Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators

Gabriel S. Zamudio; Manlio F. Márquez; Marco V. José

doi:10.1371/journal.pone.0235101

Peer Review History

Original SubmissionJune 8, 2020
29 Jul 2020 Decision Letter - Elena G. Tolkacheva, Editor PONE-D-20-17194 Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators PLOS ONE Dear Dr. José, 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 address comments indicated by the Reviewers. Please submit your revised manuscript by Sep 12 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Elena G. Tolkacheva, PhD Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 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 2. Please ensure that you have reported at the beginning of your methods or results section the key performance measures that were used to establish validity and utility of your algorithm. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 4. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical. 5. 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. [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: This is an interesting mathematical approach to look at heart rate variability and its ability to predict VT events. The analytical approach is sufficiently novel to be of interest, and it appears to show an ability to discriminate RR interval time series preceding VT events from control RR interval time series from the same patients. However, we are only really shown a representative example of time series analysis and associated derived metrics (Figure 3) and there is no tabulation or graphical representation of this for all 81 patients. So it is not clear that this is genuinely a "representative" result, or the single best time series in which discrimination occurred. Presentation of the results from the whole cohort would address this. The discussion should note that a significant clinical limitation of the work is that this type of approach is unlikely to work in patients with AF. Because the AF group with ICDs is currently a significant challenge to us clinically, this is an important limitation. Reviewer #2: In this manuscript, the authors developed a method to transform time series into graphs which is sensitive to a single parameter. And they also demonstrated the feasibility of using this method to detect early warning of VA episode. The followings are my comments to further improve this manuscript. 1. In figure 1, the authors gave an example to using �-regular graph and compare their method with visibility graph. The author could also show the result of visibility graph in figure 1 to make the comparison more straightforward. 2. From figure 2, the authors concluded “The degree distributions for the graphs constructed form the Brownian motion approximates a Gaussian curve despite its multiple modes; and the distribution from points sampled from a normal distribution approximates a lognormal distribution.” The authors simply said what they observed in the plot. They should further explain the results. 3. The authors show the complete data in supplementary files instead of providing the website source. 4. In figure 3, the authors only showed the graph with ��why is this? They should sweep this parameter and show how the graph looks like with different parameter values. They should also explain how they optimize this parameter. 5. “We propose this change in the dynamic of the R-R intervals as a measurable and detectable early warning of the VT event, occurring an average of 514.625 seconds (8:30 minutes) before the start of the VT episode.” How did the authors get this number (514.625) from the graph? They should provide the details. ****** 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.0235101.r001
Revision 1
13 Aug 2020 Author Response August 10th, 2020 Elena G. Tolkacheva, PhD Academic Editor PLOS ONE Journal: PLOS ONE Manuscript ID: PONE-D-20-17194 Title: Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators Authors: Gabriel S. Zamudio, Manlio F. Márquez, Marco V. José Dear Dr. Tolkacheva: Thank you for your email dated July 29th, 2020 and for the reviewer’s comments. We are thankful to the reviewers for their helpful criticisms. We carefully evaluated and answered all the questions posed by reviewers. Please check below. Answer to reviewers 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: This is an interesting mathematical approach to look at heart rate variability and its ability to predict VT events. The analytical approach is sufficiently novel to be of interest, and it appears to show an ability to discriminate RR interval time series preceding VT events from control RR interval time series from the same patients. However, we are only really shown a representative example of time series analysis and associated derived metrics (Figure 3) and there is no tabulation or graphical representation of this for all 81 patients. So it is not clear that this is genuinely a "representative" result, or the single best time series in which discrimination occurred. Presentation of the results from the whole cohort would address this. The result of the analysis of the 81 patients can be seen in this plot: There is a great variability among each individual patient. In Discussion we added the following paragraph: “The process of optimization of the epsilon parameter value requires a more extensive clinical experimentation. It stands to reason that the parameter value is specific for each individual person and ought to be tuned from the complete set of clinical parameters of the patient to avoid false-positives and false-negatives. In a more general case, it is also probable that the parameter value is not fixed throughout the day and is dependent of the circadian rhythm of the patient.” The discussion should note that a significant clinical limitation of the work is that this type of approach is unlikely to work in patients with AF. Because the AF group with ICDs is currently a significant challenge to us clinically, this is an important limitation. Thank you very much for pointing out this important limitation. We have now included a comment in Limitations as follows: “A significant clinical limitation of this work is the fact that this approach is restricted to patients with normal sinus rhythm and is unlikely to work in patients with atrial fibrillation or those with a pacemaker. In the former group because of the large variability of R-R intervals, and in the later because of fixed pacing rhythms.” Reviewer #2: In this manuscript, the authors developed a method to transform time series into graphs which is sensitive to a single parameter. And they also demonstrated the feasibility of using this method to detect early warning of VA episode. The followings are my comments to further improve this manuscript. 1. In figure 1, the authors gave an example to using �-regular graph and compare their method with visibility graph. The author could also show the result of visibility graph in figure 1 to make the comparison more straightforward. We modified Figure 1 to include Figure 1C that shows the transformation of the time series using the visibility graph algorithm. 2. From figure 2, the authors concluded “The degree distributions for the graphs constructed form the Brownian motion approximates a Gaussian curve despite its multiple modes; and the distribution from points sampled from a normal distribution approximates a lognormal distribution.” The authors simply said what they observed in the plot. They should further explain the results. We have now included a comment in Methods as follows: “The distributions of the degree measurements maintain, up to some extent, the statistical properties from the time series they were derived from. The difference between any two values of the Brownian motion follows a normal distribution, and this property is shown by the epsilon-regular graphs in the degree centrality measure when setting the epsilon parameter equal to values related to the standard deviation.” 3. The authors show the complete data in supplementary files instead of providing the website source. We now provide the website source of the data in the format requested by the journal guidelines, also, the URL of the websites are cited in the section Application to Imminent VT. 4. In figure 3, the authors only showed the graph with ��why is this? They should sweep this parameter and show how the graph looks like with different parameter values. They should also explain how they optimize this parameter. The parameter epsilon�� showed the best results for the current application. We have added the experimental results for the parameter values of �psilon��1, 0.02, 0.03, 0.05, and 0.06 in Supporting Information II. We have added the following paragraph in Application to Imminent VT section: “The optimization of the parameter �psilon�is based on the statistical parameters of the R-R time series. The average, minimum and maximum distance between two points of the R-R time series are: 0.043, 1.11x10^(-16), 0.12, respectively. Thus, the �psilon value of 0.04 approximates the mean of the differences. In Supporting Information II, we show the degree time series when the values ��1, 0.02, 0.03, 0.04, 0.05, and 0.06 are assigned to the parameter epsilon (Fig S1). Note that the overall pattern is preserved. In particular, the abrupt change of the dynamics is captured by the different values of the parameter epsilon”. 5. “We propose this change in the dynamic of the R-R intervals as a measurable and detectable early warning of the VT event, occurring an average of 514.625 seconds (8:30 minutes) before the start of the VT episode.” How did the authors get this number (514.625) from the graph? They should provide the details. In Application to Imminent VT we added the following sentence: “The count of 514.625 seconds corresponds to the sum of the average of the time lapses of the last R-R intervals starting from the point 276 to when the VT episode begins at point 985.” 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. All in all, we do thank the reviewers for their helpful comments and criticisms; for we feel that they have helped us to improve the quality and presentation of the paper. We expect that the present version of the manuscript answers all their concerns. Yours Sincerely, Marco V. José PhD Theoretical Biology Group Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México Apartado Postal 70228 Ciudad Universitaria C.P. 04510 CDMX, México Tel: 52-55-5622-3894 Mobile: 52-55-1320-6111 Author for correspondence: Marco V. José (marcojose@biomedicas.unam.mx) Attachments Attachment Submitted filename: PLOS ONE REPLY 2020.docx https://doi.org/10.1371/journal.pone.0235101.r002
15 Sep 2020 Decision Letter - Elena G. Tolkacheva, Editor Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators PONE-D-20-17194R1 Dear Dr. José, 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, Elena G. Tolkacheva, PhD 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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: Thanks for your responses to my previous comments on your manuscript. I really liked the figure of all 81 patients data - I thought that looked amazing, but I agree it isn't really suitable for inclusion within the manuscript. The comments within the discussion address my concerns well. Reviewer #2: (No Response) ****** 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: No https://doi.org/10.1371/journal.pone.0235101.r003
Formally Accepted
17 Sep 2020 Acceptance Letter - Elena G. Tolkacheva, Editor PONE-D-20-17194R1 Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators Dear Dr. José: 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. Elena G. Tolkacheva Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0235101.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 .