S., Upreti, V.V., Weber, B. and Cook, J. (2021), Industrial Perspective on the Benefits Realized >From the FDA’s Model-Informed Drug Development Paired Meeting Pilot Program. Clin Pharmacol Ther, 110: 1172-1175. doi:10.1002/cpt.2265

Kuemmel, C., Yang, Y., Zhang, X., Florian, J., Zhu, H., Tegenge, M., Huang, S.-M., Wang, Y., Morrison, T. and Zineh, I. (2020), Consideration of a Credibility Assessment Framework in Model-Informed Drug Development: Potential Application to Physiologically-Based Pharmacokinetic Modeling and Simulation. CPT Pharmacometrics Syst. Pharmacol., 9: 21-28. doi.org<http://doi.org>:10.1002/psp4.12479

Musuamba, FT, Skottheim Rusten, I, Lesage, R, et al. Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility. CPT Pharmacometrics Syst Pharmacol. 2021; 10: 804– 825. doi:10.1002/psp4.12669

Viceconti M, Emili L, Afshari P, et al. Possible Contexts of Use for In Silico Trials Methodologies: A Consensus-Based Review. IEEE J Biomed Health Inform. 2021;25(10):3977-3982. doi:10.1109/JBHI.2021.3090469

All the best
Alexander

On Sun, 19 Dec 2021 at 03:10, Jacob Barhak <jacob.barhak at gmail.com<mailto:jacob.barhak at gmail.com>> wrote:

Greetings to the paper contributors,

You may have seen my other message where I posted the reviews to our paper.  I am sending those again below to start a new thread discussing possible revisions.

Here is a checklist for revisions required:

  1.   We should discuss the references that reviewer 1 raised and add them as reference
  2.  Reviewer 1 asked for more discussion around V&V40 - I believe Alex added the text there originally - Alex do you think you can address the request of the reviewer?
  3.  Reviewer 1 asked to focus on COVID-19 at the title - I am not sure we wish to limit our scope since many of our ideas are applicable far beyond COVID-19 - I leave it up for discussion in the group on how to address this request by the reviewer
  4.  Reviewer 1 asked for additional graphics - I am unsure how to address this beyond ur current diagram - ideas will help
  5.  We need to check the "Contribution to the field" section for grammar and spelling - if someone can contribute more elegant text - now is the time - I looked over it now and found no issues - yet I may have missed something - this section may have been missed since it was added last and perhaps vetted less than other sections. Also Reviewer 2 asked for grammar corrections, so it is worthwhile proof reading the paper as a whole.
  6.  Reviewer 2 asks for major rewrite to emphasize why the problems are there - I think we should explain that the core of the paper is the table and perhaps emphasize it in the paper beyond what the current text - we also should reply to the reviewer and explain that the paper is composed of contributions from a large group and we made an effort to include every voice in the choir - each of those voices is important and needs to be preserved - hopefully it will convince the reviewer that change we will add will be sufficient
  7.  Reviewer 2 asks to revise the introduction  - I believe some changes are possible - yet the introduction includes contributions from many authors - at least 10 - and I fear losing something important someone contributed - if someone has an idea on how to address this reviewer without a painful transformation, please reply to this message.
  8.   Reviewer 2 wants additional discussion around the "reproducibility crisis" section  and asks a valid question about expectations we should address - "“Computational biomedical modeling… was expected to be less affected by the reproducibility crisis.” Is this true, and why would it be so? "  - My answer to the reviewer is that unlike biological processes that have random nature and experiments would not repeat if repeated, while computer software should be deterministic and it should be repeatable if designed well.  Unfortunately we are not experiencing this promise - yet I believe the reviewer wants more discussion beyond this section so I am happy to discuss this.
  9.  Reviewer 2- writes:  "Models are Hard to Locate: Are the authors suggesting that entire simulation workflows, from model construction to analysis, should be publicly available? At what point does one consider intellectual property? Do the authors advocate for such extensive publishing for all models, or only ones that are intended to be widely re-used? - those are important points we need to discuss - we need to better explain the difficulties we are having when creating models and the reviewer is absolutely correct about expanding the discussion to IP - I suggest we create a thread for this discussion and reference it - I suggest it we merged with the licensing  issue that I will address later - there is a strong connection there - the reviewer was very observant and sees the bigger problem. However,we need to eventually distill our discussion to recommendations that will inline.
  10. Reviewer 2 asks that we fix the unit standardization section - I believe Hana and myself were the largest contributors there - Hana - I will start a discussion on that topic in a separate email where we can publicly discuss how to fix this - others will be welcome to contribute.
  11. Reviewer 2 asks that we better handle the section on Data availability and measurement definitions: in think we need to emphasize solutions and separate it from issues that may not be solvable. Ideas are welcome.
  12. Reviewer 2 asks good questions with regards to licensing following our text- I personally have good answers to the reviewer and William and I had some discussion on the topic in this list I suggest we expand this discussion in a separate thread - hopefully William and perhaps others will join the discussion. This discussion should also address the IP issues raised by the reviewer for the "models are hard to locate section."
  13. Reviewer 2 asks to handle the Model Application and Implementation Barriers section. We should decide what to do there, the section may need expansion since the ideas there are solid, yet the section is short so perhaps enhancing it makes better sense. I am open to suggestions.

Those are the items I located and my suggestions. It seems we need attention from Alex, Hana, myself and william. However, anyone on the list is welcome to participate and suggest changes.

I will start the discussion threads on specific topics. Hopefully we can get it done quickly.

         Jacob

-

########### Original Reviews #############

There are 2 reviews - both require major changes. I am copying the relevant text below.  If more appear, I will let you know, yet I only got this message today although the reviews are dated a few days ago.

Reviewer 1:
Recommendation for the Editor: Substantial revision is required

Please list your revision requests for the authors and provide your detailed comments, including highlighting limitations and strengths of the review. If you have additional comments based on Q2 and Q3 you can add them as well.

Karr and co-authors made an interesting and exaustive point about the reproducibility crisis that leads to inability to reuse and integrate models, especially about COVID-19 disease.
Within the manuscript some typos and missing information are present.
I'd suggest the authors to revise the entire manuscript especially in terms of the state of the art, revising and updating the most relevant examples of computational models dealing with COVID-19 and in general about some semi-standardised proposals about the pipeline to follow for the verification and validation of model credibility. In particular, the authors failed to mention and cite some major results on in silico modeling about COVID-19 up to now. See for example:
a."In silico trial to test COVID-19 candidate vaccines: a case study with UISS platform", Russo, G., Pennisi, M., Fichera, E., ...Viceconti, M., Pappalardo, F., BMC Bioinformatics, 2020, 21, 527.
b. Russo G, Di Salvatore V, Sgroi G, Parasiliti Palumbo GA, Reche PA, Pappalardo F. "A multi-step and multi-scale bioinformatic protocol to investigate potential SARS-CoV-2 vaccine targets" [published online ahead of print, 2021 Oct 5]. Brief Bioinform. 2021;bbab403. doi:10.1093/bib/bbab403.
Moreover, when the authors mention ASME V&V40 procedure, it could be useful to spend few words about the model credibility pipeline drawn for predictive models in biomedicine, such as the one suggested in "Credibility of in Silico Trial Technologies-A Theoretical Framing", Viceconti, M., Juarez, M.A., Curreli, C., ...Russo, G., Pappalardo, F., IEEE Journal of Biomedical and Health Informatics, 2020, 24(1), pp. 4–13, 8884189.
For this specific aspect, the authors should talk about "specific question of interest" and not "specific purpose" in the paragraph called "Credibility of Models" to follow in such a way a standardised language.
Moreover, the authors should refer to COVID-19 also in the title, with a specific mention about the fact that the main topic of model integration in computational biology will be discussed inside the COVID-19 context.
Furthermore, for the model key concepts such as Reusability-Extensibility-Extractability-Portability the authors should described and outlined through a graphical sketch or visual representation that summarises these key point.
The authors should also fix some grammar and writing typos present in the "Contribution to the field" section.

a. Is the quality of the figures and tables satisfactory?
- No

b. Does the reference list cover the relevant literature adequately and in an unbiased manner?
- No

c. Does this manuscript refer only to published data? (unpublished or original data is not allowed for this article type)
- Yes

d. Does the review include a balanced, comprehensive, and critical view of the research area?
- Yes

Reviewer 2

Please list your revision requests for the authors and provide your detailed comments, including highlighting limitations and strengths of the review. If you have additional comments based on Q2 and Q3 you can add them as well.

The article often reads as a stream-of-consciousness account of the discussions that took place but lacks a clear thesis or recommendations. It is not clear what, if anything, the authors are advocating for. It is not always clear why the issues being discussed are problematic, or that they can be reasonably addressed. Some of the issues raised are indeed important and should be discussed, but the paper lacks focus and does not tell a cohesive story. I believe this manuscript requires a major re-write to be suitable for publication. The authors should consider narrowing the scope of the discussion and focusing on a cohesive set of recommendations or open questions. More specifically, I make a few suggestions below:

Major comments
1. The introduction is long and repeats itself (e.g., “much less is known about how viral infections spread throughout the body…” is repeated verbatim). It is not clear from the introduction what the main goal of the paper is or why the “reproducibility crisis” is truly a crisis. Why is the discussion of composition and black/white box models relevant to the introduction? Further, this section is subtitled “the promise of modeling”, which does not seem to match the content.
2. The Reproducibility Crisis: “Computational biomedical modeling… was expected to be less affected by the reproducibility crisis.” Is this true, and why would it be so? One would think that more complex models would suffer more from a lack of reproducibility. It may be helpful to define what exactly the “reproducibility crisis” refers to.
3. Models are Hard to Locate: Are the authors suggesting that entire simulation workflows, from model construction to analysis, should be publicly available? At what point does one consider intellectual property? Do the authors advocate for such extensive publishing for all models, or only ones that are intended to be widely re-used?
4. Unit standardization: The conversion from PFU or TCID50 to individual virions is likely to differ across viruses – are the authors focused on COVID here? Are the authors advocating for a standard conversion factor? It is not clear what the purpose of this discussion is. As the authors mention, different scales require different units. Even at a single scale, different models may require different units for numerical reasons. It is not clear what the authors are advocating for here.
5. Data availability and measurement definitions: This section seems to outline limitations of available data, but again makes no recommendations or proposed solution to any of the issues raised. Is this the intention? Most of the issues raised here reflect limitations of experimental science or data privacy, which likely cannot be meaningfully addressed by the modeling community.
6. Models are Not Consistently Licensed…: Are the authors implying here that all modeling work should be published with no rights reserved? Is it reasonable to expect modelers to make their work freely usable by others for profit? Is it reasonable for institutions to allow this? How much does this really contribute to reproducibility and utility?
7. Model Application and Implementation Barriers: This section seems unnecessary and out of place.
8. There are grammar and punctuation errors scattered throughout; please edit carefully.

a. Is the quality of the figures and tables satisfactory?
- Not Applicable

b. Does the reference list cover the relevant literature adequately and in an unbiased manner?
- Yes

c. Does this manuscript refer only to published data? (unpublished or original data is not allowed for this article type)
- Yes

d. Does the review include a balanced, comprehensive, and critical view of the research area?
No answer given.

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Modeling & simulation / Biomodeling
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DISCOVERY
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DISCOVERY
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