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<p>Hi Jacob, <br>
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<p>Here's what I suggest as a response to the reviewer:</p>
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<p><span><b>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.</b></span></p>
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<p>We agree that the conversion from pfu or TCID50 to individual virions is likely to differ across viruses. The conversion estimates cited in the manuscript are for influenza, and are, to our knowledge, the only attempts to estimate the conversion factor for
any virus. We have clarified that the conversion estimates are for influenza.</p>
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<p>We are not advocating for a standard conversion factor, since the conversion factor likely depends not only on the specific virus, but also conditions such as temperature and pH, which are known to affect viral infectivity (Rowell and Dobrovolny, 2020, Heumann
et al, 2021). Rather, we are advocating for development of new viral measurement techniques, that can more reliably quantify the number of infectious virus present in a sample. We have added this discussion to the text of the manuscript.</p>
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<p>More generally, we are advocating for clarity in the use of units. Sometimes models are used (and published) without specifying the units used for simulation parameters --- this is a practice that needs to be corrected. Tools such as
<span>ClinicalUnitMapping.Com</span> can also be helpful in assuring that standardized units are used for simulation parameters and are converted appropriately when different scales or units are needed. This discussion has also been added to the manuscript.<br>
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<p>[1] Rowell, CER, and Dobrovolny, HM (2020), <i></i><span><i>Energy Requirements for Loss of Viral Infectivity</i>, Food and Environmental Virology,
<span>12, 281-294, doi:<span>10.1007/s12560-020-09439-9</span><br>
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<p>[2] <span>Heumann, R, Duncan, C, Stobart, CC, Kaschner, S (2021) <span><i>Dynamical Differences in Respiratory Syncytial Virus</i>, Bulletin of Mathematical Biology, <span class="cit">84(1), 11</span> doi: <span class="citation-doi">10.1007/s11538-021-00971-8</span><br>
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<p><span><span><b>And changes to the manuscript:</b> <br>
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<div>Unfortunately, units of measure are not yet standardized, an open problem despite many<br>
attempts to resolve it by multiple standardization bodies such as IEEE, CDCIC, and NIST. One indication of the severity of the problem is that a Github search for "unit conversion" shows over a thousand results. Another good example of the severity of the problem
is ClincialTrials.Gov that aggregates quantitative data from around the world and this database shows over 24K different units of measure (Barhak and Schertz, 2019). One attempt at solving this standardization issue using machine learning is ClinicalUnitMapping.com,
yet this project requires more effort.</div>
<div><br>
Unit mismatches become particularly problematic when trying to integrate models across<br>
different spatial or time scales. For example, intracellular processes occur on micrometer spatial scales and seconds to minutes time scales. An in-host, tissue-level model of infection processes operates at millimeter to centimeter distances and hour to day
time scales. When trying to integrate the two into a single multiscale model, care must be taken to ensure appropriate conversion of units when transferring output of one model as input to the other. This broad range of spatial and temporal scales can also
cause computational problems requiring development of new algorithms to make computation more efficient across multiple scales (Jung and Sugita, 2017).
<span style="background-color: rgb(255, 255, 0);">While it is impossible to avoid having to convert units,
</span><span style="background-color: rgb(255, 255, 0);">we are advocating for clarity in the use of units. Sometimes models are used (and published) without specifying the units used for simulation parameters --- this is a practice that needs to be corrected.
Tools such as </span><span style="background-color: rgb(255, 255, 0);">ClinicalUnitMapping.Com</span><span style="background-color: rgb(255, 255, 0);"> can also be helpful in assuring that standardized units are used for simulation parameters and are converted
appropriately when different scales or units are needed. This discussion has also been added to the manuscript</span>.</div>
<div><br>
Lack of standard units for measurement of infectious virions is particularly problematic when trying to develop stochastic viral models. Stochastic models often require that we track individual infectious viral particles, yet it is not clear how the typical
viral titer units of TCID 50 /ml and pfu/ml convert to individual virions. Two attempts have been made to estimate the conversion factor<span style="background-color: rgb(255, 255, 0);">, both for influenza,</span> resulting in estimates of 1 TCID 50 /mL of
nasal wash corresponding to 10 2 -10 5(Handel et. al., 2007) or 3x10 4 -3x10 5 (Perelson et. al., 2012) virions at the site of infection. Such order of magnitude uncertainty in unit conversion makes it difficult to develop accurate model representations of
viral infections. <span style="background-color: rgb(255, 255, 0);">We are not advocating for a standard conversion factor, since the conversion factor likely depends not only on the specific virus, but also conditions such as temperature and pH, which are
known to affect viral infectivity (Rowell and Dobrovolny, 2020, Heumann et al, 2021). Rather, we are advocating for development of new viral measurement techniques, that can more reliably quantify the number of infectious virus present in a sample.</span></div>
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<p>Feel free to edit, or add to as you think might be needed <span>(Jacob or anyone else who has thoughts on this)</span>.</p>
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<p>Hana<br>
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<div class="PlainText">*******************************************************<br>
Dr. Hana Dobrovolny<br>
Associate Professor of Biophysics<br>
Texas Christian University<br>
TCU Box 298840<br>
Fort Worth, TX 76129<br>
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phone: (817) 257-6379 fax: (817) 257-7742<br>
email: h.dobrovolny@tcu.edu<br>
*******************************************************</div>
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<div id="divRplyFwdMsg" dir="ltr"><font style="font-size:11pt" face="Calibri, sans-serif" color="#000000"><b>From:</b> Jacob Barhak <jacob.barhak@gmail.com><br>
<b>Sent:</b> December 20, 2021 5:24 AM<br>
<b>To:</b> Dobrovolny, Hana<br>
<b>Cc:</b> vp-integration-subgroup@lists.simtk.org; vp-reproduce-subgroup@lists.simtk.org<br>
<b>Subject:</b> Unit standardization section</font>
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<p><span style="background-color:#ffff00"><strong>[EXTERNAL EMAIL WARNING]</strong> DO NOT CLICK LINKS or open attachments unless you recognize the sender and know the content is safe.</span></p>
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<div dir="ltr">Hi Hana,
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<div>You and I are the main people contributing to the unit standardization section in the paper, therefore we should try to answer reviewer 2. </div>
<div>Here is the review:</div>
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<div>"</div>
<div>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>
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<div>"</div>
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<div>I think reviewer is asking for clarity what we are suggesting as a solution - I believe that units should be well standardized so a machine will be able to comprehend those - this is why I started ClinicalUnitMapping.Com </div>
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<div>I think the reviewer is asking for a proposed solution the problem you write about - will a tool such as ClinicalUnitMapping.Com help resolve your problem if it reaches maturity or do you have other solutions in mind we can propose to answer the reviewer?</div>
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<div>If you wish to discuss more details, I will be happy to virtually meet</div>
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<div> Jacob</div>
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