<div dir="ltr">Thanks again to all contributors,<div><br></div><div>The paper was approved and Sheriffs funding statement was added. </div><div>The revised paper submitted and the note below was addressed to the editor:</div><div><br></div><div>Hopefully this concludes the dealing with the paper - and hopefully there will be some correspondence with this group after publication - some of the claims we are making should require attention from the community and from stakeholders. </div><div><br></div><div>Hopefully this gets published quickly. And if anyone gets communications related to the manuscript, please redirect it to the email lists. I really hope this will make an impact.</div><div><br></div><div> Jacob</div><div><br></div><div><br></div><div>-------------</div><div><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">Hi Shayn,</p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px"><br style="outline:0px"></p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">You will find the revised manuscript after approval from all authors of the final version and one addition of funding submitted in your submissions system.</p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px"><br style="outline:0px"></p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">Again I ask that the second affiliation of William Waites be changed prior to publication - this cannot be performed from the submission portal for some reason.</p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px"><br style="outline:0px"></p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">Here is the full affiliation list again. </p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">William Waites, Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK and Department of Computer and Information Sciences, University of Strathclyde, Glasgow, Scotland</p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">The manuscript should be ready for submission - as uploaded - I will take care of the publication costs as entered into the system - please provide information on how to proceed. </p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px"><br style="outline:0px"></p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px">Hopefully this manuscript will be published as quickly as it was processed. </p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px"><br style="outline:0px"></p><p style="margin:13px 0px 0px;font-size:12px;font-family:"Lucida Grande","Trebuchet MS",Arial,sans-serif;line-height:18px;color:rgb(62,61,64);outline:0px"> Jacob</p></div><div><br></div><div><br></div></div><br><div class="gmail_quote"><div dir="ltr" class="gmail_attr">On Tue, Jan 18, 2022 at 11:39 PM Jonathan Karr <<a href="mailto:jonrkarr@gmail.com">jonrkarr@gmail.com</a>> wrote:<br></div><blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex"><div dir="ltr">Hi Jacob,<div><br></div><div>I approve. It looks like there were efforts to address many of the reviewers' concerns.</div><div><br></div><div>Regards,</div><div>Jonathan</div></div><br><div class="gmail_quote"><div dir="ltr" class="gmail_attr">On Tue, Jan 18, 2022 at 3:09 AM Winston Garira <<a href="mailto:Winston.Garira@univen.ac.za" target="_blank">Winston.Garira@univen.ac.za</a>> wrote:<br></div><blockquote class="gmail_quote" style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex">
<div>
<div>
<div>
<div dir="ltr" style="color:rgb(0,0,0);background-color:rgb(255,255,255)">
I APPROVE! </div>
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<br>
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<div dir="ltr" style="color:rgb(0,0,0);background-color:rgb(255,255,255)">
Thank you.</div>
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<div dir="ltr" style="color:rgb(0,0,0);background-color:rgb(255,255,255)">
Winston</div>
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<div id="gmail-m_6500468691882484582gmail-m_-1340860657086694965divRplyFwdMsg" dir="ltr"><font face="Calibri, sans-serif" style="font-size:11pt" color="#000000"><b>From:</b> Ruth Bowness <<a href="mailto:rb2250@bath.ac.uk" target="_blank">rb2250@bath.ac.uk</a>><br>
<b>Sent:</b> Tuesday, January 18, 2022 7:57:53 AM<br>
<b>To:</b> Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>>; Gilberto Gonzalez-Parra <<a href="mailto:gilberto.gonzalezparra@nmt.edu" target="_blank">gilberto.gonzalezparra@nmt.edu</a>><br>
<b>Cc:</b> Faeder, James R <<a href="mailto:faeder@pitt.edu" target="_blank">faeder@pitt.edu</a>>; Rahuman Sheriff <<a href="mailto:sheriff@ebi.ac.uk" target="_blank">sheriff@ebi.ac.uk</a>>; <a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a> <<a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a>>; <a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a> <<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a>>; John Gennari
<<a href="mailto:gennari@uw.edu" target="_blank">gennari@uw.edu</a>>; Ruth Bowness <<a href="mailto:rec9@st-andrews.ac.uk" target="_blank">rec9@st-andrews.ac.uk</a>>; Winston Garira <<a href="mailto:Winston.Garira@univen.ac.za" target="_blank">Winston.Garira@univen.ac.za</a>>; Jonathan Karr <<a href="mailto:jonrkarr@gmail.com" target="_blank">jonrkarr@gmail.com</a>><br>
<b>Subject:</b> Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list</font>
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<div>I approve. Many thanks!</div>
<div>Ruth </div>
<hr style="display:inline-block;width:98%">
<div id="gmail-m_6500468691882484582gmail-m_-1340860657086694965x_divRplyFwdMsg" dir="ltr"><font face="Calibri, sans-serif" color="#000000" style="font-size:11pt"><b>From:</b> Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>><br>
<b>Sent:</b> 18 January 2022 04:48<br>
<b>To:</b> Gilberto Gonzalez-Parra <<a href="mailto:gilberto.gonzalezparra@nmt.edu" target="_blank">gilberto.gonzalezparra@nmt.edu</a>><br>
<b>Cc:</b> Faeder, James R <<a href="mailto:faeder@pitt.edu" target="_blank">faeder@pitt.edu</a>>; Rahuman Sheriff <<a href="mailto:sheriff@ebi.ac.uk" target="_blank">sheriff@ebi.ac.uk</a>>; <a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a> <<a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a>>; <a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a> <<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a>>; John Gennari
<<a href="mailto:gennari@uw.edu" target="_blank">gennari@uw.edu</a>>; Ruth Bowness <<a href="mailto:rb2250@bath.ac.uk" target="_blank">rb2250@bath.ac.uk</a>>; Ruth Bowness <<a href="mailto:rec9@st-andrews.ac.uk" target="_blank">rec9@st-andrews.ac.uk</a>>; Winston Garira <<a href="mailto:Winston.Garira@univen.ac.za" target="_blank">Winston.Garira@univen.ac.za</a>>; Jonathan Karr <<a href="mailto:jonrkarr@gmail.com" target="_blank">jonrkarr@gmail.com</a>><br>
<b>Subject:</b> Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list</font>
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<div dir="ltr">Hi Ruth, Hi Jonathan, Hi Winston,
<div><br>
</div>
<div>You are the last 3 authors that need approval - I apologize in advance if you sent your final approval and I did not get it. Sometimes it gets lost. Please REPLY TO ALL to this email with APPROVE, DISAPPROVE, or ABSTAIN so we can have your approval in
public record and resolve this quickly.</div>
<div><br>
</div>
<div>Hopefully you can do it within a day or two - both reviewers endorsed the paper and I just sent the editor the message below. </div>
<div><br>
</div>
<div><br>
</div>
<div>Sheriff, your recollection is correct - Tomas Helikar did participate in our discussions. Yet the idea of sorting the challenges belongs to John Gennari who managed one of the versions. That version was not traceable, so any text taken from it, had to
be validated by the authors that wrote that text. As far as I know no new contributions in the submitted version can be traced back to Tomas and he did not claim any contribution that was omitted nor raised any objection - and I did ask several times for objections
by anyone. So his name is not in the list of authors, yet he is acknowledged in the paper acknowledgement section since he did participate in some meetings. If you ask me, I believe he wanted to contribute when we opened the paper for contributions, yet could
not find the time.</div>
<div><br>
</div>
<div>Tomas, if I am wrong, please correct me now so we can fix this prior to finalization. .</div>
<div><br>
</div>
<div>And Sheriff, this paper is somewhat reproducible. If you trace back the versions we have public, you can find all authors listed contributing with a few exceptions. For example, John Rice contributed significant portions of the reproducibility section,
yet I uploaded the text from him into the paper - so you will see my name instead of his. Also, some contributors added comments that I edited into the paper in the early days. Some authors also contributed to the activities that generated references for the
paper - so their contribution was substantial. As far as I know the list of authors we have is complete except from John Gennari who made a large contribution to the paper, yet chose to abstain yet allowed us to proceed and use the text - I still hope he will
rejoin, yet honor his decision if he chooses not to. He is acknowledged for his contribution - this way he gains some honor. </div>
<div><br>
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<div>Hopefully the last few authors will approve as well as the editor and we can move forward.</div>
<div><br>
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<div> Jacob</div>
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<div>########## The message I send to the editor #############</div>
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Hi Shayn,</p>
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You will find a new manuscript draft in the system - I just uploaded figures in different formats in high resolution as the first reviewer requested. </p>
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I would like to add one more affiliation for one of our authors - William Waites has two affiliations - see below - I tried to update this in the system, yet the system blocks me from editing the authors list for some reason.</p>
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William Waites, Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK and Department of Computer and Information Sciences, University of Strathclyde, Glasgow, Scotland</p>
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I would ask to delay the manuscript until all our authors approve the final version - we have 15 of the 18 approve the manuscript - I will do my best to get the last 3 approve quickly. Once I get approval I can submit. </p>
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Thank you for processing this quickly. I wish our big group will be as fast as you. </p>
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Jacob</p>
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<div dir="ltr">On Mon, Jan 17, 2022 at 6:34 PM Gilberto Gonzalez-Parra <<a href="mailto:gilberto.gonzalezparra@nmt.edu" target="_blank">gilberto.gonzalezparra@nmt.edu</a>> wrote:<br>
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<blockquote style="margin:0px 0px 0px 0.8ex;border-left:1px solid rgb(204,204,204);padding-left:1ex">
<div dir="ltr">
<div dir="ltr">The status has changed to
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17 Jan 2022</td>
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<div style="padding-top:8px;padding-bottom:8px;border-bottom:medium none;outline:0px">
Review of Review Editor 1 finalized.</div>
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<div style="padding-top:8px;padding-bottom:8px;border-bottom:medium none;outline:0px">
Editorial Office reminded you to respond to reviewer 1 and/or resubmit your manuscript in the discussion forum.</div>
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10 Jan 2022</td>
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Review of Review Editor 2 finalized.</div>
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<div>So both reviewers endorsed it. BTW, approve.</div>
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<div dir="ltr">***************************************************************************</div>
<div dir="ltr">Gilberto C. Gonzalez-Parra, <span style="color:rgb(0,0,0);font-family:"Helvetica Neue",Helvetica,Arial,"Lucida Grande",sans-serif,serif,EmojiFont;font-size:13px">Ph.D in Applied Mathematics.</span></div>
<div dir="ltr"><font color="#000000" face="Helvetica Neue, Helvetica, Arial, Lucida Grande, sans-serif, serif, EmojiFont"><span style="font-size:13px">Faculty of the </span></font>Mathematics Department
<div>
<div>New Mexico Tech, NM, USA.</div>
</div>
<div>****************************************************************************</div>
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<div dir="ltr">On Mon, Jan 17, 2022 at 4:07 PM Faeder, James R <<a href="mailto:faeder@pitt.edu" target="_blank">faeder@pitt.edu</a>> wrote:<br>
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<p><span style="font-size:11pt">Approve.<u></u><u></u></span></p>
<p><span style="font-size:11pt"><u></u> <u></u></span></p>
<p><span style="font-size:11pt">Thanks Jacob and everyone else for all of your efforts on the revisions.<u></u><u></u></span></p>
<p><span style="font-size:11pt"><u></u> <u></u></span></p>
<p><span style="font-size:11pt">Best regards,<u></u><u></u></span></p>
<p><span style="font-size:11pt"><u></u> <u></u></span></p>
<p><span style="font-size:11pt">Jim<u></u><u></u></span></p>
<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p style="margin-bottom:12pt"><b><span style="font-size:12pt;color:black">From:
</span></b><span style="font-size:12pt;color:black">Rahuman Sheriff <<a href="mailto:sheriff@ebi.ac.uk" target="_blank">sheriff@ebi.ac.uk</a>><br>
<b>Date: </b>Monday, January 17, 2022 at 5:02 PM<br>
<b>To: </b>Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>><br>
<b>Cc: </b><a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a> <<a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a>>,
<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a> <<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a>>, John Gennari <<a href="mailto:gennari@uw.edu" target="_blank">gennari@uw.edu</a>>,
Faeder, James R <<a href="mailto:faeder@pitt.edu" target="_blank">faeder@pitt.edu</a>>, Alexander Kulesza <<a href="mailto:alexander.kulesza@novadiscovery.com" target="_blank">alexander.kulesza@novadiscovery.com</a>><br>
<b>Subject: </b>Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list<u></u><u></u></span></p>
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<p><span style="font-size:11pt">Dear Jacob, <u></u><u></u></span></p>
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<p><span style="font-size:11pt">Please find the Figure 1 attached.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">It is not clear to me whether the manuscript has been accepted. If the reviewer1’s response is overdue, we need to wait. If the review1 doesn’t respond at all, the editor might assign the manuscript to another
reviewer.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Irrespective of that I approve. <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">On a different note, if I remember correctly, Tomas Helikar also contributed to the ordering of the table which is used in the figure. probably he mad other contributions too in John Gennari’s version.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Best regards<u></u><u></u></span></p>
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<p><span style="font-size:11pt">Sheriff<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><br>
<br>
<u></u><u></u></span></p>
<blockquote style="margin-top:5pt;margin-bottom:5pt">
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<p><span style="font-size:11pt">On 14 Jan 2022, at 13:19, Alexander Kulesza <<a href="mailto:alexander.kulesza@novadiscovery.com" target="_blank">alexander.kulesza@novadiscovery.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Dear Jacob, dear all, <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">APPROVE<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Attached, Figure 2 in HR in different formats. <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Best <u></u><u></u></span></p>
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<p><span style="font-size:11pt">Alexander <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">On Fri, 14 Jan 2022 at 07:38, Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:11pt">Thanks Marcella, <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">In that case, it seems we have no reviewer objection and hopefully the editor will be positive as well . To speed up the process we need the following::<u></u><u></u></span></p>
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<p><span style="font-size:11pt">1. Sheriff - please send a high resolution image for Figure 1<u></u><u></u></span></p>
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<p><span style="font-size:11pt">2. Alex - Please send a high resolution image for Figure 2<u></u><u></u></span></p>
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<p><span style="font-size:11pt">3. Everyone please review the manuscript and Reply to all in this email with one word - either APPROVE, DISAPPROVE, ABSTAIN<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Where:<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">APPROVE means you are ok with the version we reached - please note that we do have some new elements there and your approval means you understand what it means - please read the paper well and understand
the nuances of approval.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">DISAPPROVE- means that you no longer agree with the version we reached and we need to discuss the paper more and withdraw it - if you have some serious objection, it is the last chance to get the paper back
to the drawing board<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">ABSTAIN - You have no objection for the paper being published, yet you want your name withdrawn <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Also, if anyone else has any objections for this paper being published, please raise them now so we can discuss them. <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">I call again to John Gennarri to join us as an author - he did substantial work and many of his contributions are in the final version - including the order in figure 2. I can trace back many of his contributions
and I think he should get credit for it - hopefully my last call will be accepted and he will rejoin.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">William - I did not forget your second affiliation - I just could not change it in the system - I will write to the editor about that when we get the final acceptance notice.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">I look forward to seeing your final decisions - hopefully it will be fast this time.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">On Thu, Jan 13, 2022 at 8:50 PM Torres, Marcella <<a href="mailto:mtorres@richmond.edu" target="_blank">mtorres@richmond.edu</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<span style="background:white">This is to remind you that your response to the reviewer 1 is overdue in the interactive review forum of your manuscript 822606 under consideration for publication in Frontiers in Systems Biology, section Multiscale Mechanistic
Modeling.</span><br>
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<p style="margin-bottom:12pt"><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<div id="gmail-m_6500468691882484582gmail-m_-1340860657086694965x_x_gmail-m_6412313573616942904gmail-m_-3294684017859721461x_gmail-m_2835791917185613053gmail-m_5027109128376032515Signature">
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Marcella Torres, Ph.D.<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Director of Mathematical Studies<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">University of Richmond<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Jepson Hall Room 212<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">221 Richmond Way<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Richmond, VA 23173<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">(804) 289-8081<u></u><u></u></span></p>
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<div>
<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Pronouns: she/her<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
</div>
</div>
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<div align="center" style="text-align:center"><span style="font-size:11pt">
<hr size="0" width="100%" align="center">
</span></div>
<div id="gmail-m_6500468691882484582gmail-m_-1340860657086694965x_x_gmail-m_6412313573616942904gmail-m_-3294684017859721461x_gmail-m_2835791917185613053gmail-m_5027109128376032515divRplyFwdMsg">
<p><b><span style="font-size:11pt">From:</span></b><span style="font-size:11pt"> Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>><br>
<b>Sent:</b> Thursday, January 13, 2022 8:14 PM<br>
<b>To:</b> Torres, Marcella <<a href="mailto:mtorres@richmond.edu" target="_blank">mtorres@richmond.edu</a>><br>
<b>Cc:</b> Rahuman Sheriff <<a href="mailto:sheriff@ebi.ac.uk" target="_blank">sheriff@ebi.ac.uk</a>>;
<a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a> <<a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a>>;
<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a> <<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a>>; John Gennari <<a href="mailto:gennari@uw.edu" target="_blank">gennari@uw.edu</a>>;
Faeder, James R <<a href="mailto:faeder@pitt.edu" target="_blank">faeder@pitt.edu</a>><br>
<b>Subject:</b> Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list
<u></u><u></u></span></p>
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<p><span style="font-size:11pt"> <u></u><u></u></span></p>
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<div style="border:1pt solid red;padding:2pt">
<p style="background:yellow"><b><span style="font-family:Arial,sans-serif;color:red">External Email:</span></b><span style="font-family:Arial,sans-serif;color:black"> Use caution in opening links, attachments, and buying gift cards.</span><span style="font-family:Arial,sans-serif"><u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Thanks Marcella, Thanks Gilberto,
<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Since the second reviewer did not respond, I think we have more time - we did respond in time however. <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Section 2.2.2 in the instruction provides information about the image quality:<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.frontiersin.org%2Fabout%2Fauthor-guidelines&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036368924%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=%2BsG%2F%2FjiC3IvJdSbwVKG%2FWlOdYMufQ2JI0ebuJH55Lm8%3D&reserved=0" target="_blank">https://www.frontiersin.org/about/author-guidelines</a><u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Hopefully we can have those ready.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">On Thu, Jan 13, 2022 at 1:05 PM Torres, Marcella <<a href="mailto:mtorres@richmond.edu" target="_blank">mtorres@richmond.edu</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">Hi again all,<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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)?<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Reviewer 2 has endorsed the manuscript.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><image.png><u></u><u></u></span></p>
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<p><span style="font-size:12pt;color:black;background:white">Reviewer 1 comment:</span><span style="font-size:12pt">
<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:9pt;font-family:"Lucida Grande",sans-serif;color:rgb(62,61,64)"> </span><strong><span style="font-size:9pt;font-family:"Lucida Grande",sans-serif;color:rgb(124,93,82)">Reviewer 1</span></strong><span style="font-size:9pt;font-family:"Lucida Grande",sans-serif;color:rgb(124,93,82)"> |
07 Jan 2022 | 14:36</span><span style="font-size:9pt;font-family:"Lucida Grande",sans-serif;color:rgb(62,61,64)">
<u></u><u></u></span></p>
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<p style="background:white"><b><span style="font-size:8.5pt;font-family:"Lucida Grande",sans-serif;color:rgb(112,113,115)">#3<u></u><u></u></span></b></p>
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<p style="margin-top:9.75pt;line-height:13.5pt;background:white">
<span style="font-size:9pt;font-family:"Lucida Grande",sans-serif;color:rgb(62,61,64)">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Marcella Torres, Ph.D.<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Director of Mathematical Studies<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">University of Richmond<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Jepson Hall Room 212<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">221 Richmond Way<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Richmond, VA 23173<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">(804) 289-8081<u></u><u></u></span></p>
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<p style="background:white"><span style="font-size:10.5pt;color:rgb(32,31,30)">Pronouns: she/her<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><b><span style="font-size:11pt">From:</span></b><span style="font-size:11pt"> Vp-reproduce-subgroup <<a href="mailto:vp-reproduce-subgroup-bounces@lists.simtk.org" target="_blank">vp-reproduce-subgroup-bounces@lists.simtk.org</a>> on
behalf of Rahuman Sheriff <<a href="mailto:sheriff@ebi.ac.uk" target="_blank">sheriff@ebi.ac.uk</a>><br>
<b>Sent:</b> Monday, January 10, 2022 3:09 PM<br>
<b>To:</b> Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>><br>
<b>Cc:</b> <a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">
vp-reproduce-subgroup@lists.simtk.org</a> <<a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">vp-reproduce-subgroup@lists.simtk.org</a>>;
<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a> <<a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">vp-integration-subgroup@lists.simtk.org</a>>; John Gennari <<a href="mailto:gennari@uw.edu" target="_blank">gennari@uw.edu</a>>;
Faeder, James R <<a href="mailto:faeder@pitt.edu" target="_blank">faeder@pitt.edu</a>><br>
<b>Subject:</b> Re: [Vp-reproduce-subgroup] [Vp-integration-subgroup] Paper review and revision check list
<u></u><u></u></span></p>
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<p><span style="font-size:11pt"> <u></u><u></u></span></p>
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<p style="background:yellow"><b><span style="font-family:Arial,sans-serif;color:red">External Email:</span></b><span style="font-family:Arial,sans-serif;color:black"> Use caution in opening links, attachments, and buying gift cards.</span><span style="font-family:Arial,sans-serif"><u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Thanks Jakob for submitting the revision and others for the support. Thanks William for editing my response.
<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Best<u></u><u></u></span></p>
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<p><span style="font-size:11pt">Sheriff<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"><br>
<br>
<u></u><u></u></span></p>
<blockquote style="margin-top:5pt;margin-bottom:5pt">
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<p><span style="font-size:11pt">On 7 Jan 2022, at 04:52, Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">Thanks Hana, Thanks William, and thanks to Gilberto, Alex, and Sheriff,
<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">With your help and some effort, the revised paper was resubmitted in time - just now.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt">On Thu, Jan 6, 2022 at 3:51 PM Dobrovolny, Hana <<a href="mailto:h.dobrovolny@tcu.edu" target="_blank">h.dobrovolny@tcu.edu</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">I've read through the paper and fixed a few grammar mistakes.<u></u><u></u></span></p>
<p><span style="font-size:12pt">Hana<u></u><u></u></span></p>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p>*******************************************************<br>
Dr. Hana Dobrovolny<br>
Associate Professor of Biophysics<br>
Texas Christian University<br>
TCU Box 298840<br>
Fort Worth, TX 76129<br>
<br>
phone: (817) 257-6379 fax: (817) 257-7742<br>
email: <a href="mailto:h.dobrovolny@tcu.edu" target="_blank">h.dobrovolny@tcu.edu</a><br>
*******************************************************<u></u><u></u></p>
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<p style="margin-bottom:12pt"><span style="font-size:12pt"><u></u> <u></u></span></p>
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<div align="center" style="text-align:center"><span style="font-size:12pt">
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<div id="gmail-m_6500468691882484582gmail-m_-1340860657086694965x_x_gmail-m_6412313573616942904gmail-m_-3294684017859721461x_gmail-m_2835791917185613053gmail-m_5027109128376032515x_gmail-m_698229277573520101x_gmail-m_8456291084743863762divRplyFwdMsg">
<p><b><span style="font-size:11pt">From:</span></b><span style="font-size:11pt"> Vp-integration-subgroup <<a href="mailto:vp-integration-subgroup-bounces@lists.simtk.org" target="_blank">vp-integration-subgroup-bounces@lists.simtk.org</a>>
on behalf of Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>><br>
<b>Sent:</b> January 5, 2022 11:48 PM<br>
<b>To:</b> William Waites; James Glazier<br>
<b>Cc:</b> <a href="mailto:vp-reproduce-subgroup@lists.simtk.org" target="_blank">
vp-reproduce-subgroup@lists.simtk.org</a>; <a href="mailto:vp-integration-subgroup@lists.simtk.org" target="_blank">
vp-integration-subgroup@lists.simtk.org</a>; John Gennari; Faeder, James R<br>
<b>Subject:</b> Re: [Vp-integration-subgroup] [Vp-reproduce-subgroup] Paper review and revision check list</span><span style="font-size:12pt">
<u></u><u></u></span></p>
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<p><span style="font-size:12pt"> <u></u><u></u></span></p>
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<p><strong><span style="font-size:12pt;font-family:Calibri,sans-serif;color:black;background:yellow">[EXTERNAL EMAIL WARNING]</span></strong><span style="font-size:12pt;color:black;background:yellow"> DO NOT CLICK LINKS or open attachments
unless you recognize the sender and know the content is safe.</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt">Greetings paper contributors,
<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Gilberto has addressed the final point and added text in the paper and review, thus concluding our response.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">I went over the paper from start to finish again and cleaned it up.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">There are two last comments in the paper addressed to William Waites and James Glazier - if you can quickly check those, it would help. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">If anyone has any objections, now is the time to raise them so we can withdraw rather than submit. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Here is the link to the revised paper:<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Furldefense.com%2Fv3%2F__https%3A%2F%2Fdocs.google.com%2Fdocument%2Fd%2F1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM%2Fedit%3Fusp%3Dsharing__%3B!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0hvK3OmJ8%24&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036368924%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=PoFOhzAK3pEKiW%2FX6ByEKYp73FLvnTIymhTEWvPjbHo%3D&reserved=0" target="_blank">https://docs.google.com/document/d/1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM/edit?usp=sharing</a><u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Here is the link to response for reviewers:<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Furldefense.com%2Fv3%2F__https%3A%2F%2Fdocs.google.com%2Fdocument%2Fd%2F1bO1CDbMMlyyweYayP9rGohPIfgvIhfe14sFchtJMJ-s%2Fedit%3Fusp%3Dsharing__%3B!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0haRkeB0o%24&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036368924%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=h0HPOc5XUCGG0%2FQKqTmRTOT4LOumAf7j6n1c9ZOzTmo%3D&reserved=0" target="_blank">https://docs.google.com/document/d/1bO1CDbMMlyyweYayP9rGohPIfgvIhfe14sFchtJMJ-s/edit?usp=sharing</a><u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Hopefully there will be no objections and can submit this tomorrow.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">On Tue, Jan 4, 2022 at 11:30 PM Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">Hi Alex, Hi William, Hi Gilberto, and all other contributors.
<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Alex, William and Gilberto are mentioned since we are the most active contributors.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">We have 2 days to finish edits. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">William - I attempted to add your suggestions to the paper regarding issue 11. You are free to revise further. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Hopefully we can get it done in time.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">On Tue, Jan 4, 2022 at 7:25 AM Alexander Kulesza <<a href="mailto:alexander.kulesza@novadiscovery.com" target="_blank">alexander.kulesza@novadiscovery.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">Dear Jacob, dear all, <u></u><u></u></span></p>
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<p><span style="font-size:12pt">thanks for endorsing my figure. I'll gladly add this. Please find enclosed the .png. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">I therefore reverted the table change (disconnecting ist from Figure 1) and suggest the following Figure caption: <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">"Figure 2: </span><span style="font-size:11pt;font-family:Arial,sans-serif">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. "
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">With that sentence we can discuss the difficulties in any order.
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Best
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Alexander
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">On Tue, 4 Jan 2022 at 13:24, Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">Yes Alex,<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"> 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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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 <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Hopefully my arguments make sense.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">On Tue, Jan 4, 2022, 06:45 Alexander Kulesza <<a href="mailto:alexander.kulesza@novadiscovery.com" target="_blank">alexander.kulesza@novadiscovery.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">Dear all, <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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). <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">@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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><image.png> <u></u><u></u></span></p>
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<p><span style="font-size:12pt">The table with Difficulties (hurdles) and solutions would then be <u></u><u></u></span></p>
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<p><b><span style="font-size:11pt;font-family:Arial,sans-serif">Difficulty</span></b><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><b><span style="font-size:11pt;font-family:Arial,sans-serif">Potential Solutions</span></b><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt"><u></u> <u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Reproducibility </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Models are written in different languages</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Common transport specifications such as SBML or CellML, and proper documentation and annotation</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Models are hard to locate </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Archive web sites such as: BioModels, SimTK, IMAGWiki, and the future modeleXchange</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Lack of common platforms for executing models and simulations</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Platforms such as BioSimulators, and runBioSimulations</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Unit standardization</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Standardization efforts, and machine learning solutions such as
<a href="https://nam04.safelinks.protection.outlook.com/?url=http%3A%2F%2Fclinicalunitmapping.com%2F&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036368924%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=ctmyqlzzJKJ%2F41ZusRl2q4fJYWbJ6%2FuPzv%2BDs40dqZs%3D&reserved=0" target="_blank">
ClinicalUnitMapping.com</a> </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Credibility</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Models have built-in barriers to Evaluating model credibility </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Better modeling practices, documentation, and tests.</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Data availability and measurement definitions</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Models that merge human interpretation, and newer measurement devices</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Missing annotations in models</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Adoption of policies such as those COMBINE suggests</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Utility </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Models are not consistently licensed to allow for reuse</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Abandoning some old school open source licenses and promoting licenses that release to public domain </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Different scales and modeling paradigms</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Standardization effort and centralization tools</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Stochastic modeling difficulties</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Development of tools that guarantee repeatability and standards to address stochastic simulations </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Integration </span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Model application and implementation barriers</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Education of modelers, users, and the public</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Modeling requires adaptation towards integration</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:11pt;font-family:Arial,sans-serif">Tools for composing models such as SBML-Comp, and SemGen</span><span style="font-size:11pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
<p><span style="font-size:12pt">Following this assignment.<u></u><u></u></span></p>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
<p><span style="font-size:12pt">Please let me know what you think. I have added this suggestion in track changes mode to the revision draft. <u></u><u></u></span></p>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
<p><span style="font-size:12pt">Best <u></u><u></u></span></p>
<p><span style="font-size:12pt">Alexander <u></u><u></u></span></p>
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<p><span style="font-size:12pt"> <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">On Mon, 3 Jan 2022 at 07:27, Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>> wrote:<u></u><u></u></span></p>
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<p><span style="font-size:12pt">Thanks Alex, <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">It seems most points have been answered to some level - even a figure was created - although I wish I was a better artist. <u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Many thanks to all those who contributed. <u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"> Jacob<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"> <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">On Sun, Jan 2, 2022 at 7:27 AM Alexander Kulesza <<a href="mailto:alexander.kulesza@novadiscovery.com" target="_blank">alexander.kulesza@novadiscovery.com</a>> wrote:<u></u><u></u></span></p>
</div>
<blockquote style="border-top:none;border-right:none;border-bottom:none;border-left:1pt solid rgb(204,204,204);padding:0in 0in 0in 6pt;margin-left:4.8pt;margin-right:0in">
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<p><span style="font-size:12pt">Dear all, <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
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<p><span style="font-size:12pt">Happy new year to everyone. I hope that you are all well and safe and have spent a nice holiday season. <u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">I have tried to address <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><i><span style="font-size:12pt;color:red">Reviewer 2 </span></i><span style="font-size:12pt"><u></u><u></u></span></p>
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<div>
<p><i><span style="font-size:12pt;color:red">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.<br>
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.</span></i><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">I have worked on the followng document in "track changes" mode: <br>
<a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Furldefense.com%2Fv3%2F__https%3A%2F%2Fdocs.google.com%2Fdocument%2Fd%2F1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM%2Fedit__%3B!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0hrtFQ-XI%24&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036368924%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=mseGpx%2Fs%2BDeFvZSJ6m4S%2BpZCA4zZ6k3%2BMsibt91pbNg%3D&reserved=0" target="_blank">https://docs.google.com/document/d/1IMEgmdNkx-EsnOjGuegpenSIMmKIkK00Lc8Gred3QxM/edit</a><u></u><u></u></span></p>
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<div>
<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">I suggest the following formulation in the rebuttal letter: <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<div>
<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">We now roughly follow the following flow of writing: <u></u><u></u></span></p>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt"> - Every model needs a purpose and credibility is tied to that purpose as well as repeatability and reproducibility<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt">- Credibility is essential for models that have impact on regulated areas or people's lives which is why regulatory authorities issue guidance<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">- 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<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">- 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<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">- More work is needed to harmonize, stay up to date and to be more inclusive <u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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).<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt;color:black;background:yellow">" 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)." </span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt;color:black;background:white">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. </span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
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<p><span style="font-size:12pt;color:black;background:white">We therefore have added the following statement </span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt;color:black;background:yellow">" 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." </span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
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<p><span style="font-size:12pt;color:black;background:white">We additionally strengthened our argumentation by citing additional literature </span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<div>
<p><span style="font-size:12pt;font-family:Arial,sans-serif">Bai, JPF, Earp, JC, Florian, J, et al.
<i>Quantitative systems pharmacology: Landscape analysis of regulatory submissions to the US Food and Drug Administration.
</i>CPT Pharmacometrics Syst Pharmacol. 2021; 10: 1479– 1484. <a href="https://nam04.safelinks.protection.outlook.com/?url=http%3A%2F%2Fdoi.org%2F&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036368924%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=NnEHJ7f3YFOuD%2FvDv4BoJA1Qu1QSaIaW1YEZ%2BajyDK0%3D&reserved=0" target="_blank">
doi.org</a>:10.1002/psp4.12709</span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt;font-family:Arial,sans-serif">FDA (2021b). Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions.
<i>FDA</i><br>
Available at: </span><span style="font-size:12pt"><a href="https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Furldefense.com%2Fv3%2F__https%3A%2F%2Fwww.fda.gov%2Fregulatory-information%2Fsearch-fda-guidance-documents%2Fassessing-credibility-computational-modeling-and-simulation-medical-device-submissions__%3B!!K6Z8K8YTIA!Qmy11SwUfgLnvEtA_Yy8DDA-OCSuTnTFPcnArqqv3zx410koRSJz-doddC0harP7IHc%24&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036525180%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=kzgGEch2DZXOsiGGFqhDAeNEjb3zrAynsOcfF0X%2FSYg%3D&reserved=0" target="_blank"><span style="font-family:Arial,sans-serif">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-credibility-computational-modeling-and-simulation-medical-device-submissions</span></a></span><span style="font-size:12pt;font-family:Arial,sans-serif">
[Accessed January 2, 2022]<br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt;font-family:Arial,sans-serif"><br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<div>
<p><span style="font-size:12pt;font-family:Arial,sans-serif">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,
<i>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</i>. Clin Pharmacol Ther, 110: 1172-1175. doi:10.1002/cpt.2265<br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt;font-family:Arial,sans-serif"><br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt;font-family:Arial,sans-serif">Kuemmel, C., Yang, Y., Zhang, X., Florian, J., Zhu, H., Tegenge, M., Huang, S.-M., Wang, Y., Morrison, T. and Zineh, I. (2020),
<i>Consideration of a Credibility Assessment Framework in Model-Informed Drug Development: Potential Application to Physiologically-Based Pharmacokinetic Modeling and Simulation.</i> CPT Pharmacometrics Syst. Pharmacol., 9: 21-28.
<a href="https://nam04.safelinks.protection.outlook.com/?url=http%3A%2F%2Fdoi.org%2F&data=04%7C01%7CWinston.Garira%40univen.ac.za%7Ce905d707905f4301190c08d9da477a53%7Cf38ba9d8554c48a2ae4213b1e7f3c797%7C0%7C0%7C637780823036525180%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=Fn7pJ5EAgXXyqFcPBl1NljHVQDpwyfshvjb5NwUtwBM%3D&reserved=0" target="_blank">
doi.org</a>:10.1002/psp4.12479<br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt;font-family:Arial,sans-serif"><br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<div>
<p><span style="font-size:12pt;font-family:Arial,sans-serif">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</span><span style="font-size:12pt;color:black;background:yellow"> </span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt;font-family:Roboto;color:rgb(33,33,33)">Viceconti M, Emili L, Afshari P, et al. Possible Contexts of Use for In Silico Trials Methodologies: A Consensus-Based Review.
<i>IEEE J Biomed Health Inform</i>. 2021;25(10):3977-3982. doi:10.1109/JBHI.2021.3090469</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<div>
<p><span style="font-size:12pt;font-family:Roboto;color:rgb(33,33,33)"><br>
<br>
</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt;font-family:Roboto;color:rgb(33,33,33)"><br>
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</span><span style="font-size:12pt"><u></u><u></u></span></p>
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<p><span style="font-size:12pt;font-family:Roboto;color:rgb(33,33,33)">All the best
</span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt;font-family:Roboto;color:rgb(33,33,33)">Alexander</span><span style="font-size:12pt"><u></u><u></u></span></p>
</div>
</div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
<div>
<div>
<p><span style="font-size:12pt">On Sun, 19 Dec 2021 at 03:10, Jacob Barhak <<a href="mailto:jacob.barhak@gmail.com" target="_blank">jacob.barhak@gmail.com</a>> wrote:<u></u><u></u></span></p>
</div>
<blockquote style="border-top:none;border-right:none;border-bottom:none;border-left:1pt solid rgb(204,204,204);padding:0in 0in 0in 6pt;margin-left:4.8pt;margin-right:0in">
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Greetings to the paper contributors,<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<div>
<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">Here is a checklist for revisions required:<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<ol start="1" type="1">
<li><span style="font-size:12pt"> We should discuss the references that reviewer 1 raised and add them as reference<u></u><u></u></span></li><li><span style="font-size:12pt">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?<u></u><u></u></span></li><li><span style="font-size:12pt">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 <u></u><u></u></span></li><li><span style="font-size:12pt">Reviewer 1 asked for additional graphics - I am unsure how to address this beyond ur current diagram - ideas will help<u></u><u></u></span></li><li><span style="font-size:12pt">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.<u></u><u></u></span></li><li><span style="font-size:12pt">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<u></u><u></u></span></li><li><span style="font-size:12pt">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.<u></u><u></u></span></li><li><span style="font-size:12pt"> 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.<u></u><u></u></span></li><li><span style="font-size:12pt">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. <u></u><u></u></span></li><li><span style="font-size:12pt">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. <u></u><u></u></span></li><li><span style="font-size:12pt">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.<u></u><u></u></span></li><li><span style="font-size:12pt">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."<u></u><u></u></span></li><li><span style="font-size:12pt">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. <u></u><u></u></span></li></ol>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">I will start the discussion threads on specific topics. Hopefully we can get it done quickly.<u></u><u></u></span></p>
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<p><span style="font-size:12pt"> Jacob<u></u><u></u></span></p>
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<p><span style="font-size:12pt">- <u></u><u></u></span></p>
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<p><span style="font-size:12pt">########### Original Reviews #############<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">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. <u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<p><span style="font-size:12pt">Reviewer 1: <u></u><u></u></span></p>
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<p><span style="font-size:9pt;font-family:"Lucida Grande",sans-serif;color:rgb(62,61,64)">Recommendation for the Editor: </span><span style="font-size:12pt">Substantial revision is required<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">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.<br>
Within the manuscript some typos and missing information are present.<br>
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:<br>
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.<br>
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.<br>
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.<br>
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.<br>
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.<br>
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.<br>
The authors should also fix some grammar and writing typos present in the "Contribution to the field" section.<u></u><u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
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<div style="border-right:none;border-bottom:none;border-left:none;border-top:1pt solid rgb(217,217,217);padding:0in;outline:0px">
<div>
<div>
<p><span style="font-size:12pt">a. Is the quality of the figures and tables satisfactory?<br>
- No<br>
<br>
b. Does the reference list cover the relevant literature adequately and in an unbiased manner?<br>
- No<br>
<br>
c. Does this manuscript refer only to published data? (unpublished or original data is not allowed for this article type)<br>
- Yes<br>
<br>
d. Does the review include a balanced, comprehensive, and critical view of the research area?<br>
- Yes<u></u><u></u></span></p>
</div>
</div>
</div>
<div style="margin-left:15pt;margin-top:7.5pt;outline:0px">
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
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<div style="margin-left:15pt;margin-top:7.5pt;outline:0px">
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div style="margin-left:15pt;margin-top:7.5pt;outline:0px">
<p><span style="font-size:12pt">Reviewer 2<u></u><u></u></span></p>
</div>
<div style="margin-left:15pt;margin-top:7.5pt;outline:0px">
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div style="margin-left:15pt;margin-top:7.5pt;outline:0px">
<p><span style="font-size:12pt">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.<u></u><u></u></span></p>
</div>
<div style="margin-left:15pt;margin-top:7.5pt;outline:0px">
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">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:<br>
<br>
Major comments<br>
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.<br>
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.<br>
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?<br>
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.<br>
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.<br>
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?<br>
7. Model Application and Implementation Barriers: This section seems unnecessary and out of place.<br>
8. There are grammar and punctuation errors scattered throughout; please edit carefully.<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">a. Is the quality of the figures and tables satisfactory?<br>
- Not Applicable<br>
<br>
b. Does the reference list cover the relevant literature adequately and in an unbiased manner?<br>
- Yes<br>
<br>
c. Does this manuscript refer only to published data? (unpublished or original data is not allowed for this article type)<br>
- Yes<br>
<br>
d. Does the review include a balanced, comprehensive, and critical view of the research area?<br>
No answer given.<u></u><u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
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<p><span style="font-size:12pt"><u></u> <u></u></span></p>
</div>
<div>
<p><span style="font-size:12pt">========<u></u><u></u></span></p>
</div>
</div>
</div>
</div>
<p><span style="font-size:12pt">_______________________________________________<br>
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