A physiologically-based model of localized mucociliary clearance in the airways

Monica E. Shapiro; Timothy E. Corcoran; Carol A. Bertrand; Robert S. Parker

doi:10.1371/journal.pone.0320103

Peer Review History

Original SubmissionFebruary 24, 2025
20 Jun 2025 Decision Letter - Saidul Islam, Editor Dear Dr. Corcoran, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Aug 04 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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We look forward to receiving your revised manuscript. Kind regards, Saidul Islam, Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf . 2. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, we expect all author-generated code to be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. 3. In the online submission form, you indicated that [Insert text from online submission form here]. All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. 4. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: The authors have developed a unique and novel dynamic model for the mucociliary clearance (MC) to account for heterogeneous probe aerosol deposition patterns and mucus transport. Their future study for their model update to be more completely informed with data from more subjects at different age ranges could be a perfect fit to be published as a following paper in PLOS One. Reviewer #2: This paper describes a novel mathematical method for analyzing the regional deposition, and more to the point, the regional mucociliary clearance of particles deposited in the human lung airways. Applied to pharmaceutical interventions in lung diseases, it can produce a more nuanced measure of clearance activity than the predominant current methods. 1. Page 2, line 34/35. Abstract - “significantly depressed MC rates in CF corresponding to the lower lobe.” Somewhere in the abstract should state this applies to right lung only since only that lung was analyzed. 2. Page 7, line 135. Image Processing- Was the scaling of standard Alcoforado ROIs done by subject height, lung volume, linear dimensions, CT scan? Would that affect pixel size or pixel count? 1. Page 7, line 135. Image Processing- Alcoforado ROIs are presumably done with normal HC, but it is known that CF, over-weights, dense breast tissue can have a different transmission scan profile. In addition, CT scans done supine in Alcoforado models may produce different lung shapes than MC image done recumbent. Could these affect the regional analysis? Or not by much? 2. Page 7, line 140. Image Processing- “corrections for background activity were applied at this point”. This was done after the camera software had done the isotope decay factoring. It has been my contention that the camera decay factor did not include a previous background subtraction, or used a preset background, therefore also decay correcting the background counts, which is incorrect. This calculation would have a disproportionate effect in areas of lower counts, i.e., peripheral, compared to areas of high counts such as large airways or “local hot spots”. Was this effect accounted for during your background subtraction? Or is it moot? Were local regional background counts subtracted or whole lung counts? 3. Page 7, line 147. Image Processing- “Note that the image processing procedures here were different from those used in our previous publication”. This is a creditable warning. This begs two questions though. 1. How is this procedure different from previous, its impact on the change and why the change, or 2. What is the reason for mentioning the previous procedure since it does not apply? 4. Page 8. Image Processing- ““non-clearable activity” which we estimated as the lower 25% quartile of activity…” This may be a completely valid approach, but the use of the value of 25% would benefit from a better explanation for determining this cutoff. Why not choose 5%, 23%, 42% etc.? How does 25% compare to an average value at the end of the study? 5. Page 12, line 260 and Figure 2- It would be beneficial to illustrate in a separate figure how the analysis fits to CF in order to compare/evaluate its relevance. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org https://doi.org/10.1371/journal.pone.0320103.r001
Revision 1
17 Sep 2025 Author Response Reviewer #1: The authors have developed a unique and novel dynamic model for the mucociliary clearance (MC) to account for heterogeneous probe aerosol deposition patterns and mucus transport. Their future study for their model update to be more completely informed with data from more subjects at different age ranges could be a perfect fit to be published as a following paper in PLOS One. We thank the reviewer for their comments. In the future we plan to more completely inform the model and would hope to include a range of ages. Reviewer #2: This paper describes a novel mathematical method for analyzing the regional deposition, and more to the point, the regional mucociliary clearance of particles deposited in the human lung airways. Applied to pharmaceutical interventions in lung diseases, it can produce a more nuanced measure of clearance activity than the predominant current methods. 1. Page 2, line 34/35. Abstract - “significantly depressed MC rates in CF corresponding to the lower lobe.” Somewhere in the abstract should state this applies to right lung only since only that lung was analyzed. Added to the upper portion of the abstract. Line 26 2. Page 7, line 135. Image Processing- Was the scaling of standard Alcoforado ROIs done by subject height, lung volume, linear dimensions, CT scan? Would that affect pixel size or pixel count? The scaling of the ROI was done manually in ImageJ. There are no changes to the image itself made during that scaling so there should be any changes in pixel size. After scaling, pixel counts inside the ROI would be similar to what would be seen with a hand drawn lung outline. I’ve added some words to the methods to make this a bit clearer. 1. Page 7, line 135. Image Processing- Alcoforado ROIs are presumably done with normal HC, but it is known that CF, over-weights, dense breast tissue can have a different transmission scan profile. In addition, CT scans done supine in Alcoforado models may produce different lung shapes than MC image done recumbent. Could these affect the regional analysis? Or not by much? Everything in Alcoforado and in our work was done with participants supine, so that matches. (I’ve corrected our text which originally said recumbent which is less specific than supine.) I think the manual scaling was accurate enough that the standard outlines were well matched to the participant’s lung shape and thus that any differences in regional clearance caused by their use was minimal. 2. Page 7, line 140. Image Processing- “corrections for background activity were applied at this point”. This was done after the camera software had done the isotope decay factoring. It has been my contention that the camera decay factor did not include a previous background subtraction, or used a preset background, therefore also decay correcting the background counts, which is incorrect. This calculation would have a disproportionate effect in areas of lower counts, i.e., peripheral, compared to areas of high counts such as large airways or “local hot spots”. Was this effect accounted for during your background subtraction? Or is it moot? Were local regional background counts subtracted or whole lung counts? I suspect the reviewer is correct that there was not a uniform background subtraction performed as part of the machine’s decay correction and that the machine is therefore decay correcting noise and adding it to the image. As the reviewer is aware, the machine-borne software is somewhat of a black box. We had a single measurement for background that we subtracted from whole lung Technetium counts at all time points. I ran some numbers on this and it seems like the amount of error this would have caused is relatively minimal. The “the decay corrected background” would have amounted to about 2% of the image counts. We have added words to the discussion describing this limitation. 3. Page 7, line 147. Image Processing- “Note that the image processing procedures here were different from those used in our previous publication”. This is a creditable warning. This begs two questions though. 1. How is this procedure different from previous, its impact on the change and why the change, or 2. What is the reason for mentioning the previous procedure since it does not apply? The major difference is the use of anterior and posterior counts with geometric mean correction. We view this specific effort to be exploratory. It made sense to publish the original data using more conventional methods to allow comparisons to previous work. We’ve added some words to explain this major difference. 4. Page 8. Image Processing- ““non-clearable activity” which we estimated as the lower 25% quartile of activity…” This may be a completely valid approach, but the use of the value of 25% would benefit from a better explanation for determining this cutoff. Why not choose 5%, 23%, 42% etc.? How does 25% compare to an average value at the end of the study? We chose this value (which corresponds to 10 data points) as a balance between using sufficient data to mitigate noise in the measurements without losing data to inform the dynamic parameters of the model (the model states can never go below 0 and thus subtracting off too much “non-clearable activity” can result in negative data points that the model cannot fit). We compared using fewer and more data points to define “non-clearable activity” and found 10 points to provide a better balance across all individuals. In grids that have their lowest activity at the end of the study, these values are very comparable, but for grids where the activity increases during the study, the values can be quite different. If we just use the final measurements in those grids, the dynamics all occur at values <0 and thus cannot be fit by our model. 5. Page 12, line 260 and Figure 2- It would be beneficial to illustrate in a separate figure how the analysis fits to CF in order to compare/evaluate its relevance. We have added the suggested figure with model fits to CF individuals. While we did not use the CF individuals for model development, the new figure highlights the applicability of using this model in that population. Attachments Attachment Submitted filename: Corcoran cover revision 8-2025.docx https://doi.org/10.1371/journal.pone.0320103.r002
15 Oct 2025 Decision Letter - Saidul Islam, Editor A Physiologically-based Model of Localized Mucociliary Clearance in the Airways PONE-D-25-07038R1 Dear Dr. Corcoran, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Saidul Islam, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0320103.r003
Formally Accepted
Acceptance Letter - Saidul Islam, Editor PONE-D-25-07038R1 PLOS ONE Dear Dr. Corcoran, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr Saidul Islam Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0320103.r004

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