Fatty infiltration in cervical flexors and extensors in patients with degenerative cervical myelopathy using a multi-muscle segmentation model

Monica Paliwal; Kenneth A. Weber II; Andrew C. Smith; James M. Elliott; Fauziyya Muhammad; Nader S. Dahdaleh; Jerzy Bodurka; Yasin Dhaher; Todd B. Parrish; Sean Mackey; Zachary A. Smith

doi:10.1371/journal.pone.0253863

Peer Review History

Original SubmissionMay 11, 2021
4 Jun 2021 Decision Letter - Jonathan H Sherman, Editor PONE-D-21-15609 Fatty Infiltration in Cervical Flexors and Extensors in Patients with Degenerative Cervical Myelopathy Using a Multi-Muscle Segmentation Model PLOS ONE Dear Dr. Paliwal, 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 Jul 19 2021 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. 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Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [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: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know 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: Yes 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: This manuscript looks at fatty infiltration of muscles in the neck in normal patients compared to patients with Cervical myelopathy and tries to assess any associations between amount of fatty infiltration and clinical disability as well as to determine if it predicts post surgical recovery. They use 18 patients with DCM and 25 controls. They look at fatty infiltration using MRI sequence with segmentation software Clinical outcomes were measured with the modified Japanese orthopedic association scoring and Nurick Introduction: well written and introduces topic clearly. Cleary lays out objectives of the study Methods: The JoA scores seem high for the DCM group for the most part they seem like high functioning with little symptoms. Is this representative of patients with DCM? Anecdotally I see patients with much lower scores with this pathology and wonder if you would see bigger differences in more severe longstanding pathology. In that same vein it would be important to determine if length of symptoms and how this factored in with MIF and recovery prediction. The failure of patients to improve may be related to how long the damage was present. Discussion: Authors make is seem that they believe the MIF is the cause of the lack of clinical improvement. Doesn’t it make more sense that it is a symptom of damage and is merely a predictor of lack of improvement not a cause. In the discussion line 356-358 authors suggest that in addition to demyelination muscle composition may impact resolution of symptoms after therapeutic interventions. I realize they say may but I think that is still a pretty strong statement with no real evidence. I agree it is necessary to explore this question but it think exploration needs to be done before such a statement is made. but i think that statement should be softened a bit more. Figures are easy to understand. Also how different is this paper from the 2018 paper looking at MFI in multifidus musculature on the surface it seems very similar. authors should bring up older paper in introduction (if they do i missed it) and add how this advances that data. Reviewer #2: This is an interesting foundational work in attempting to use machine learning to assess differences in patients with CSM as compared to controls. The authors present their data clearly, but need to avoid any confusion of causation with association, which is not assessed by their study. For example, this statement in the conclusion is not supported: "Differences in MFI may explain the variability in clinical presentation of symptoms, augment assessments, inform interventions, and enhance healthcare received by patients with DCM" While the authors have only assessed CSM vs controls in this early foundational work, this has the potential to be clinically useful and I hope next steps for the authors will include utilizing this methodology to comparatively assess differential recovery amongst patients with CSM after surgery. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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Revision 1
11 Jun 2021 Author Response Reviewer #1: This manuscript looks at fatty infiltration of muscles in the neck in normal patients compared to patients with Cervical myelopathy and tries to assess any associations between amount of fatty infiltration and clinical disability as well as to determine if it predicts post surgical recovery. They use 18 patients with DCM and 25 controls. They look at fatty infiltration using MRI sequence with segmentation software Clinical outcomes were measured with the modified Japanese orthopedic association scoring and Nurick Introduction: well written and introduces topic clearly. Cleary lays out objectives of the study Methods: The JoA scores seem high for the DCM group for the most part they seem like high functioning with little symptoms. Is this representative of patients with DCM? Anecdotally I see patients with much lower scores with this pathology and wonder if you would see bigger differences in more severe longstanding pathology. We thank the reviewer for this question. We agree the current group of patients is quite high functioning. We did not exclude severe disease. However, there were instances when patients presented with severe myelopathy and intervention was planned in an expeditious manner. We felt that waiting for an opening on MRI calendar date was likely not in the best interest of the patient. Secondly, many of these patients were also, quite anxious, and less amenable to the study. We know these are quite practical reasons, but we always tried to be respectful of the situation and clinical care. We list this as a limitation of our study in line 393-394. Additionally, in patients with severe myelopathy, surgery is often beneficial. However, clinical decision making in the treatment of patients with mild compression is the most variable in clinical practices. With mild disease, there is nuance in understanding the associations between anatomic injury and both symptoms and recovery. We are hoping this is a small step forward in better understanding this group of patients. In that same vein it would be important to determine if length of symptoms and how this factored in with MIF and recovery prediction. The failure of patients to improve may be related to how long the damage was present. This is an excellent question. Cervical myelopathy, like many other musculoskeletal diseases, is a result of slowly progressing degenerative processes. While assessing patient histories, there was quite poor recall about the onset of symptoms. Therefore, we do not feel we can appropriately give an estimate of true symptom duration. We are currently planning to study patients with mild disease who have are treated with conservative care to assess longitudinal changes in MFI. Discussion: Authors make is seem that they believe the MIF is the cause of the lack of clinical improvement. Doesn’t it make more sense that it is a symptom of damage and is merely a predictor of lack of improvement not a cause. In the discussion line 356-358 authors suggest that in addition to demyelination muscle composition may impact resolution of symptoms after therapeutic interventions. I realize they say may but I think that is still a pretty strong statement with no real evidence. I agree it is necessary to explore this question but it think exploration needs to be done before such a statement is made. but i think that statement should be softened a bit more. Figures are easy to understand. We acknowledge this critique. We agree that MFI is only a predictor, and the current work shows an association with lack of clinical improvement. But we do not believe this work shows causation. We have revised the language reflects this. We have removed statements on the impact of MFI on resolution of symptoms. We have modified discussion lines 356-359 as “In this study … pre-surgical MFI in LC muscles is adversely related to post-surgical improvement in clinical scores of mJOA and Nurick. It can be hypothesized that cervical flexor training before and after surgery may promote surgical outcomes …”. Also how different is this paper from the 2018 paper looking at MFI in multifidus musculature on the surface it seems very similar. authors should bring up older paper in introduction (if they do i missed it) and add how this advances that data. This work built upon our previous investigation. A small subset of these patients was previously studied (in 2018 paper) with a less robust technique (manual region of interest analysis for the multifidus muscle). We refer to our 2018 paper in the line 81 in the introduction and in line 121 in methods. The two primary ways this work advances the data are: 1) we previously did not report on specific muscles. The current work assesses MFI in 7 bilateral cervical muscle groups. Given that different muscles of the neck have unique roles and potential contributions to health and disability, we felt this was a significant new contribution. 2) The current work uses machine learning to identify, segment and quantify MFI in these 7 bilateral muscles in a consistent automated method. We demonstrate the application of this new technical contribution for patients with DCM. However, this technique may be used in future studies to identify both normal and abnormal anatomy and in unique disease states. We have added “We build upon our previous work (14) utilizing this multi-muscle model that can be easily applied to the cervical spine in DCM and other pathologies.” at line 409 in conclusion. Reviewer #2: This is an interesting foundational work in attempting to use machine learning to assess differences in patients with CSM as compared to controls. The authors present their data clearly, but need to avoid any confusion of causation with association, which is not assessed by their study. For example, this statement in the conclusion is not supported: "Differences in MFI may explain the variability in clinical presentation of symptoms, augment assessments, inform interventions, and enhance healthcare received by patients with DCM" While the authors have only assessed CSM vs controls in this early foundational work, this has the potential to be clinically useful and I hope next steps for the authors will include utilizing this methodology to comparatively assess differential recovery amongst patients with CSM after surgery. We thank the reviewer for their comments. We agree the results show an association and we are not supportive of causation. The specific sentence that was cited by Reviewer #2 has been fully removed and re-written as “MFI could be a potential biomarker for patient assessments, better candidate selection for surgery and prognosis” in line 401. Further, we have added “Future investigations focusing on predictive utility of fat water imaging should compare differential recovery among patients with DCM after surgery.” in line 402 to note our future directions in exploring a methodology to assess differential recovery, as noted by this reviewer. This work is an early step for us to build upon. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253863.r002
15 Jun 2021 Decision Letter - Jonathan H Sherman, Editor Fatty Infiltration in Cervical Flexors and Extensors in Patients with Degenerative Cervical Myelopathy Using a Multi-Muscle Segmentation Model PONE-D-21-15609R1 Dear Dr. Paliwal, 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, Jonathan H Sherman Academic Editor PLOS ONE Additional Editor Comments (optional): 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: Thanks for the responses and changes to this work. I have no further concerns and look forward to reading future work by this group. ****** 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 #2: No https://doi.org/10.1371/journal.pone.0253863.r003
Formally Accepted
17 Jun 2021 Acceptance Letter - Jonathan H Sherman, Editor PONE-D-21-15609R1 Fatty Infiltration in Cervical Flexors and Extensors in Patients with Degenerative Cervical Myelopathy Using a Multi-Muscle Segmentation Model Dear Dr. Paliwal: 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 Dr. Jonathan H Sherman Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0253863.r004

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