Automated extracellular volume fraction measurement for diagnosis and prognostication in patients with light-chain cardiac amyloidosis

In-Chang Hwang; Eun Ju Chun; Pan Ki Kim; Myeongju Kim; Jiesuck Park; Hong-Mi Choi; Yeonyee E. Yoon; Goo-Yeong Cho; Byoung Wook Choi

doi:10.1371/journal.pone.0317741

Peer Review History

Original SubmissionJune 6, 2024
6 Nov 2024 Decision Letter - Giuseppe Limongelli, Editor PONE-D-24-22784Automated Extracellular Volume Fraction Measurement for Diagnosis and Prognostication in Patients with Light-Chain Cardiac AmyloidosisPLOS ONE Dear Dr. Hwang, Thank you for submitting your manuscript to PLOS ONE and apologise for the delay in revising it. 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 Dec 21 2024 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Giuseppe Limongelli 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 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 2. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. 3. Thank you for stating in your Funding Statement: This work was supported by the Medical AI Clinic Program through the National IT Industry Promotion Agency (NIPA) funded by the Ministry of Science and ICT (MSIT) of the Republic of Korea, and by research grants from Seoul National University Bundang Hospital (Grant No. 02-2017-0040 and 06-2020-0130). Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. 4. Thank you for stating the following in the Competing Interests section: Pan Ki Kim and Byoung Wook Choi are founders of Phantomics, Inc. (Seoul, Korea), which supports the software used in this study; however, they did not participate in the data analysis. The other authors declare no conflicts of interest. We note that one or more of the authors are employed by a commercial company: Phantomics, Inc. (Seoul, Korea) a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests) . If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf. 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments Dear author I apologise for the delay in the revision process. please find attached reviewers' comments below. [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: the authors present an interesting study on the ability of AI automated segmentation T1 mapping to detect cardiac amyloidosis (CA) in patients with LVH. Also, they show that automated ECV measurements in patients with AL-CA improve prognostication of the disease. It would be useful to clarify few points: - were the patients with suspicion of LVH consecutive patients referred for MRI due to LVH ? if not, why? - why was prognostic value of ECV calculated only for AL patients and not for ATTR as well? Reviewer #2: The authors present a study on the use of a artificial intelligence (AI) -based T1 mapping in 300 patients diagnosed with left ventricular hypertrophy (LVH). CMR AI-based T1-mapping was able to detect cardiac amyloidosis (CA) and provided prognostic information in those with AL-CA. The potential use of AI based T1-mapping and automated extracellular volume (ECV) calculation in diagnosis and prognostication of LVH is clinically relevant. While I understand quantitative assessment of LGE was not available to the authors, it would be useful to include how many patients presented with LGE and the distribution in the myocardium. Also,, CMR-derived LVEF and LVEDV measures should be included in Table 1. Finally it should be highlighted in the limitations that there is no testing/validation cohort and the results might not be generalisable. ****** 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.0317741.r001
Revision 1
1 Dec 2024 Author Response *** Please refer to the attached "Response Letter". ================================= Point-by-point Responses to Reviewer #1 Comments to Author: General comment The authors present an interesting study on the ability of AI automated segmentation T1 mapping to detect cardiac amyloidosis (CA) in patients with LVH. Also, they show that automated ECV measurements in patients with AL-CA improve prognostication of the disease. Response to the general comment We thank the reviewer’s considerate review and comments. We believe that the revision processes have further improved the strengths of our study. We tried our best to clarify the raised comments, and if the issues were not able to be addressed within the present study, we honestly acknowledged the limitations of our study, in order to provide appropriate background information for the readers. We just hope that the revised version with responses to the reviewer can better comply with the publication standards of PLOS ONE. Comment #1 It would be useful to clarify few points: were the patients with suspicion of LVH consecutive patients referred for MRI due to LVH ? If not, why? Response to comment #1 We sincerely thank the reviewer for this valuable comment. In the present study, we identified consecutive patients who underwent cardiac MRI for differential diagnosis of the etiology, between 2011 and 2023. In the revised manuscript, we indicated that the study population was retrospectively identified on a consecutive manner. Changes in accordance with comment #1 • Abstract (page 2): A total of 300 consecutive patients who underwent CMR for differential diagnosis of LVH were analyzed. • Methods – Study design and cohort (page 4): We retrospectively identified 300 consecutive patients (47 with HHD, 198 with HCM, 50 with CA [39 with AL-CA, and 11 with TTR-CA], and 5 with Fabry disease [FD]) (Fig 1) who underwent CMR for differential diagnosis of the etiology, based on the detection of LVH on echocardiography, between 2011 and 2023. Comment #2 Why was prognostic value of ECV calculated only for AL patients and not for ATTR as well? Response to comment #2 Thank you for your valuable feedback. Among the total 300 consecutive patients who underwent CMR for differential diagnosis of LVH, we have found 50 patients with cardiac amyloidosis, consisting of 39 patients with AL-CA and 11 patients with TTR-CA. Those 11 patients with TTR-CA were further divided according to the subtype of TTR: 3 patients with hereditary TTR-CA (genetic; hATTR) and 8 patients with wild-type TTR-CA (senile; wtATTR). Given the number of patients in each ATTR subgroup (hATTR and wtATTR), we performed survival analysis among the total 11 patients with TTR-CA according to the ECV. Although we could not obtain statistically significant results due to the small number of patients, it was observed that the patients with TTR-CA and higher ECV levels (automated ECV ≥40%) tended to have higher risk of composite outcomes (cardiovascular death and heart failure hospitalization) compared to those with lower ECV levels (<40%). In the revised manuscript, we added these findings as Supplementary results and provided interpretations in the Limitation section, as below: Changes in accordance with comment #2 • Results (page 16): Prognostic value of ECV in patients with TTR. The prognostic value of the automated ECV was further assessed in patients with TTR-CA. Among the 11 patients with TTR-CA included in the present study (3 with hereditary TTR-CA [genetic; hATTR] and 8 with wild-type TTR-CA [senile; wtATTR]), 1 patient died of cardiovascular cause and 6 patients experienced hospitalization for heart failure. The AUC values for the study outcome using the automated native T1 and ECV were 0.600 (95% CI 0.226–0.974; p=0.584) and 0.700 (95% CI 0.376–1.000; p=0.273), respectively. These patients with TTR-CA were dichotomized according to the median value of automated ECV (40%), and the prognosis was compared between those with ECV <40% and those with ECV ≥40% (S4 Fig.). Although we could not obtain statistically significant results due to the small number of patients, it was observed that the patients with TTR-CA and higher ECV levels (automated ECV ≥40%) tended to have higher risk of composite outcomes (cardiovascular death and heart failure hospitalization) compared to those with lower ECV levels (<40%) (Log-rank p=0.218; unadjusted HR 3.629, 95% CI 0.405–32.556, p=0.250). • S4 Fig. Event-free survival of patients with TTR-CA according to the automated ECV • Limitation (page 21): Second, the prognostic value of T1 mapping parameters was assessed only among the patients with AL-CA, but not for those with other etiologies. We observed a trend toward worse prognosis in patients with TTR-CA and higher ECV (automated ECV ≥40%) compared to those with lower ECV; however, the number of TTR-CA cases in this study was limited to 11, necessitating future studies for statistically meaningful analysis. Patients with HCM and HHD did not experience sufficient number of events, and the number of patients with FD was too small for further analysis. ================================= Point-by-point Responses to Reviewer #2 Comments to Author: General comment The authors present a study on the use of an artificial intelligence (AI) -based T1 mapping in 300 patients diagnosed with left ventricular hypertrophy (LVH). CMR AI-based T1-mapping was able to detect cardiac amyloidosis (CA) and provided prognostic information in those with AL-CA. The potential use of AI based T1-mapping and automated extracellular volume (ECV) calculation in diagnosis and prognostication of LVH is clinically relevant. Response to the general comment We appreciate the reviewer’s thoughtful comments and feedback. We believe that the revision process has helped enhance the strengths of our study. We have made every effort to address the comments raised, and where certain issues could not be fully resolved within the scope of this study, we have acknowledged these limitations to provide readers with a clear context. We hope that the revised version now aligns more closely with the publication standards of PLOS ONE. Comment #1 While I understand quantitative assessment of LGE was not available to the authors, it would be useful to include how many patients presented with LGE and the distribution in the myocardium. Comment #2 Also, CMR-derived LVEF and LVEDV measures should be included in Table 1. Response to comments #1 and #2 We sincerely thank the reviewer for this valuable comment. According to the reviewer’s advice, we have added the assessment of LGE, as well as LV volumetric measures. The LV-EDV was the smallest in patients with AL-CA (74.0±24.9 mL), followed by those with TTR-CA (81.2±24.4 mL), and was the largest in patients with Fabry disease (107.7±57.8 mL). LV-EF was similar across the subgroups of HHD, HCM, and Fabry disease, but was significantly lower in patients with AL-CA (59.0±11.0%). It was noted that LGE was observed in most of the patients with HCM (97.0%), AL-CA (97.4%), TTR-CA (100.0%), and Fabry disease (80.0%), whereas 40% of patients with HHD had LGE, which mainly showed focally-distributed patchy LGE. Typically, patients with AL-CA and TTR-CA showed diffuse distribution of LGE with subendocardial ring-type enhancement, and patients with HCM showed focal or multifocal distribution of LGE with patchy segmental enhancement. It was noted that the extent and distribution pattern of LGE were not associated with study outcomes, because of the typically similar LGE patterns observed in patients with AL-CA (35 patients [89.7%] of AL-CA had diffuse LGE with subendocardial ring-type distribution). In the revised manuscript, we added descriptions regarding the LV volumetric measures and LGE assessment findings in the Methods section, Results section, Limitations section, and Table 1, as below. Changes in accordance with comments #1 and #2 • Methods (pages 6 – 7): LGE extent was categorized into focal (localized distribution), multifocal (distribution across several locations), and diffuse (involving at least three contiguous myocardial segments). Additionally, the distribution patterns were classified into six distinct types and analyzed as follows; patchy segmental, transmural, mid-layer, RV insertion point, subendocardial ring, and nonspecific. • Results (page 9): The mean LVMI was 118.7±33.7 g/m2 in patients with HHD, 134.9±32.7 g/m2 in those with HCM, 134.0±36.1 g/m2 in those with AL-CA, 143.0±54.0 g/m2 in those with TTR-CA, and 162.2±80.2 g/m2 in those with FD. LV-EDV measured by CMR was smallest in patients with AL-CA (74.0±24.9 mL), followed by those with TTR-CA (81.2±24.4 mL), and largest in patients with Fabry disease (107.7±57.8 mL). LV-EF measured by CMR was comparable among patients with HHD, HCM, and Fabry disease but was significantly lower in those with AL-CA (59.0±11.0%). LGE was observed in the majority of patients with HCM (97.0%), AL-CA (97.4%), TTR-CA (100.0%), and Fabry disease (80.0%). In contrast, only 40% of patients with HHD showed LGE, which primarily presented as focal, patchy enhancement. Patients with AL-CA and TTR-CA typically exhibited diffuse LGE with a subendocardial ring-like pattern, while those with HCM demonstrated focal or multifocal LGE with patchy, segmental enhancement. Patients with CA had the highest native T1 values (1444.6±83.4 msec in AL-CA, and 1418.3±72.8 msec in TTR-CA), followed by patients with HCM (1319.4±56.9 msec), and those with HHD (1291.4±38.9 msec), and patients with FD (1143.9±80.3 msec) (Fig 3A). • Results (page 13): The extent and distribution pattern of LGE were not associated with the study outcomes due to the predominantly similar LGE patterns observed in patients with AL-CA: specifically, 35 patients (89.7%) with AL-CA exhibited diffuse LGE with a characteristic subendocardial ring-type distribution (Table 1 and S1 Table). • Limitations (page 21): Third, while the qualitative assessment of LGE, including its distribution and pattern, proved useful for differentiating LVH etiologies in our study population, it was not employed for prognostication due to the typically similar LGE patterns observed in patients with AL-CA. Additionally, we could not provide a quantitative assessment of LGE in this study. Instead, we focused on the clinical usefulness of the automated T1 mapping parameters by DL algorithm. Nonetheless, we acknowledge that future studies on the radiomics features of LGE in the automated CMR interpretation are warranted. • Revised Table 1. Baseline characteristics • Revised S1 Table. Univariable predictors of the composite outcome among patients with AL-CA Comment #3 Finally, it should be highlighted in the limitations that there is no testing/validation cohort and the results might not be generalisable. Response to comment #3 We agree with the reviewer’s valuable comment. According to the reviewer’s advice, we added in the limitation that, because of the lack of testing/validation cohorts, our findings should be interpreted with caution and might not be generalizable in other study populations or different clinical settings. Changes in accordance with comment #3 • Limitations (page 21): Finally, due to the absence of a testing or validation cohort in this study, our findings should be interpreted with caution and warrant prospective validation in terms of improving the diagnostic process and prognosis. ================================= Point-by-point Responses to the Journal Requirements: Item #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 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 Response to Item #1 In the revised manuscript, we followed the PLOS ONE’s style requirements. Item #2 Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. Response to Item #2 According to the PLOS ONE’s guidelines on code sharing, we provided the codes for statistical analyses in the revised manuscript files (https://github.com/Inchang-Hwang/CMR-ECV-for-AL-CA). Regarding the automated measurements of native T1 and ECV on cardiac MR images, we believe that the deep learning algorithm for automatically measuring native T1 and ECV in cardiac MRI images is not directly relevant to the content of this study, as it is incorporated into an analysis program whose accuracy has already been validated in multiple prior studies (Ref: Korean J Radiol. 2022;23(12):1251-9 / Korean J Radiol. 2023;24(5):395-405). Additionally, as this analysis program, which includes the deep learning algorithm, is commercialized by Phantomics Inc., we ask for your understanding that specific details cannot be disclosed due to company confidentiality. Below is the revised Data Availability Statement. • Data availability statement: Data used in this study cannot be made publicly available because of the strict ethical restrictions set by the IRB of Seoul National University Bundang Hospital (https://e-irb.snubh.org). Please contact the corresponding authors (inchang.hwang@gmail.com or humandr@snubh.org) or the ethics board at SNUBH (snubhirb@gmail.com) for further inquiries regarding data availability within the scope permitted by the IRB. The code for statistical analysis utilized in the present study was released (https://github.com/Inchang-Hwang/CMR-ECV-for-AL-CA). Item #3 Thank you for stating in your Funding Statement: This work was supported by the Medical AI Clinic Program through the National IT Industry Promotion Agency (NIPA) funded by the Ministry of Science and ICT (MSIT) of the Republic of Korea, and by research grants from Seoul National University Bundang Hospital (Grant No. 02-2017-0040 and 06-2020-0130). Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. Response to Item #3 We confirm that there was no additional external funding received for this study. According to the journal’s requirements, we amended Funding Statement, Competing Interests Statement, and Author Contributions Statement, as below: • Funding: This work was supported by the Medical AI Clinic Program through the National IT Industry Promotion Agency (NIPA), funded by the Ministry of Science and ICT (MSIT) of the Republic of Korea, and by research grants from Seoul National University Bundang Hospital (Grant Nos. 02-2017-0040 and 06-2020-0130). Pan Ki Kim and Byoung Wook Choi are founders of Phantomics, Inc. (Seoul, Korea), which provided support for the software used in this study. Phantomics, Inc. also funded salaries for PKK and BWC but had no role in the study design, data collection, analysis, publication decisions, or manuscript preparation. The specific contributions of each author are detailed in the ‘author contributions’ section. No additional external funding was received for this study. • Competing Interests: Pan Ki Kim and Byoung Wook Choi are founders of Phantomics, Inc. (Seoul, Korea), which provided support for the software used in this study. Phantomics, Inc. also funded salaries for PKK and Attachments Attachment Submitted filename: Response letter_PLOS One_R1.docx https://doi.org/10.1371/journal.pone.0317741.r002
6 Jan 2025 Decision Letter - Giuseppe Limongelli, Editor Automated extracellular volume fraction measurement for diagnosis and prognostication in patients with light-chain cardiac amyloidosis PONE-D-24-22784R1 Dear Dr. In-Chang Hwang 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Giuseppe Limongelli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0317741.r003
Formally Accepted
9 Jan 2025 Acceptance Letter - Giuseppe Limongelli, Editor PONE-D-24-22784R1 PLOS ONE Dear Dr. Hwang, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Giuseppe Limongelli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0317741.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .