Respiratory frequency-tunable dynamic imaging for lung function: New exam method using chest X-ray cine imaging considering various respiratory diseases

Takehiko Abe; Norifumi Yoshida; Tetsuo Shimada; Masanao Nakashima; Atsushi Nagai

doi:10.1371/journal.pone.0276859

Peer Review History

Original SubmissionNovember 30, 2021
9 Aug 2022 Decision Letter - Aleksandra Barac, Editor PONE-D-21-37867A proposed new examination method using chest X-ray cine imaging: Respiratory frequency-tunable imaging for lung function visualization by Fourier analysis considering various respiratory diseases, including COVID-19PLOS ONE Dear Dr. Abe, 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 Sep 23 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. 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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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: Thank you for your valuable work. The authors presented an interesting research work of respiratory frequency-tunable imaging aiming to apply in lung function visualization as a suggested new method of investigation. The new examination method, as the authors explained, will be a fruitful alternative to the traditional pulmonary function testing in situations where there is a fear of infection transmission during a pandemic like the current SARS COV2, also, in cases when the patient is unable to do the forced maneuver due to weakness or a probable contraindication. I appreciated this idea especially the manuscript is also well presented, and the authors followed a good scientific approach. Title: • Informative, reflects the paper’s content. Abstract: • Well written, well structured, informative. Introduction: • Adequate background information. • References are adequate. • Stated the specific study objectives. • Writing is clear and concise. Methods: • The outcome variables are well described. • The measurement procedures as well as statistical methods chosen are appropriate. • The writing is clear. Results: • The data are well presented, well written. Discussion: • Well presented, good writing. • Adequate references and comparative discussion. References: • Adequate and appropriately cited. • The authors adopted recent references. Tables: are clear. Figures: are clear. Videos are reasonable and of acceptable quality. Reviewer #2: Τhe authors in this interesting study aimed to assess respiratory function using continuous fluoroscopic images during breathing. Their method presents some advantages as less exposure than scintigraphy and CT, and no need for contrast media. The idea is intriguing – although the concept not entirely novel. They present nicely their technique and I see from the literature that they have experience on this field. However, I have some concerns both for the method and for the paper itself. The authors have not provided evidence that the method is comparable in terms of physiology or clinical usefulness with other established tests. The paper is rather a technical report and it could be presented better in this form. In more detail 1. Title. The title is too long 2. Abstract. It does not represent well the paper, especially in the section of results. Conclusions are also not well supported by the results and the section for an abstract is long. 3. Purpose. The purpose is rather confusing as it is expressed in the text. 4. Methods. The authors should define better their primary outcome, independent and dependent variables and method of their assessment. 5. Results. Based on the aim of the study, one expects that that there will be a correlation between the results of the presented method and spirometry. However, I do not see such a test but a brief report for some cases. The authors should either quantify the results of continuous fluoroscopy so they can correlate them with spirometry. Either wise if they cannot quantify the results of the test in a simple variable they should pick another hypothesis i.e. continuous fluoroscopy correlates with exercise capacity i.e. 6mwt, BODE etc 6. The authors present no evaluation of agreement between observers. 7. Discussion. I think that there are some main points that have to be depicted in this study. Feasibility, simplicity, variability of the interpretation of the results, physiologic meaning and clinical utility. I believe that authors should attempt to provide answers to the above in a clear way. 8. To my view a key point in discussion is in the paragraph where the authors report that the signals in patients with COPD generally differed, causing partial signal reduction and becoming a mosaic signal. As COPD became more severe, there was a reduction in heterogeneity and global signals which may reflect the lung-wide heterogeneity, segmental changes, and global hypointense changes due to the progression of lung fibrosis and emphysematous changes caused by COPD. I agree but the authors should provide more insight for the production of the signal. They use a technique that reflects regional ventilation differences which may not correlate so well with dynamic flows (i.e. FEV1). There are other physiologic elements in COPD which might be related to ventilation inequalities such as IC, FRC, iPEEP, Compliance. I suggest that, at the end, ventilation inequalities could be better reflected in exercise capacity. In this respect I suggest to correlated the technique with a variable that reflects exercise capacity. ****** 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: Hesham Atef AbdelHalim Reviewer #2: Yes: DEMOSTHENES MAKRIS ******** [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". 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Revision 1
13 Oct 2022 Author Response Answer for Reviewer 1 Thank you for your valuable work. The authors presented an interesting research work of respiratory frequency-tunable imaging aiming to apply in lung function visualization as a suggested new method of investigation. The new examination method, as the authors explained, will be a fruitful alternative to the traditional pulmonary function testing in situations where there is a fear of infection transmission during a pandemic like the current SARS COV2, also, in cases when the patient is unable to do the forced maneuver due to weakness or a probable contraindication. I appreciated this idea especially the manuscript is also well presented, and the authors followed a good scientific approach. Title: • Informative, reflects the paper’s content. Abstract: • Well written, well structured, informative. Introduction: • Adequate background information. • References are adequate. • Stated the specific study objectives. • Writing is clear and concise. Methods: • The outcome variables are well described. • The measurement procedures as well as statistical methods chosen are appropriate. • The writing is clear. Results: • The data are well presented, well written. Discussion: • Well presented, good writing. • Adequate references and comparative discussion. References: • Adequate and appropriately cited. • The authors adopted recent references. Tables: are clear. Figures: are clear. Videos are reasonable and of acceptable quality. Thank you very much for your good comments. Answer for Reviewer 2 The authors in this interesting study aimed to assess respiratory function using continuous fluoroscopic images during breathing. Their method presents some advantages as less exposure than scintigraphy and CT, and no need for contrast media. The idea is intriguing – although the concept not entirely novel. They present nicely their technique and I see from the literature that they have experience on this field. However, I have some concerns both for the method and for the paper itself. The authors have not provided evidence that the method is comparable in terms of physiology or clinical usefulness with other established tests. The paper is rather a technical report and it could be presented better in this form. Thank you very much for your comments. We will respond to your individual points as follows. 1. Title. The title is too long Thank you very much for your comments. Based on your remarks, we will change the title to the following. Respiratory frequency-tunable dynamic imaging for lung function: New exam method using chest X-ray cine imaging considering various respiratory diseases 2. Abstract. It does not represent well the paper, especially in the section of results. Conclusions are also not well supported by the results and the section for an abstract is long. Thank you very much for your comments. Based on your remarks, we have revised the Results in the Abstract. The revisions are shown below. The mean total dose for all volunteers was 0.2 mGy. There was no major discrepancy in the detection of lung field geometry, and no diagnostic problems were noted by the radiologist and physician. 3. Purpose. The purpose is rather confusing as it is expressed in the text. Thank you very much for your suggestion. We will change the first section to Introduction, and the Purpose will also be listed in the Introduction. 4. Methods. The authors should define better their primary outcome, independent and dependent variables and method of their assessment. Thank you very much for your suggestion. The following text has been added to the Materials and Methods section as the primary outcome. The primary outcome of this study is listed below. 1) XP is a three-dimensional structure, with thicker areas in front and behind having higher signal, and thinner areas having lower signal. 2) Whether the structure is drawn at the beginning of breathing, bronchus -> bronchioles -> alveoli, alveoli -> bronchioles -> bronchus according to the momentum during breathing. 3) Does the signal change along the wave of respiration and its depth? 4) Exclude artifact (rib artifact, lobular fissure artifact, diaphragm or mediastinum, hilum artifact) 5. Results. Based on the aim of the study, one expects that that there will be a correlation between the results of the presented method and spirometry. However, I do not see such a test but a brief report for some cases. The authors should either quantify the results of continuous fluoroscopy so they can correlate them with spirometry. Either wise if they cannot quantify the results of the test in a simple variable they should pick another hypothesis i.e. continuous fluoroscopy correlates with exercise capacity i.e. 6mwt, BODE etc Thank you very much for your attention. The following sentences have been added to the Limitation in Discussion section. In this study, the FEV1 was used to clinically perform GOLD classification to determine the grade of COPD. Based on these results, we are comparing the results with the images. The correlation is not calculated due to the small sample size and the fact that this is not the focus of this study. 6. The authors present no evaluation of agreement between observers. Since the judgment in this study was made jointly by radiologists and respiratory physicians, individual judgment was not made. Therefore, the following text has been added to the Limitation. The visual evaluations were ultimately judged jointly by the radiologist and the respiratory physician. 7. Discussion. I think that there are some main points that have to be depicted in this study. Feasibility, simplicity, variability of the interpretation of the results, physiologic meaning and clinical utility. I believe that authors should attempt to provide answers to the above in a clear way. Thank you for your suggestion. Based on your suggestion, we have added the following sentences to the Discussion. The method presented in this study can be performed with all angiography and fluoroscopy equipment, provided that continuous fluoroscopic images can be stored, images can be taken under fixed fluoroscopic conditions, and images can be output in DICOM, respectively. In addition, images can be output in as little as 5 minutes. Although some issues, such as rib delineation, may cause variability in interpretation of results, this method seems to be one major indicator. 8. To my view a key point in discussion is in the paragraph where the authors report that the signals in patients with COPD generally differed, causing partial signal reduction and becoming a mosaic signal. As COPD became more severe, there was a reduction in heterogeneity and global signals which may reflect the lung-wide heterogeneity, segmental changes, and global hypointense changes due to the progression of lung fibrosis and emphysematous changes caused by COPD. I agree but the authors should provide more insight for the production of the signal. They use a technique that reflects regional ventilation differences which may not correlate so well with dynamic flows (i.e. FEV1). There are other physiologic elements in COPD which might be related to ventilation inequalities such as IC, FRC, iPEEP, Compliance. I suggest that, at the end, ventilation inequalities could be better reflected in exercise capacity. In this respect I suggest to correlated the technique with a variable that reflects exercise capacity. Thank you for your suggestion. Based on your suggestion, we have added the following sentences to the Discussion. The signal was generated in accordance with the periodic component of respiration of XP, thus removing the periodic component of blood flow, the frequency components of other organs, and the synthetic wave component. The evaluation of each frequency is different from the focus of this study and may be necessary in other work. The imbalance of ventilation is of course an issue, and together with the dynamics of pulmonary blood flow, which is evaluated at the same time, is likely to be reflected in cardiopulmonary function and exercise capacity, but this is not the focus of this study. The relevance of this finding to the way patients move is an issue for the future. In this study, we first took data from patients with COPD. Although there are other physiological factors in COPD that are associated with ventilatory imbalance, it is future work to reflect these factors in the testing methods presented in this paper. Attachments Attachment Submitted filename: Response_to_Reviewers.docx https://doi.org/10.1371/journal.pone.0276859.r002
17 Oct 2022 Decision Letter - Aleksandra Barac, Editor Respiratory frequency-tunable dynamic imaging for lung function: New exam method using chest X-ray cine imaging considering various respiratory diseases PONE-D-21-37867R1 Dear Dr. Abe, 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, Aleksandra Barac Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276859.r003
Formally Accepted
27 Oct 2022 Acceptance Letter - Aleksandra Barac, Editor PONE-D-21-37867R1 Respiratory frequency-tunable dynamic imaging for lung function: New exam method using chest X-ray cine imaging considering various respiratory diseases Dear Dr. Abe: 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. Aleksandra Barac Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276859.r004

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