Plantar threshold sensitivity assessment using an automated tool—Clinical assessment comparison between a control population without type 2 diabetes mellitus, and populations with type 2 diabetes mellitus, with and without neuropathy symptoms

Vitale Kyle Castellano; Jon Commander; Thomas Burch; Hayden Burch; Jessica Remy; Benjamin Harman; Michael E. Zabala

doi:10.1371/journal.pone.0286559

Peer Review History

Original SubmissionAugust 3, 2022
13 Oct 2022 Decision Letter - Yaodong Gu, Editor PONE-D-22-20166Plantar threshold sensitivity assessment using an automated tool - Clinical assessment comparison between a control population without type 2 diabetes mellitus, and populations with type 2 diabetes mellitus, with and without neuropathy symptomsPLOS ONE Dear Dr. Castellano, 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 Nov 27 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Yaodong Gu 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. We note that you have a patent relating to material pertinent to this article. Please provide an amended statement of Competing Interests to declare this patent (17027464), along with any other relevant declarations relating to employment, consultancy, patents, products in development or modified products etc. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. This information should be included in your cover letter; we will change the online submission form on your behalf. 3. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. [Yes, the clinical data from the control subjects was included in a publication currently in review in a different journal. The other paper was primarily concerned about device performance, but I did present the comparison between the control subject's sensitivity and their medical characteristics. However this paper compares the control subjects' results to those from type 2 diabetic groups and draws conclusions based on the differences between the groups. The paper being submitted to PLOS ONE does use similar calculations and methods from the other pending manuscript, but the statistical analysis is different and the goal of this paper is to draw conclusions about how diabetics affects threshold sensitivity, while the other paper is more focused on device performance.] Please clarify whether this publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript. Additional Editor Comments: Please describe the sample selection criteria. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Overall, this study addresses an important public health and Diabetes Complications Diabetic peripheral neuropathy is often classified as a loss of sensation in the extremities, particularly in elderly populations. The most common diagnosis technique is with the use of the hand-applied Semmes-Weinstein monofilament. This study’s first aim was to quantify and compare sensation on the plantar surface in healthy and Type 2 diabetes mellitus (DM2) populations with the standard Semmes-Weinstein hand-applied methodology and a tool that automates this approach. The second was to evaluate correlations between sensation and the subjects’ medical characteristics. a) There is no mention of how the sample was selected and what type of sample was being selected (based on convenience sample?). b) What are inclusion and exclusion criteria? c) The response rate was not stated. e) It seems subject participants are voluntary and non-randomly selected which subject and conclusion might be considered as a bias Approximately 22.5% of locations assessed were sensitive to the hand-applied monofilament, yet insensitive to the automated tool. Age and sensation were only significantly correlated in Group 1 (R2=0.3422, P=0.004). Sensation was not significantly correlated with the other medical characteristics per group. Differences in sensation between the groups were not significant (P=0.063). Caution is recommended when using hand-applied monofilaments. Group 1’s sensation was correlated to age. The other medical characteristics failed to corelate with sensation, despite group. The authors should report some of the key limitations of this study in detailed, I think the major concern of this submission is it lacks sufficient novelty and or original study, although, the study does not contribute novel knowledge or add sufficiently to the current literature, but, it would help local policy makers. Reviewer #2: The paper "Plantar threshold sensitivity assessment using an automated tool - Clinical assessment comparison between a control population without type 2 diabetes mellitus, and populations with type 2 diabetes mellitus, with and without neuropathy symptoms" is carefully reviewed. Authors studied the role of an automated tool to determine plantar surface threshold sensitivity in diabetic and non-diabetic subjects. The manuscript sound scientific and ethical enough. The novelty can not be ignored. However, there are few issues that should be revised. - I recommend against use of abbreviations in first mention in the abstract and in the text (Several samples; BMI, ABI, and HbA1c). - Methods expressed very well as did statistical analyses. However, I suggest moving statistics under a Statistical Analyses subheading. - Results make sense and I think objective of the study were met. Tables are informative. Expression of significant p values as bold characters is advised. - Discussion is too short. I recommend discussing similar works along with the results of the present study's results. Moreover, not only limitations, but also strengths of the present work should be mentioned. Lastly, comment on possible clinical translation of the study outcomes. - Twelve of the references listed are older than 10 years. If appropriate, replace them with novel works, please. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Ptrof. Abdulbari BENER Reviewer #2: Yes: Gulali Aktas ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0286559.r001
Revision 1
25 Nov 2022 Author Response Comments from the Editor • Comment 1: "Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming." Response: Thank you for providing the formatting guidelines for PLOS ONE and for the opportunity to submit revisions. The manuscript has been updated to reflect these requirements. • Comment 2: "We note that you have a patent relating to material pertinent to this article. Please provide an amended statement of Competing Interests to declare this patent (17027464), along with any other relevant declarations relating to employment, consultancy, patents, products in development or modified products etc. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. This information should be included in your cover letter; we will change the online submission form on your behalf." Response: Recently the USPTO has granted us a patent on the automated tool under patent US11426121B1. Therefore, this does not alter our adherence to PLOS ONE policies on sharing data and materials. We have updated our cover letter and our declaration of interest statements to reflect this, including the updated patent number. • Comment 3: "We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. [Yes, the clinical data from the control subjects was included in a publication currently in review in a different journal. The other paper was primarily concerned about device performance, but I did present the comparison between the control subject's sensitivity and their medical characteristics. However this paper compares the control subjects' results to those from type 2 diabetic groups and draws conclusions based on the differences between the groups. The paper being submitted to PLOS ONE does use similar calculations and methods from the other pending manuscript, but the statistical analysis is different and the goal of this paper is to draw conclusions about how diabetics affects threshold sensitivity, while the other paper is more focused on device performance.] Please clarify whether this publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript." Response: At this time the other manuscript is still in the review process at the other journal and has not been formally published. We have updated the cover letter to state this and why this other manuscript does not constitute a dual publication. • Comment 4: "Please describe the sample selection criteria." Response: The sample was based on convenience of the medical clinic where the research took place. Subjects were not randomly selected; each subject had to volunteer themselves to be a part of the study. The Populations and exclusion criteria section of the manuscript has been updated to make this clearer. Comments from Reviewer #1 • Comment 1: "There is no mention of how the sample was selected and what type of sample was being selected (based on convenience sample?)." Response: The sample was based on convenience of the medical clinic where the research took place. Subjects were not randomly selected; each subject had to volunteer themselves to be a part of the study. The Populations and exclusion criteria section of the manuscript has been updated to make this clearer. • Comment 2: "What are inclusion and exclusion criteria?" Response: Thank you for your question. The inclusion and exclusion criteria were documented under the Populations and exclusion criteria subheading and the Medical chart review and ABI assessment subheading, both are located in the Materials and Methods of the manuscript. All participants had to have an ABI greater than or equal to 1.0 mmHg and needed to be forty years of age or older. The control subjects had to be non-diabetics. The diabetic groups were grouped based on the presence or absence of neuropathy symptoms. • Comment 3: "The response rate was not stated." Response: Thank you for your comment. Since all subjects volunteered themselves and were not randomly selected from a larger sample there is not a response rate for this study. Our IRB prevented us from directly recruiting subjects. All subjects had to express their interest to participate. • Comment 4: "It seems subject participants are voluntary and non-randomly selected which subject and conclusion might be considered as a bias." Response: Thank you for your insight on this point. This is correct, all subjects voluntarily participated in the study and were not randomly selected. In order to address the bias this poses on the study we have added a study limitations section in the discussion of this manuscript. • Comment 5: "Approximately 22.5% of locations assessed were sensitive to the hand-applied monofilament, yet insensitive to the automated tool. Age and sensation were only significantly correlated in Group 1 (R2=0.3422, P=0.004). Sensation was not significantly correlated with the other medical characteristics per group. Differences in sensation between the groups were not significant (P=0.063). Caution is recommended when using hand-applied monofilaments. Group 1’s sensation was correlated to age. The other medical characteristics failed to corelate with sensation, despite group. The authors should report some of the key limitations of this study in detailed." Response: Thank you for the recommendation on reporting the limitations of this study. We agree that this should be included in our manuscript. A dedicated limitations section has been added to the manuscript as a result of your feedback. • Comment 6: "I think the major concern of this submission is it lacks sufficient novelty and or original study, although, the study does not contribute novel knowledge or add sufficiently to the current literature, but, it would help local policy makers." Response: We would like to thank you for the time you have taken to review our manuscript and to provide valuable feedback. We feel that the device is novel, as it allows for the threshold sensitivity on the plantar surface to be mapped and documented. Although there are similar devices, there are currently no scholarly works that thoroughly depict how these similar devices work and what their limitations are. We feel that we have been very transparent on our automated tool, not only in terms of the design and how it functions but also in the results of the clinical study. The medical findings of our study have also been observed by other researchers, which we feel inadvertently validates this study. Comments from Reviewer #2 • Comment 1: "I recommend against use of abbreviations in first mention in the abstract and in the text (Several samples; BMI, ABI, and HbA1c)." Response: We would like to thank you for the time you have taken to review our manuscript and to offer your feedback. We have updated the abstract to remove the abbreviations. We used hyperglycemia metrics to remove HbA1c from the abstract. However, we feel that ABI, BMI, and HbA1c are very commonplace medical abbreviations and would prefer to leave them in the text and or figures/tables. • Comment 2: "Methods expressed very well as did statistical analyses. However, I suggest moving statistics under a Statistical Analyses subheading." Response: Thank you for this suggestion, we agree that this is a beneficial change and have created a Statistical analyses subheading. • Comment 3: "Results make sense and I think objective of the study were met. Tables are informative. Expression of significant p values as bold characters is advised." Response: The authors agree that bolding the significant p values is beneficial. This was carried out in the text, figure captions, and table 1. • Comment 4: "Discussion is too short. I recommend discussing similar works along with the results of the present study's results. Moreover, not only limitations, but also strengths of the present work should be mentioned. Lastly, comment on possible clinical translation of the study outcomes." Response: Thank you for your suggestion. We have updated our manuscript to include a limitations section, as well as a clinical translations and significance section. As of the time of this manuscript, there are no other works/manuscripts that are similar to this work. Although there are others who have invented similar automated tools for sensation loss evaluation, none of the other devices have been used in a clinical study similar to ours. Outside of other patents, there are some research articles on other inventions, but they are not as transparent with how their devices work and lacked the population size that we had. No other studies have used an automated tool that provides a range of forces to determine the threshold sensitivity for its subjects. We didn’t feel it was necessary to compare our device to the other inventions, since the focus of this paper was to use our automated tool to determine threshold sensitivity and then compare threshold sensitivity to medical characteristics. The goal of this paper was not to be a design paper, but rather a clinical assessment of our automated tool. We focused on comparing our medical results to those observed in other studies using different assessment techniques and general medicinal knowledge. • Comment 5: "Twelve of the references listed are older than 10 years. If appropriate, replace them with novel works, please." Response: After reviewing the twelve references that were older than 10 years, we have removed six of them from our manuscript. We feel that the other references are still relevant to our paper and provided adequate background on neuropathy. We have cited similar devices in our introduction, but there are very few automated tools developed by other researchers. The ones that we did cite did not analyze sensation loss to medical characteristics. Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0286559.r002
20 Mar 2023 Decision Letter - Yaodong Gu, Editor PONE-D-22-20166R1Plantar threshold sensitivity assessment using an automated tool - Clinical assessment comparison between a control population without type 2 diabetes mellitus, and populations with type 2 diabetes mellitus, with and without neuropathy symptomsPLOS ONE Dear Dr. Castellano, 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 May 04 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Hanna Landenmark Staff Editor, PLOS ONE on behalf of Yaodong Gu Academic Editor, PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Note from Staff Editor Hanna Landenmark (hlandenmark@plos.org): Please provide a completely transparent report of the design of the designed automated tool. We feel that without this, the manuscript is not fully reproducible as per PLOS ONE publication criterion number 3 (https://journals.plos.org/plosone/s/criteria-for-publication#loc-3). [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: (No Response) Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I am very pleased to confirm that the authors staisfactorily addressed and responded to my queries. Reviewer #2: Thank you for addressing my comments appropriately. I recommend for publication of the paper in its current form. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Prof. Abdülbari BENER Reviewer #2: Yes: Prof. Gulali Aktas ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0286559.r003
Revision 2
26 Apr 2023 Author Response Comments from the Editor- Submitted April 2023 • Comment 1: 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. Response: Thank you for bringing this to our attention. We have verified that all references are complete and correct and that the Works cited is up to date. The second reviewer requested that we remove all sources older than 10 years, however after careful consideration we only removed 6 of the 12 that were older than 10 years. These sources were validated by sources that were already present in the manuscript and therefore replacements were not needed. The other 6 were left in because they remained relevant and are accurate based on our research and our collective experiences. We did not cite any papers that have been retracted. • Comment 2: Note from Staff Editor Hanna Landenmark (hlandenmark@plos.org): Please provide a completely transparent report of the design of the designed automated tool. We feel that without this, the manuscript is not fully reproducible as per PLOS ONE publication criterion number 3 (https://journals.plos.org/plosone/s/criteria-for-publication#loc-3). Response: Thank you Hanna Landenmark for your time in reviewing our revised manuscript and for responding to my emailing regarding your suggestion. We have added in more details that fully disclosures the automated tool and makes it reproducible. We added specific specifications on the electronics used and added in more supporting details on how the machine operators. Additional figures accompanied these revisions. Previously we have provided all MATLAB and Arduino codes needed to operate the device. We hope these additions are satisfactory for publication in PLOS ONE, which we are very excited and grateful to be in. Comments from the Editor- Submitted November 2022 • Comment 1: Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Response: Thank you for providing the formatting guidelines for PLOS ONE and for the opportunity to submit revisions. The manuscript has been updated to reflect these requirements. • Comment 2: We note that you have a patent relating to material pertinent to this article. Please provide an amended statement of Competing Interests to declare this patent (17027464), along with any other relevant declarations relating to employment, consultancy, patents, products in development or modified products etc. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. This information should be included in your cover letter; we will change the online submission form on your behalf. Response: Recently the USPTO has granted us a patent on the automated tool under patent US11426121B1. Therefore, this does not alter our adherence to PLOS ONE policies on sharing data and materials. We have updated our cover letter and our declaration of interest statements to reflect this, including the updated patent number. • Comment 3: We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. [Yes, the clinical data from the control subjects was included in a publication currently in review in a different journal. The other paper was primarily concerned about device performance, but I did present the comparison between the control subject's sensitivity and their medical characteristics. However this paper compares the control subjects' results to those from type 2 diabetic groups and draws conclusions based on the differences between the groups. The paper being submitted to PLOS ONE does use similar calculations and methods from the other pending manuscript, but the statistical analysis is different and the goal of this paper is to draw conclusions about how diabetics affects threshold sensitivity, while the other paper is more focused on device performance.] Please clarify whether this publication was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript. Response: At this time the other manuscript is still in the review process at the other journal and has not been formally published. We have updated the cover letter to state this and why this other manuscript does not constitute a dual publication. • Comment 4: Please describe the sample selection criteria. Response: The sample was based on convenience of the medical clinic where the research took place. Subjects were not randomly selected; each subject had to volunteer themselves to be a part of the study. The Populations and exclusion criteria section of the manuscript has been updated to make this clearer. Comments from Reviewer #1- Submitted November 2022 • Comment 1: There is no mention of how the sample was selected and what type of sample was being selected (based on convenience sample?). Response: The sample was based on convenience of the medical clinic where the research took place. Subjects were not randomly selected; each subject had to volunteer themselves to be a part of the study. The Populations and exclusion criteria section of the manuscript has been updated to make this clearer. • Comment 2: What are inclusion and exclusion criteria? Response: Thank you for your question. The inclusion and exclusion criteria were documented under the Populations and exclusion criteria subheading and the Medical chart review and ABI assessment subheading, both are located in the Materials and Methods of the manuscript. All participants had to have an ABI greater than or equal to 1.0 mmHg and needed to be forty years of age or older. The control subjects had to be non-diabetics. The diabetic groups were grouped based on the presence or absence of neuropathy symptoms. • Comment 3: The response rate was not stated. Response: Thank you for your comment. Since all subjects volunteered themselves and were not randomly selected from a larger sample there is not a response rate for this study. Our IRB prevented us from directly recruiting subjects. All subjects had to express their interest to participate. • Comment 4: It seems subject participants are voluntary and non-randomly selected which subject and conclusion might be considered as a bias. Response: Thank you for your insight on this point. This is correct, all subjects voluntarily participated in the study and were not randomly selected. In order to address the bias this poses on the study we have added a study limitations section in the discussion of this manuscript. • Comment 5: Approximately 22.5% of locations assessed were sensitive to the hand-applied monofilament, yet insensitive to the automated tool. Age and sensation were only significantly correlated in Group 1 (R2=0.3422, P=0.004). Sensation was not significantly correlated with the other medical characteristics per group. Differences in sensation between the groups were not significant (P=0.063). Caution is recommended when using hand-applied monofilaments. Group 1’s sensation was correlated to age. The other medical characteristics failed to corelate with sensation, despite group. The authors should report some of the key limitations of this study in detailed. Response: Thank you for the recommendation on reporting the limitations of this study. We agree that this should be included in our manuscript. A dedicated limitations section has been added to the manuscript as a result of your feedback. • Comment 6: I think the major concern of this submission is it lacks sufficient novelty and or original study, although, the study does not contribute novel knowledge or add sufficiently to the current literature, but, it would help local policy makers. Response: We would like to thank you for the time you have taken to review our manuscript and to provide valuable feedback. We feel that the device is novel, as it allows for the threshold sensitivity on the plantar surface to be mapped and documented. Although there are similar devices, there are currently no scholarly works that thoroughly depict how these similar devices work and what their limitations are. We feel that we have been very transparent on our automated tool, not only in terms of the design and how it functions but also in the results of the clinical study. The medical findings of our study have also been observed by other researchers, which we feel inadvertently validates this study. Comments from Reviewer #2- Submitted November 2022 • Comment 1: I recommend against use of abbreviations in first mention in the abstract and in the text (Several samples; BMI, ABI, and HbA1c). Response: We would like to thank you for the time you have taken to review our manuscript and to offer your feedback. We have updated the abstract to remove the abbreviations. We used hyperglycemia metrics to remove HbA1c from the abstract. However, we feel that ABI, BMI, and HbA1c are very commonplace medical abbreviations and would prefer to leave them in the text and or figures/tables. • Comment 2: Methods expressed very well as did statistical analyses. However, I suggest moving statistics under a Statistical Analyses subheading. Response: Thank you for this suggestion, we agree that this is a beneficial change and have created a Statistical analyses subheading. • Comment 3: Results make sense and I think objective of the study were met. Tables are informative. Expression of significant p values as bold characters is advised. Response: The authors agree that bolding the significant p values is beneficial. This was carried out in the text, figure captions, and table 1. • Comment 4: Discussion is too short. I recommend discussing similar works along with the results of the present study's results. Moreover, not only limitations, but also strengths of the present work should be mentioned. Lastly, comment on possible clinical translation of the study outcomes. Response: Thank you for your suggestion. We have updated our manuscript to include a limitations section, as well as a clinical translations and significance section. As of the time of this manuscript, there are no other works/manuscripts that are similar to this work. Although there are others who have invented similar automated tools for sensation loss evaluation, none of the other devices have been used in a clinical study similar to ours. Outside of other patents, there are some research articles on other inventions, but they are not as transparent with how their devices work and lacked the population size that we had. No other studies have used an automated tool that provides a range of forces to determine the threshold sensitivity for its subjects. We didn’t feel it was necessary to compare our device to the other inventions, since the focus of this paper was to use our automated tool to determine threshold sensitivity and then compare threshold sensitivity to medical characteristics. The goal of this paper was not to be a design paper, but rather a clinical assessment of our automated tool. We focused on comparing our medical results to those observed in other studies using different assessment techniques and general medicinal knowledge. • Comment 5: Twelve of the references listed are older than 10 years. If appropriate, replace them with novel works, please. Response: After reviewing the twelve references that were older than 10 years, we have removed six of them from our manuscript. We feel that the other references are still relevant to our paper and provided adequate background on neuropathy. We have cited similar devices in our introduction, but there are very few automated tools developed by other researchers. The ones that we did cite did not analyze sensation loss to medical characteristics. Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0286559.r004
19 May 2023 Decision Letter - Yaodong Gu, Editor Plantar threshold sensitivity assessment using an automated tool - Clinical assessment comparison between a control population without type 2 diabetes mellitus, and populations with type 2 diabetes mellitus, with and without neuropathy symptoms PONE-D-22-20166R2 Dear Dr. Castellano, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Yaodong Gu Academic Editor PLOS ONE Additional Editor Comments (optional): The authors have done a good revision. Reviewers' comments: https://doi.org/10.1371/journal.pone.0286559.r005
Formally Accepted
29 Jun 2023 Acceptance Letter - Yaodong Gu, Editor PONE-D-22-20166R2 Plantar threshold sensitivity assessment using an automated tool - Clinical assessment comparison between a control population without type 2 diabetes mellitus, and populations with type 2 diabetes mellitus, with and without neuropathy symptoms Dear Dr. Castellano: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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. If we can help with anything else, please email us at plosone@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 Professor Yaodong Gu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0286559.r006

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