Variation in aorta attenuation in contrast-enhanced CT and its implications for calcification thresholds

Sven A. Holcombe; Steven R. Horbal; Brian E. Ross; Edward Brown; Brian A. Derstine; Stewart C. Wang

doi:10.1371/journal.pone.0277111

Peer Review History

Original SubmissionJune 30, 2022
9 Sep 2022 Decision Letter - Jianhong Zhou, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-22-18603Variation in baseline aorta attenuation in contrast-enhanced CT and its implications for calcification thresholdsPLOS ONE Dear Dr. Horbal, 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 Oct 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: 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: General Comments The authors assessed variation in baseline and contrast-enhanced aorta attenuation in CT and its implications for calcification thresholds. They found that uniform CT thresholds for calcified plaques incur high rates of pixel classification errors in contrast-enhanced scans, which can be minimized using dynamic thresholds based on local aorta attenuation. In addition, they found that females had higher aorta attenuation than males in contrast-enhanced scans but not in non-contrast scans and that weight was negatively correlated with aorta attenuation. The main strength of this study is that imaging tools, which allow risk assessment for cardiovascular diseases, could reduce cardiovascular events due to timely reduction of risk factors and timely onset of therapy. The main weakness is that some findings of this study are already well known and that there is no information on how the model introduced by the authors (dynamic thresholds based on local aorta attenuation) influenced cardiovascular risk prediction in their patient population. Specific Comments 1. Title. As also variation in attenuation in contrast-enhanced CT and not only in baseline aorta attenuation was assessed the title should be adapted. 2. Materials and Methods. Patient Populations. Clear inclusion and exclusion criteria should be provided, additionally visualized with a flow chart. 3. Materials and Methods. Calcification Analysis. This section is confusing. It is not clear how false-negatives and false-positives were assessed. Parts of this section should also be included in the Patient population section. 4. Results. Information on how dynamic thresholds based on local aorta attenuation improved cardiovascular risk prediction compared to uniform CT thresholds in the study population would be very interesting. Reviewer #2: Thank you for this interesting manuscript, which raises optimal contrasting in different contrast phases to an epidemiologic level. Interesting general observations were made, such as that women generally require a smaller amount of contrast than men and that the formulas used today do not ideally reflect the lean body weight that should be used. Here, I would suggest that you propose a factor, based on your data, of what percentage less contrast agent could be used in women compared to men. In addition, the issue of automatic plaque classification is very important because it can be used to derive prognostic values that can be applied to individuals as part of risk stratification and the next step of risk prevention. Certainly, there has been similar work in the past, but this appears to be of high professional quality. Abstract. OK Introduction: may be shortened, but ok Results: ok Diskussion: ok Conclusion: justified, ok ****** 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: Yes: PD Dr. Christoph Artzner ******** [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.0277111.r001
Revision 1
19 Sep 2022 Author Response 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 We have reviewed the journal requirements and believe they are consistent with those outlined by PLOS One. Our file names have been renamed. Thank you. 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. The IRB approval was included, and we agree was not thorough enough. We have added the additional sentence and reflects the situation. “All data was anonymized prior to review and IRB review included the waiving of informed consent due to the retrospective nature of the data”. 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. We have included a caption for the supporting information file at the end of the manuscript. Reviewer #1: General Comments The authors assessed variation in baseline and contrast-enhanced aorta attenuation in CT and its implications for calcification thresholds. They found that uniform CT thresholds for calcified plaques incur high rates of pixel classification errors in contrast-enhanced scans, which can be minimized using dynamic thresholds based on local aorta attenuation. In addition, they found that females had higher aorta attenuation than males in contrast-enhanced scans but not in non-contrast scans and that weight was negatively correlated with aorta attenuation. The main strength of this study is that imaging tools, which allow risk assessment for cardiovascular diseases, could reduce cardiovascular events due to timely reduction of risk factors and timely onset of therapy. The main weakness is that some findings of this study are already well known and that there is no information on how the model introduced by the authors (dynamic thresholds based on local aorta attenuation) influenced cardiovascular risk prediction in their patient population. Thank you for thorough review of our manuscript. While we agree that some of this information is known, this work provides a mechanism by which the individualized aortic attenuation determines the calcification threshold for more accurate identification of calcification, not necessarily risk prediction in the patient population. The ability to compare heterogenous scans in various contrast phases are important towards harmonizing cardiovascular cohorts, regardless of contrast status, as well as building individualized, unbiased, cardiovascular risk prediction models, Specific Comments 1. Title. As also variation in attenuation in contrast-enhanced CT and not only in baseline aorta attenuation was assessed the title should be adapted.\\ Please see that we have removed the word ‘baseline’ from the title. The "baseline” here is intended to delineate the vessel attenuation within the subluminal space wherein contrast material may directly influence attenuation (as opposed to the lumen or other regions of the vessel wall which may accumulate calcification). We chose this term rather than the less accessible “subluminal attenuation” since our target audience includes algorithm developers as much as clinical professions. 2. Materials and Methods. Patient Populations. Clear inclusion and exclusion criteria should be provided, additionally visualized with a flow chart. We have added a flow chart to clear up the inclusion criteria—these include 3 already existing cohorts that we have cited more in-depth descriptions of in other published work. We also added “already existing” to the first sentence of the patient population paragraph. No exclusion criteria were utilized. We hope this clears up any potential confusion. 3. Materials and Methods. Calcification Analysis. This section is confusing. It is not clear how false-negatives and false-positives were assessed. Parts of this section should also be included in the Patient population section. Fair comment. To reduce confusion, we have retitled this section “Calcification threshold analysis”. Please note that our paper does not assess false-negatives and false-positives of, say, vascular disease or other clinical outcome which might be tabulated at the patient level. Instead, this paper analyses false-negative and false-positive pixels that would be identified (or not) as being part of a calcification site on any given scan. Here, the ground truth against which false positive/negatives are assessed is simply the current established standard threshold of 130 HU when applied to a non-contrast scan. If a given subject has an unusually high attenuation within their aorta (typically due to contrast media) then this established threshold is likely to produce false-positive pixels exceeding this threshold that get identified as calcified plaques by a naïve automatic algorithm. We measure the percentage of their vessel which would (erroneously) be labeled as such. 4. Results. Information on how dynamic thresholds based on local aorta attenuation improved cardiovascular risk prediction compared to uniform CT thresholds in the study population would be very interesting. While we certainly agree this would be ideal, accurate CVD diagnosis for the study population is currently unavailable. We can assure you that there are initiatives to provide greater data interoperability solutions, as well as expert diagnostic mechanisms are being developed by our lab and our working partners for future research capabilities. Reviewer #2: Thank you for this interesting manuscript, which raises optimal contrasting in different contrast phases to an epidemiologic level. Interesting general observations were made, such as that women generally require a smaller amount of contrast than men and that the formulas used today do not ideally reflect the lean body weight that should be used. Here, I would suggest that you propose a factor, based on your data, of what percentage less contrast agent could be used in women compared to men. In addition, the issue of automatic plaque classification is very important because it can be used to derive prognostic values that can be applied to individuals as part of risk stratification and the next step of risk prevention. Certainly, there has been similar work in the past, but this appears to be of high professional quality. Abstract. OK Introduction: may be shortened, but ok Results: ok Diskussion: ok Conclusion: justified, ok Thank you for the flattering assessment of our work. Given the scope of our expertise, we do not believe that we are in an appropriate position to make recommendations for contrast agent dosing. We were surprised to find this higher aortic enhancement in females relative to males but was only obvious after operationalization of the dynamic threshold concept. Given the biases in our study population, as well as institutional protocols, universal recommendations may be unsuitable. As this work is relatively novel, we hope to inspire other researchers to investigate and reproduce these finding in similar patient-serving environments. These may include inter- and multidisciplinary solutions in general medicine, radiology (and nuclear medicine), computer science, biomedical engineering, and other applicable fields. Hopefully, this work generates interest in highlighting this disparity and influences proper solutions. We have added a few sentences to the discussion to encourage further work. Attachments Attachment Submitted filename: R1_Response_to_Reviewers.docx https://doi.org/10.1371/journal.pone.0277111.r002
20 Oct 2022 Decision Letter - Helmut Schoellnast, Editor Variation in aorta attenuation in contrast-enhanced CT and its implications for calcification thresholds PONE-D-22-18603R1 Dear Dr. Horbal, 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, Helmut Schoellnast Guest Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0277111.r003
Formally Accepted
2 Nov 2022 Acceptance Letter - Helmut Schoellnast, Editor PONE-D-22-18603R1 Variation in aorta attenuation in contrast-enhanced CT and its implications for calcification thresholds Dear Dr. Horbal: 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. Helmut Schoellnast Guest Editor PLOS ONE https://doi.org/10.1371/journal.pone.0277111.r004

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