Whole body MRI in multiple myeloma: Optimising image acquisition and read times

Saurabh Singh; Elly Pilavachi; Alexandra Dudek; Timothy J. P. Bray; Arash Latifoltojar; Kannan Rajesparan; Shonit Punwani; Margaret A. Hall-Craggs

doi:10.1371/journal.pone.0228424

Peer Review History

Original SubmissionSeptember 16, 2019
13 Nov 2019 Decision Letter - Pascal A. T. Baltzer, Editor PONE-D-19-26051 Whole Body MRI in Multiple Myeloma: Optimising Image Acquisition and Read Times PLOS ONE Dear Professor Hall-Craggs, 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. We would appreciate receiving your revised manuscript by Dec 28 2019 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Pascal A. T. Baltzer, M.D. Academic Editor PLOS ONE Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. 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 http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.1371journal.pone.0180562 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed. 3. We have noticed that you report some instances of p = 0. Since this is not strictly possible, please report the exact p value in your results. 4. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere: The cohort of patients has been studied in previously published work. Two publications by Latifoltojar et al in 2017 studied 21 out of 30 patients in the context of changes in quantitative imaging biomarkers in response to treatment. A previous study by Bray et al 2017, studied the detection of myeloma lesions on pre-contrast imaging in this cohort. This study differs from both as we studied all available imaging including DWI and post contrast Dixon imaging in the entire 30 patient cohort. We have also included new patient by patient analysis, not performed in the paper by Bray et al 2017. We have also focussed on MR value. We have measured read times for the scans for different readers, allowing estimation of time saving if scans are selectively reviewed.. Please clarify whether this [conference proceeding or 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. [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: 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: 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: A complete full body protocol is used as a reference. In comparison, the individual sequences are analyzed sequentially. They are examined in detail with regard to their diagnostic accuracy. Finally, it is examined whether the combination of the best with the less important sequence offers an incremental benefit. This approach is generally convincing and worthy of being published. This is all the more true, since the data obviously come from a database that has already been published, which is, however, sufficiently noted. A few points of criticism I would like to mention which should be addressed by the authors. 1. It should be made clear that this is an artificially shortened protocol. In fact, the full state-of-the-art protocol includes more sequences (https://doi.org/10.1148/radiol.2019181949, figure 1). In this respect, the reference standard is somewhat misleading and the actual accuracy of the sequences is presumably lower. 2. The authors mainly focus on parameters of lesion detection (sensitivity and PPV etc.). Just as important - especially in the context of efficiency - are the negative ratings. As far as I can see, these can also be analyzed by the data, which in my opinion should be revised. 3. The terminology efficiency and effectiveness is clearly defined, highly relevant, but unfortunately - in my opinion - not outlined clearly enough in the paper. In fact, the authors convincingly demonstrate that the shortening of the full protocol produces a significantly worse diagnostic result: E.g. lesion count / sensitivity of DWI = 72 %, which means a 28% worse detection rate vs. the gold standard. This, in turn, was not measured completely (see above). Of course, it is impossible to examine all this in one paper, but it should be named more clearly and discussed more objectively. This is all the more true in the context of the clinical relevance: The exact definition of the lesion load is vital for optimized outcome (etc.) as mentioned by the authors. 4. "Fat and water image reconstructions are mandatory and should be used to generate fat fraction maps": this clear statement in the above-mentioned cited paper is somewhat contradictory to the authors' conclusions. This, too, should be quite discussed. 5. The analysis of reading time is highly relevant and should be clearer presented. In every multiparametric analysis, one sequence is read as a "main sequence" and the other parameters are evaluated as add-ons. A simple addition of the reading times as given by the independent read is thus misleading in a certain way, but at least it overestimates the potential time saving effect. 6. CNR analysis: How were lesions not detectable in all sequences analyzed. A more detailed explanation is recommended. 7. Discussion: “increased (...) morbidity for patients” introduced by contrast agents. Unclear sentence. In which context side effects of CA could play a clinically relevant role in the management of MM patients? 8. Since MRI is a multiparametric method and will probably remain so, according to the data of the authors, a more detailed presentation of the data regarding the combination of several sequences is desirable ("determine which image types add diagnostic value"). 9. Bland Altman analysis of the key results is recommended for better assessment of a proportional or systematic bias. 10. The main result is potential time savings for a different MRI protocols. I recommend to present these results more clearly in a graphical illustration. Reviewer #2: Dear authors, i have read your paper with great interest as there is only few data on evaluating specific sequences in WB/MRI in MM. I have found methodology, reporting and the conclusions drawn concise and comprehensible. I would like to ask you to comment on a. if there was any histopathologic correlation or consequent work-up by PET/CT in these 30 patients and b. if the readers have had ADC maps when evaluation DWI. Overall my recommendation would be: minor revisions. With my best regards ****** 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: No Reviewer #2: No [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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0228424.r001
Revision 1
13 Dec 2019 Author Response Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. 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 http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf The guidelines have been reviewed and followed. 2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.1371journal.pone.0180562 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed. Outside the methods (and we have acknowledged and referenced the previous paper [15]), there is very little overlapping text as the results are of a different study. All sources have been cited. 3. We have noticed that you report some instances of p = 0. Since this is not strictly possible, please report the exact p value in your results. The p values recorded as p = 0.000 have been amended to p<0.001. 4. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere: The cohort of patients has been studied in previously published work. Two publications by Latifoltojar et al in 2017 studied 21 out of 30 patients in the context of changes in quantitative imaging biomarkers in response to treatment. A previous study by Bray et al 2017, studied the detection of myeloma lesions on pre-contrast imaging in this cohort. This study differs from both as we studied all available imaging including DWI and post contrast Dixon imaging in the entire 30 patient cohort. We have also included new patient by patient analysis, not performed in the paper by Bray et al 2017. We have also focussed on MR value. We have measured read times for the scans for different readers, allowing estimation of time saving if scans are selectively reviewed.. Please clarify whether this [conference proceeding or 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. I think that the covering letter quoted from above was confusing and misleading. The paragraph below has been expanded to make it clear that the data submitted in the current study are new. Apologies for the confusion. “The CURRENT SUBMITTED study differs from both (the previous studies ) as we studied all available imaging including DWI and post contrast Dixon imaging in the entire 30 patient cohort. We have also included new patient by patient analysis, not performed in the paper by Bray et al 2017. We have also focussed on MR value. We have measured read times for the scans for different readers, allowing estimation of time saving if scans are selectively reviewed.” We confirm that the new data included in the submitted paper have not been published elsewhere and this is not duplicate publication. Response to Comments to the Author Reviewer #1: A complete full body protocol is used as a reference. In comparison, the individual sequences are analyzed sequentially. They are examined in detail with regard to their diagnostic accuracy. Finally, it is examined whether the combination of the best with the less important sequence offers an incremental benefit. This approach is generally convincing and worthy of being published. This is all the more true, since the data obviously come from a database that has already been published, which is, however, sufficiently noted. A few points of criticism I would like to mention which should be addressed by the authors. 1. It should be made clear that this is an artificially shortened protocol. In fact, the full state-of-the-art protocol includes more sequences (https://doi.org/10.1148/radiol.2019181949, figure 1). In this respect, the reference standard is somewhat misleading and the actual accuracy of the sequences is presumably lower. In the paper referred to by the reviewer, a different protocol was used to the one described in our study. We do not routinely image the spine, but if there is any abnormality seen in the spine on the Dixon and diffusion images, we go on to do dedicated spine images as an additional procedure. This saves time and is supported by data from the paper from our group authored by Latifoltojar (reference 16). We do routinely do T2 images, but the main reason for doing the T2 is to assess for extramedullary disease and for treatment response following chemotherapy. In the current paper we have not included the T2 images as it well established in the literature, and in general practice, that for patients before treatment the T2 images are non-contributory for the assessment of bone lesions over and above diffusion and Dixon images. We have clarified in the text the use of T2 images. “Although other sequences were acquired during the standard whole body protocol, these were not included for assessment as these are acquired mainly for assessment of extramedullary disease (axial T2) and for measurement of response to therapy (T2, ADC and fat fraction maps before and after treatment).” 2. The authors mainly focus on parameters of lesion detection (sensitivity and PPV etc.). Just as important - especially in the context of efficiency - are the negative ratings. As far as I can see, these can also be analyzed by the data, which in my opinion should be revised. In our cohort all our patients had a high clinical suspicion of myeloma and our current study was to compare the performances of different sequences and not the performance of whole body MRI. To do this we have to take a lesion and compare it on different sequences – we cannot take ‘no lesion’ [= true negative] and compare this between sequences. Consequently in this study we have no ‘true negatives’ as we are labelling lesions and not patients. We have true positives, false positives and false negatives. True negatives do not exist within this study. 3. The terminology efficiency and effectiveness is clearly defined, highly relevant, but unfortunately - in my opinion - not outlined clearly enough in the paper. In fact, the authors convincingly demonstrate that the shortening of the full protocol produces a significantly worse diagnostic result: E.g. lesion count / sensitivity of DWI = 72 %, which means a 28% worse detection rate vs. the gold standard. This, in turn, was not measured completely (see above). Of course, it is impossible to examine all this in one paper, but it should be named more clearly and discussed more objectively. This is all the more true in the context of the clinical relevance: The exact definition of the lesion load is vital for optimized outcome (etc.) as mentioned by the authors. We agree this is an important point. We have added a sentence to elaborate on why we think preferentially reading DWI and post contrast would lead to increased reporting efficiency in the Discussion “This can be supplemented by review of the other imaging sequences, particularly where identifying a further lesion would impact on patient management. As commented above, identifying a second lesion in a patient with smouldering myeloma would have greater impact on disease management that identifying an additional lesion in a patient where multiple lesions were already seen. This reading strategy would reduce overall read times in some patients.” 4. "Fat and water image reconstructions are mandatory and should be used to generate fat fraction maps": this clear statement in the above-mentioned cited paper is somewhat contradictory to the authors' conclusions. This, too, should be quite discussed. We do understand this point and agree that it is a relative limitation of our study. However fat fraction maps most useful in a clinical setting for measuring disease response to therapy, and our study was about identifying lesions in disease and not quantifying response to treatment. We have added a paragraph to clarify this. “In our study we have not assessed the use of fat fraction maps as in clinical practise these are used for assessment of disease response during therapy, rather than for initial lesion identification.” 5. The analysis of reading time is highly relevant and should be clearer presented. In every multiparametric analysis, one sequence is read as a "main sequence" and the other parameters are evaluated as add-ons. A simple addition of the reading times as given by the independent read is thus misleading in a certain way, but at least it overestimates the potential time saving effect. We agree this is a limitation of the way reading time was measured. However as each individual image type was being assessed, we did not use a ‘’locked sequential read”. We have added a sentence expanding on this within the limitations section. “Reading times were recorded per image type. However in clinical practice, two or more types of images may be reviewed in parallel. Consequently simply summating reading times gives an indication of the potential time saving, but is not a precise measurement of time saved to read a whole scan.” 6. CNR analysis: How were lesions not detectable in all sequences analyzed. A more detailed explanation is recommended. For measurement of CNR we selected lesions which were visible on all sequences. This has been clarified in the manuscript. Percent Contrast and Contrast-to-Noise Ratio In patients with at least three focal lesions greater than 5 mm in diameter, visible on all image types, percent contrast and contrast-to-noise ratio (CNR) were calculated using a previously described method (11). 7. Discussion: “increased (...) morbidity for patients” introduced by contrast agents. Unclear sentence. In which context side effects of CA could play a clinically relevant role in the management of MM patients? We have altered this sentence as we agree that following the cases of NSF, and the introduction of new guidelines for administration of IV contrast, there should be no increase in morbidity other than contrast reactions. 8. Since MRI is a multiparametric method and will probably remain so, according to the data of the authors, a more detailed presentation of the data regarding the combination of several sequences is desirable ("determine which image types add diagnostic value"). We agree that this would be interesting, but is beyond the scope of this study which was directed towards lesion detection. A different study would be needed to address diagnostic value/outcome analysis. 9. Bland Altman analysis of the key results is recommended for better assessment of a proportional or systematic bias. We do not feel that Bland Altman would be the appropriate test of our data. Bland Altman is fundamentally an analysis of agreement. We are using a reference ‘gold’ standard and so we can simply compare this with other sequences. 10. The main result is potential time savings for a different MRI protocols. I recommend to present these results more clearly in a graphical illustration. We have not really compared different MRI protocols in this study, we used one protocol only, and so it would be difficult to compare this graphically – as this is not fundamentally what we have measured. We have looked at lesion detection and read time for different sequences, and these are presented numerically in the text. Reviewer #2: Dear authors, i have read your paper with great interest as there is only few data on evaluating specific sequences in WB/MRI in MM. I have found methodology, reporting and the conclusions drawn concise and comprehensible. I would like to ask you to comment on a. if there was any histopathologic correlation or consequent work-up by PET/CT in these 30 patients and b. if the readers have had ADC maps when evaluation DWI. Overall my recommendation would be: minor revisions. Thank you for your positive review. The patients had their bone marrow examined but focal lesions were not biopsied. The readers did not have ADC maps to review although these were automatically produced by the vendor software. As with most read protocols, the long b value diffusion images are used for lesion detection (the focus of this study) whereas ADC maps and change in ADC are used for assessment of treatment response. Attachments Attachment Submitted filename: Response to Reviewers .docx https://doi.org/10.1371/journal.pone.0228424.r002
15 Jan 2020 Decision Letter - Pascal A. T. Baltzer, Editor Whole Body MRI in Multiple Myeloma: Optimising Image Acquisition and Read Times PONE-D-19-26051R1 Dear Dr. Hall-Craggs, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, Pascal A. T. Baltzer, M.D. 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: Dear authors, i am happy with the manuscript as it is right now and i have no further questions. Best regards. ****** 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.0228424.r003
Formally Accepted
23 Jan 2020 Acceptance Letter - Pascal A. T. Baltzer, Editor PONE-D-19-26051R1 Whole Body MRI in Multiple Myeloma: Optimising Image Acquisition and Read Times Dear Dr. Hall-Craggs: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Pascal A. T. Baltzer Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0228424.r004

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