Using ultra-widefield red channel images to improve the detection of ischemic central retinal vein occlusion

Akinori Sato; Ryo Asaoka; Shin Tanaka; Koichi Nagura; Yui Tanaka; Rei Arasaki; Kazuyoshi Okawa; Shohei Kitahata; Kentaro Nakamura; Shouko Ikeda; Tatsuya Inoue; Yasuo Yanagi; Maiko Maruyama-Inoue; Kazuaki Kadonosono

doi:10.1371/journal.pone.0260383

Peer Review History

Original SubmissionJune 11, 2021
24 Sep 2021 Decision Letter - Alon Harris, Editor PONE-D-21-19313Using ultra-widefield red channel images to improve the detection of ischemic central retinal vein occlusionPLOS ONE Dear Dr. Tatsuya Inoue, 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 October 23. 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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We will update your Data Availability statement to reflect the information you provide in your cover letter [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: No 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: There is a great discrepancy between the results and the interpretation. Specificity increased at 5 of the 6 reviewers, but interestingly the specificity decreased at the reviewer with the best sensitivity. The sensitivity of the various reviewers has an enormous range from 45 to 90. The sensitivity decreased in 3 of the 6 reviewers. All these facts were not discussed and referred to. You can not just put everything in one pot and masking and ignore the details. Reviewer #2: This is a well-designed and well written article. The authors do a good job of clearly explaining why using red channel imaging can be helpful to determine ischemic vs non ischemic status in eyes with CRVO (especially if no rubeosis present). Can the authors explain in further detail why Groups B and C still included the non-ischemic eyes instead of just analyzing ischemic eyes (with and without rubeosis) separately? It is unclear how much the findings in this paper would change management of ischemic CVRO. Do the authors think PRP or anti-VEGF therapy is warranted earlier in these ischemic CRVO patients as opposed to waiting for rubeosis ? Page 15, line 228: I would tone down the language a bit in this sentence, as “serious” FA induced allergy is actually quite rare (1/3800 for bronchospasm, 1/5300 for cardiovascular events, 1/220k for death). Skin reactions such as urticaria occur in 1.2% of patients but that seems to be a minor adverse event. https://www.jacionline.org/article/S0091-6749(18)30586-4/fulltext ****** 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.] 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.0260383.r001
Revision 1
6 Oct 2021 Author Response Academic Editor PLOS ONE Dear Prof. Alon Harris, We appreciate you and the reviewers for the constructive and insightful comments. Please find our enclosed point-by-point responses (in red) to the reviewers’ comments. We hope that this revision will meet your expectations, and that our revised manuscript will better suit for publication on PLOS ONE. Reviewer #1: There is a great discrepancy between the results and the interpretation. Specificity increased at 5 of the 6 reviewers, but interestingly the specificity decreased at the reviewer with the best sensitivity. The sensitivity of the various reviewers has an enormous range from 45 to 90. The sensitivity decreased in 3 of the 6 reviewers. All these facts were not discussed and referred to. You can not just put everything in one pot and masking and ignore the details. Thank you for the suggestion. As the Reviewer pointed out, the result of sensitivity and specificity of 6 resident investigators was not discussed in detail, therefore we have revised our manuscript as follows. Our result suggests that no significant differences in the sensitivity and the specificity were observed between two imaging modalities in Group A, B and C. This might be due to the data variation and we added the description in the revised manuscript. “In the current study, as shown in Table2, the specificity in 4 of 6 resident investigators increased when using red channel images. On the other hand, one resident investigator with the best sensitivity showed a decreased specificity (Table 2). Furthermore, the sensitivity of resident investigators has an enormous range in the present study. This variation may have resulted in no significant differences in the sensitivity and specificity between two imaging modalities in Group A, B and C. On the other hand, an improvement was observed in the accuracy of diagnosing the ischemic status using red channel imaging in CRVO eyes without rubeosis (Group C), while this was not the case when all the enrolled CRVO eyes were analyzed together (Group A).” Reviewer #2: This is a well-designed and well written article. The authors do a good job of clearly explaining why using red channel imaging can be helpful to determine ischemic vs non ischemic status in eyes with CRVO (especially if no rubeosis present). Can the authors explain in further detail why Groups B and C still included the non-ischemic eyes instead of just analyzing ischemic eyes (with and without rubeosis) separately? Thank you for the comment and we are sorry for the confusion. In the current study, we first compared the sensitivity and specificity associated with two types of images between ischemic (rubeotic + non-rubeotic) and non-ischemic CRVO eyes using Group A. However, no significant improvement in sensitivity and specificity when using red channel images was seen in Group A and no significant correlation was observed between the types of images (color or red channel image) and the accuracy of predictions. Therefore, we next divided ischemic group into rubeotic and non-rubeotic groups and statistical analyses were performed using Group B (non-ischemic + rubeotic) and Group C (non-ischemic + non-rubeotic). As a result, a significant correlation was observed between the types of images and the accuracy of predictions in Group C (p=0.026, linear mixed model). The reason why the improvement of prediction was seen only in Group C still remains unclear, however it is possible that the existence of rubeosis may have made the color fundus image sufficient to discriminate ischemic status in CRVO eyes. On the other hand, red channel image might be useful to detect the ischemic status in eyes without rubeosis, compared to color fundus image. It is unclear how much the findings in this paper would change management of ischemic CVRO. Do the authors think PRP or anti-VEGF therapy is warranted earlier in these ischemic CRVO patients as opposed to waiting for rubeosis ? Thank you for the insightful comment. As mentioned in the Discussion, one-third of non-ischemic CRVO eyes have been reported to convert to ischemic CRVO during the 3-year’s follow-up. On the other hand, it is clinically often experienced that it is difficult to detect the ischemic eyes without a delay, because fluorescein angiography cannot be performed in all cases. The current results imply that it is clinically relevant to examine the ischemic status using the red channel image, not only the conventional colour images, so that eyes needing the fluorescein angiography is detected more accurately. . Page 15, line 228: I would tone down the language a bit in this sentence, as “serious” FA induced allergy is actually quite rare (1/3800 for bronchospasm, 1/5300 for cardiovascular events, 1/220k for death). Skin reactions such as urticaria occur in 1.2% of patients but that seems to be a minor adverse event. https://www.jacionline.org/article/S0091-6749(18)30586-4/fulltext Thank you for the comment. According to the Reviewer’s suggestion, we have toned down the sentence. Attachments Attachment Submitted filename: Comment to PLos One.docx https://doi.org/10.1371/journal.pone.0260383.r002
9 Nov 2021 Decision Letter - Alon Harris, Editor Using ultra-widefield red channel images to improve the detection of ischemic central retinal vein occlusion PONE-D-21-19313R1 Dear Dr. Tatsuya Inoue, 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, Alon Harris 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 #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: Yes 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: (No Response) Reviewer #2: The authors have sufficiently addressed my concerns from the original review. I recommend acceptance without modification. ****** 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: No Reviewer #2: Yes:** Rehan M Hussain https://doi.org/10.1371/journal.pone.0260383.r003
Formally Accepted
15 Nov 2021 Acceptance Letter - Alon Harris, Editor PONE-D-21-19313R1 Using ultra-widefield red channel images to improve the detection of ischemic central retinal vein occlusion Dear Dr. Inoue: 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. Alon Harris Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0260383.r004

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