Prediction of recurrent stroke among ischemic stroke patients with atrial fibrillation: Development and validation of a risk score model

Beom Joon Kim; Keon-Joo Lee; Eun Lyeong Park; Kanta Tanaka; Masatoshi Koga; Sohei Yoshimura; Ryo Itabashi; Jae-Kwan Cha; Byung-Chul Lee; Hisanao Akiyama; Yoshinari Nagakane; Juneyoung Lee; Kazunori Toyoda; for the SAMURAI Study Investigators; Hee-Joon Bae; for the CRCS-K Investigators

doi:10.1371/journal.pone.0258377

Peer Review History

Original SubmissionMay 23, 2021
29 Jun 2021 Decision Letter - Adam Wiśniewski, Editor PONE-D-21-16999 Prediction of recurrent stroke among ischemic stroke patients with atrial fibrillation: Development and validation of a risk score model PLOS ONE Dear Dr. Kim, 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 Aug 13 2021 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. 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Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 7. One of the noted authors is a group or consortium "SAMURAI Study Investigators and CRCS-K Investigators". In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. Additional Editor Comments (if provided): I am sorry but we are not able to process the paper in the present form. If You feel You can extensively modify and significantly improve Your paper according to the Reviewer's criticism - we give You a chance for a major revision. [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: Partly ******** 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: This study aimed to develop and test a risk prediction model for recurrent stroke in patients with AF who had experienced an initial stroke. The sample size was sufficient and the methods were sound for answering this question. The authors found that the risk prediction model was not superior to current models of CHADS2 and CHA2DS2-VASC and ATRIA. The authors make reasonable conclusions regarding the need for additional measures/imaging to improve recurrent stroke prediction in these patients. The paper validates the tools in an East Asian Population (Korea and Japan) and therefore this does add to the body of evidence on this topic. The paper is presented in a logical manner and is well written. I have no major comments to make on the paper. Reviewer #2: The Authors tried to develop a comprehensive risk prediction model for recurrent stroke from non-valvular AF stroke patients in Korea and Japan registry database. The model was subsequently externally-validated in another dataset, also from Korea/Japan registry. After carefully validated, both internally and externally, the final model included 21 variables as well as several interaction terms. However, the performance of this model only reached modest performance with unsatisfactory discriminative ability among patients with middle score range, which could not surpass the currently-used popular risk score systems. Since current prediction model contains numerous detailed variables and its application would depend on solid electric medical records and programmed automated calculation, the clinical feasibility could be low under not-outstanding prediction performance. Furthermore, I have some other concerns: 1. There is a crucial diversity between the developmental and validated cohort: the percentage of DOAC use. In the model (Table 2), DOAC use at discharge only revealed 0.29 coefficient, maybe partly related to the low use rate of the developmental cohort. However, years after, in the validated cohort, the percentage of DOAC use abruptly increased. The Authors also addressed this issue and presumed the stroke risk modification in the DOAC era. Hence, the developmental dataset may need to be modified, eg.: using 2015-2016 stroke cohort for further model development. 2. The model was built under "Fine-Gray sub-distribution hazard model". Though reasonable in current risk competing model, the final event estimation rate would be lower, especially the high 1-year mortality rate (16%) was noted in the cohort. This might also affect the model performance. 3. The rating score 1-10 was not appropriately described. Readers could only tell the numerous comprehensive predictors listed in Table 2 and their coefficients. The Authors did not explain how these weighted parameters transformed into 1-10 scores. ****** 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". 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Revision 1
20 Aug 2021 Author Response Rebuttal to the reviewers' comment PLoS One Manuscript ID, PONE-D-21-16999R1 Manuscript title: Prediction of recurrent stroke among ischemic stroke patients with atrial fibrillation: Development and validation of a risk score model Aug 21, 2021 Dear reviewers, Dr. Adam Wiśniewski, editorial staff, and Dr. Emily Chenette We thank you and the referees of PLoS One for taking the time to review our manuscript and giving us a chance to revise the paper. Our responses follow the itemized list of reviewers' and editor's original comments. We are thankful to reviewers and editors for their constructive and helpful suggestions, and we tried our best to meet the scientific and literary level of PLoS One. We also followed all the requests from the editorial office on August 20, 2021. Additionally, we modified several sentences to clarify our point, some of which were not requested by the reviewers and not specified in the rebuttal. The marked version contains all the changes from the previous version of our manuscript. EDITORIAL COMMENTS: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Reply to 1) We read the journal style requirements and followed them as requested. 2. Thank you for including your ethics statement: "The local institutional review boards (IRBs) of all participating centers approved the study with a waiver of consent. Secondary use of the registry data and additional review of medical records for this study were approved by IRBs [B-1705/396-306]." a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the "Ethics Statement" field of the submission form (via "Edit Submission"). Reply to 2) We specified the name of the institution that has given the final approval of this study. The list of all participating centers is provided in the Acknowledgement. Secondary use of the registry data and additional review of medical records for this study were approved by the IRB of Seoul National University Bundang Hospital [B-1705/396-306]. 3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. Reply to 3) We concur with the principle of data sharing led by the PLoS group. Unfortunately, however, we have to write that the source data could not be made publicly available due to legal constraints, specifically the Personal Information Protection Act (2014). No explicit informed consent for public archiving of the pseudonymized source data has been obtained, in which case local regulations preclude public archiving of the data. Pseudonymized data that support the findings of this study are available from the corresponding author, Dr. Hee-Joon Bae, upon request, subsequent approval from the Institutional Review Board of the Seoul National University Bundang Hospital, and completion of a legal data sharing agreement. Link to the full text of the Personal Information Protection Act: https://www.law.go.kr/LSW/lsInfoP.do?chrClsCd=010203&lsiSeq=142563&viewCls=engLsInfoR&urlMode=engLsInfoR#0000 4. Thank you for stating the following in the Financial Disclosure section: "This study was supported by Bristol‒Myers Squibb Korea and the Korea Centers for Disease Control and Prevention (no. 2020ER620200#) granted to HJB and a Grant-in- Aid (H23-Junkanki-Ippan-010) from the Ministry of Health, Labour and Welfare, Japan granted to KT. The funding sources did not participate in any part of the study, from conception to article preparation." We note that you received funding from a commercial source: "Bristol‒Myers Squibb" Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. Within this Competing Interests Statement, please confirm that this 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 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 your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf. Reply to 4) Thank you for pointing out this. We amended the Competing Interests Statement as indicated. 5. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests Reply to 5) This point is duly noted. The competing interests statements were changed along with point #4. 6. 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. Reply to 6) We read the journal style requirements and followed as indicated. 7. One of the noted authors is a group or consortium "SAMURAI Study Investigators and CRCS-K Investigators". In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. Reply to 7) We explicitly stated lead authors for the two study groups and indicated the complete list of participating researchers in the acknowledgments section. Reviewer #1: Reviewer #1: This study aimed to develop and test a risk prediction model for recurrent stroke in patients with AF who had experienced an initial stroke. The sample size was sufficient and the methods were sound for answering this question. The authors found that the risk prediction model was not superior to current models of CHADS2 and CHA2DS2-VASC and ATRIA. The authors make reasonable conclusions regarding the need for additional measures/imaging to improve recurrent stroke prediction in these patients. The paper validates the tools in an East Asian Population (Korea and Japan) and therefore this does add to the body of evidence on this topic. The paper is presented in a logical manner and is well written. I have no major comments to make on the paper. Reply to Reviewer #1) We appreciate Reviewer #1's positive evaluation of our study. Reviewer #2: Reviewer #2: The Authors tried to develop a comprehensive risk prediction model for recurrent stroke from non-valvular AF stroke patients in Korea and Japan registry database. The model was subsequently externally-validated in another dataset, also from Korea/Japan registry. After carefully validated, both internally and externally, the final model included 21 variables as well as several interaction terms. However, the performance of this model only reached modest performance with unsatisfactory discriminative ability among patients with middle score range, which could not surpass the currently-used popular risk score systems. Since current prediction model contains numerous detailed variables and its application would depend on solid electric medical records and programmed automated calculation, the clinical feasibility could be low under not-outstanding prediction performance. Reply to the critique. We appreciate reviewer #2's thoughtful and constructive points. We concur with the critic that our model was not superior to the conventional scores and, in short of its clinical feasibility due to the use of extensive clinical information. Based on the newly developed model's performance, we could infer the following points; 1) However extensive stroke physicians have gathered clinical variables, it is still incapable of accurately predicting stroke survivors' prognosis. 2) The performance of conventional models, including CHADS2, CHA2DS2-VASc, and ATRIA scores, was only par with our model, showing unsatisfactory prediction of recurrent ischemic stroke. In short, by developing an extensive risk prediction model and comparing it to conventional scores, we concluded that further mechanistic information is required to build a more robust and precise risk prediction model, such as brain imaging, serum biomarkers, and cardiac function. Furthermore, I have some other concerns: 1. There is a crucial diversity between the developmental and validated cohort: the percentage of DOAC use. In the model (Table 2), DOAC use at discharge only revealed 0.29 coefficient, maybe partly related to the low use rate of the developmental cohort. However, years after, in the validated cohort, the percentage of DOAC use abruptly increased. The Authors also addressed this issue and presumed the stroke risk modification in the DOAC era. Hence, the developmental dataset may need to be modified, eg.: using 2015-2016 stroke cohort for further model development. Reply to 1) We agree with the reviewer's point. After the efficacy of DOACs was proven through randomized clinical trials around 2011, the widespread use of DOACs began after 2015, when the reimbursement of DOACs by the Korean government was started. Thus, it was impossible to gather patients with atrial fibrillation taking vitamin K antagonists instead of DOACs in Korea and Japan. Additionally, DOAC became the treatment of choice for the prevention of recurrent ischemic events after stroke. Therefore, it is more appropriate to validate the estimated recurrent stroke risk in patients with DOACs. Lastly, most clinical trials reported the comparable efficacy of VKA and DOAC, which also made it reasonable to validate the developed model in a dataset of higher DOAC usage. Regarding the above discussion, we added the following sentence to the discussion section; Thus, the proportion of DOAC usage increased to 49% in the external validation set from 10% in the development set. 2. The model was built under "Fine-Gray sub-distribution hazard model". Though reasonable in current risk competing model, the final event estimation rate would be lower, especially the high 1-year mortality rate (16%) was noted in the cohort. This might also affect the model performance. Reply to 2) We thank the reviewer for pointing this out. The mortality rate of ischemic stroke patients with atrial fibrillation varies by geographic and demographic characteristics. A pooled analysis of seven prospective cohort studies reported a mortality rate of around 10% per year with oral anticoagulation. [Seiffge. Ann Neurol. 2020] From a health maintenance organization database in the US, the 1-year mortality after ischemic stroke with atrial fibrillation was reported to be 40%; however, the average age of included patients was higher than that of our cohort, the US database included a higher prevalence of cancer history, and the treatment information was missing in the study. [Fang. Neurology. 2014] In a cohort with a relatively high mortality rate, it is required to consider the effect of competing risk. Estimation of incidence in the presence of competing risks is known to be biased upwards if the competing event, i.e., mortality for our study, is ignored. [Austin P. Stat Med. 2016] Abdel-Qadir et al. reported that the stroke incidence was overestimated by a relative factor of 39% when the Fine-Gray model was not applied to an atrial fibrillation cohort from the Ontario provincial health care database. [Abdel-Qadir. Circ Cardiovasc Qual Outcome. 2018] Therefore, we consider the Fine-Gray model is appropriate for estimating recurrent stroke risk from ischemic stroke patients with atrial fibrillation. 3. The rating score 1-10 was not appropriately described. Readers could only tell the numerous comprehensive predictors listed in Table 2 and their coefficients. The Authors did not explain how these weighted parameters transformed into 1-10 scores. Reply to 3) We appreciate the reviewer for letting us elaborate on this. The output from our model is not a score ranging from 1 to 10, but an individual probability of having recurrent stroke ranging from 0 to 1. We categorized the individual probability into deciles to compare it with traditional scoring systems. We added the following sentence as a caption after Table 3 and Figure 2. The estimated individual probability of recurrent stroke was categorized into deciles for the purpose of comparison. Additional edits requested from the editorial office on August 20, 2021 1. Please upload a Response to Reviewers letter which should include a point by point response to each of the points made by the Editor and / or Reviewers. (This should be uploaded as a 'Response to Reviewers' file type.) Please follow this link for more information: http://blogs.PLOS.org/everyone/2011/05/10/how-to-submit-your-revised-manuscript/ Reply to 1) We uploaded the document file. 2. Thank you for stating the following in the Acknowledgments Section of your manuscript: "This study was supported by Bristol‒Myers Squibb Korea and the Korea Centers for Disease Control and Prevention (no. 2020ER620200#) and a Grant-in-Aid (H23-Junkanki-Ippan-010) from the Ministry of Health, Labour and Welfare, Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The funding sources did not participate in any part of the study, from conception to article preparation. " We note that you have provided funding information that is currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please include your amended statements within your cover letter; we will change the online submission form on your behalf." Reply to 2) We deleted the funding information from the acknowledgement section. The statement is added to the cover letter. 3. Please upload a new copy of Figure 2 as the detail is not clear. Please follow the link for more information: https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/ Reply to 3) We increased the font size of Figure 2 and uploaded it. 4. Please provide additional details regarding participant consent. In the Methods section, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal). 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. Reply to 4) All the participants had given their written informed consents when they participated in the original CRCS-K and SAMURAI-NVAF studies. For the current post-hoc study, written consents were waived by the institutional review board of the Seoul National University Bundang Hospital. This information was cleared mentioned in the method section. 5. Thank you for updating your Data Availability statement which we note as the following: "The pseudonymized data that support the findings of this study are available from the corresponding author, Dr. Hee-Joon Bae, upon reasonable request, subsequent approval from the local IRB, and completion of a legal data sharing agreement. We concur with the principle of data sharing led by the PLoS group. Unfortunately, however, we have to write that the source data could not be made publicly available due to legal constraints, specifically the Personal Information Protection Act (2014). No explicit informed consent for public archiving of the pseudonymized source data has been obtained, in which case local regulations preclude public archiving of the data. Pseudonymized data that support the findings of this study are available from the corresponding author, Dr. Hee-Joon Bae, upon request, subsequent approval from the Institutional Review Board of the Seoul National University Bundang Hospital, and completion of a legal data sharing agreement. Link to the full text of the Personal Information Protection Act: https://www.law.go.kr/LSW/lsInfoP.do?chrClsCd=010203&lsiSeq=142563&viewCls=engLsInfoR&urlMode=engLsInfoR#0000" PLOS journals require authors to make all data necessary to replicate their study’s findings publicly available without restriction at the time of publication. When specific legal or ethical restrictions prohibit public sharing of a data set, authors must indicate how others may obtain access to the data. Thank you for providing information regarding the ethical restrictions for your data. Please provide contact information for the ethics committee or governing body mandating this restriction. Please note it is not acceptable for an author to be the sole named individual responsible for ensuring data access. We hope to hear from you soon. Reply to 5) We amended the section as following, adding highlighted sentences; Secondary use of the registry data and additional review of medical records for the current study were approved by the IRB of Seoul National University Bundang Hospital [B-1705/396-306]. The source data could not be made publicly available due to legal constraints, specifically the Personal Information Protection Act (2014). No explicit informed consent for public archiving of the pseudonymized source data has been obtained, in which case local regulations preclude public archiving of the data. The pseudonymized data that support the findings of this study are available from the corresponding author, Dr. Hee-Joon Bae, or the IRB of Seoul National University Bundang Hospital (82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13605, South Korea; https://msri.snubh.org) upon reasonable request, subsequent approval from the local IRB, and completion of a legal data sharing agreement. Attachments Attachment Submitted filename: EAST-Af modeling_03) PLoS One_14 Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0258377.r002
27 Sep 2021 Decision Letter - Adam Wiśniewski, Editor Prediction of recurrent stroke among ischemic stroke patients with atrial fibrillation: Development and validation of a risk score model PONE-D-21-16999R1 Dear Dr. Kim, 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. 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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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: 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 #3: 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 #3: 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 #3: Comments to the Author The authors present developmental series consisted of 4483 Korean and 1165 Japanese patients as to risk prediction model for recurrent events among patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). The patient population in the present study is large. In this study, 338 patients (6%) had recurrent stroke. The authors found there were no statistically significant differences between the newly developed model and the conventional risk scores (ATRIA, CHADS2, and CHA2DS2-VASc scores) assessing recurrence risk. The data and methods may certainly be of use for neurologists and strokologists. Overall, this manuscript is of a potential interest to the clinicians. I believe the paper will be of interest to the readership of PLOS ONE and would recommend it for acceptance ****** 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 #3: No https://doi.org/10.1371/journal.pone.0258377.r003
Formally Accepted
30 Sep 2021 Acceptance Letter - Adam Wiśniewski, Editor PONE-D-21-16999R1 Prediction of recurrent stroke among ischemic stroke patients with atrial fibrillation: Development and validation of a risk score model Dear Dr. Kim: 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. Adam Wiśniewski Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0258377.r004

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