Treatment-induced increase in total body potassium in patients at high risk of ventricular arrhythmias; a randomized POTCAST substudy

Ulrik Winsløw; Tharsika Sakthivel; Chaoqun Zheng; Helle Bosselmann; Ketil Haugan; Niels Bruun; Charlotte Larroudé; Kasper Iversen; Hillah Saffi; Emil Frandsen; Peter Oturai; Holger Jan Jensen; Michael Vinther; Niels Risum; Henning Bundgaard; Christian Jøns

doi:10.1371/journal.pone.0288756

Peer Review History

Original SubmissionJanuary 30, 2023
6 Mar 2023 Decision Letter - Yoshihiro Fukumoto, Editor PONE-D-23-02299Treatment-induced increase in total body potassium in patients at high risk of ventricular arrhythmias; a randomized POTCAST substudyPLOS ONE Dear Dr. Winsløw, 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 Apr 20 2023 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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Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: No ****** 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: No Reviewer #2: No ****** 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 manuscript addresses a potentially interesting topic. The study is single-center and this may limit its usefulness. Similarly, the methods are rather basic and not fully discussed. Some comments follow. 1. Please, upload the code used to get the results. This ensures the reproducibility of the results and allows the reviewer to check for the correctness of the results. 2. The sample size is rather small. This may strongly affect statistical inference. Even though basic tests are employed, no matter which parametric approach is considered, the assumptions underlying the statistical methods must be carefully checked and discussed. 3. I appreciate the use of mixed effects modelling as the data have a clear longitudinal structure. Nevertheless, the results are not well discussed. Firstly, it is rather unclear what the outcome is. The paper discusses mean differences at multiple times, and the regression modelling is swept under the carpet. Again, model's assumptions must be checked, investigated and discussed. A residual analysis must be provided and results must be shown to support your statements. Moreover, I am wondering how the Gaussian assumption for the random effects is tenable for such a small sample. Overall, it is rather unclear if confounders are considered or not, and the empircal specification of the linear predictor is not discussed. Reviewer #2: This is an interesting study considering that serum potassium level is significantly associated with the cardiovascular event risk. Another important point suggested from the study is that p-K level and TBK are rather differently regulated and do not behave parallelly in the living body homeostasis. However, the reviewer has concerns as below. #1. Only value differences were plotted in Figure 2. The measurement values should definitely be separately presented in each group with statistical standard deviations. #2.The authors’ idea about the sample size calculation is questionable. The reviewer agree with the idea that the study was powered to detect an increase in TBK of 5%. However, as shown in Supplemental Figure 2, the mean difference between measurements in the same sample was 0.024 g/kg body weight, which may up-to 1.6% of the absolute value. Considering the measurement error, the reviewer can not believe that the sample size calculation is sufficient to interpret the results. The sample size calculation should definitely be revised. I guess more number of samples should be included to lead a conclusion. ****** 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.0288756.r001
Revision 1
9 Jun 2023 Author Response Reviewer #1: The manuscript addresses a potentially interesting topic. The study is single-center and this may limit its usefulness. Similarly, the methods are rather basic and not fully discussed. Some comments follow. 1. Please, upload the code used to get the results. This ensures the reproducibility of the results and allows the reviewer to check for the correctness of the results. Response: Certainly. The code for main results is presented below. Using the Statistics software R version 4.1.0 and the open-source package lme4: #loading package for mixed linear regression analysis library(lme4) # "golden standard" for mixed-effects modelling in R #Creating a dataframe with long format data required for mixed regression analysis. glm_tbk<-c(tbk_baseline,tbk_6weeks, tbk_6months) glm_pk<-c(pk_baseline, pk_6weeks,pk_6months) glm_fu<-gl(3,14) glm_fu<-as.numeric(glm_fu) glm_pt_nr<-c(1:14,1:14,1:14) glm_group<-c(group, group, group) glm_group<-as.factor(glm_group) glm_koen<-c(koen, koen, koen) glm.data<-data.frame(glm_tbk, glm_pk, glm_fu, glm_pt_nr, glm_group) #changing the unit of glm_tbk from g/kg to mg/kg glm.data$glm_tbk<-glm.data$glm_tbk1000 #changing class of glm_fu and glm_group to factor glm.data$glm_fu<-as.factor(glm.data$glm_fu) glm.data$glm_group<-as.factor(glm.data$glm_group) #linear mixed regressio nmodel with patient ID (glm_pt_nr) as random effect. lmer<-lmer(glm_tbk~glm_fuglm_group+(1\|glm_pt_nr), data=glm.data3, REML=F) #visual inspection of residual normality qqnorm(resid(lmer)) qqline(resid(lmer)) #formal statistical test for residual normality shapiro.test(resid(lmer)) #extracting model results summary(lmer) confint(lmer) coef(lmer) #linear mixed regression model of p-K with patient ID (glm_pt_nr) as random effect. lmer2<-lmer(glm_pk~glm_fuglm_group+glm_group+(1\|glm_pt_nr), data=glm.data3, REML=F) #visual inspection of residual normality qqnorm(resid(lmer2)) qqline(resid(lmer2)) #formal statistical test for residual normality shapiro.test(resid(lmer2)) #extracting model results summary(lmer2) confint(lmer2) coef(lmer2) 2. The sample size is rather small. This may strongly affect statistical inference. Even though basic tests are employed, no matter which parametric approach is considered, the assumptions underlying the statistical methods must be carefully checked and discussed. 3. I appreciate the use of mixed effects modelling as the data have a clear longitudinal structure. Nevertheless, the results are not well discussed. Firstly, it is rather unclear what the outcome is. The paper discusses mean differences at multiple times, and the regression modelling is swept under the carpet. Again, model's assumptions must be checked, investigated and discussed. A residual analysis must be provided and results must be shown to support your statements. Moreover, I am wondering how the Gaussian assumption for the random effects is tenable for such a small sample. Overall, it is rather unclear if confounders are considered or not, and the empirical specification of the linear predictor is not discussed. Response: Thank you for these two important comments on sample size and statistical modelling. We agree that checking the assumptions behind any statistical test is of vital importance. The underlying test for the main results in the present paper is the linear mixed random effects regression model and the assumptions was tested during data analysis. The code is shown in comment 1. We have included a residual analysis in the manuscript: Page 7, line 167: The assumption of normal distribution of model residuals was tested by Shapiro-Wilk test. For changes in p-K the W statistic was 0.97, P=0.39 and for TBK the W statistic was 0.96, P=0.11. The outcome was predefined as between-group difference in changes in p-K and TBK from baseline to six weeks and from baseline to six months. This has been made clearer on page 6 line 134: Main outcome measures: Between-group difference in changes in TBK and p-K from baseline to six weeks, and from baseline to six months. As for confounding factors and generalizability, the study is a randomized trial and such trial of its kind. However, we do agree that the relatively low sample size, the between-study heterogeneity, may affect the generalizability of the results. This has now been addressed in the limitations section on page 14 line 276: Changes made to the manuscript: Due to the low sample size and heterogeneous study population, larger studies with a number of subgroups are needed to confirm the generalizability of the findings. Reviewer #2: This is an interesting study considering that serum potassium level is significantly associated with the cardiovascular event risk. Another important point suggested from the study is that p-K level and TBK are rather differently regulated and do not behave parallelly in the living body homeostasis. However, the reviewer has concerns as below. #1. Only value differences were plotted in Figure 2. The measurement values should definitely be separately presented in each group with statistical standard deviations. Response: Thank you for this comment. We chose to keep the study simple by only presenting differences in outcome between the two groups in the main paper. We realize that some readers may be interested to know the changes in each group separately along with standard deviations and this data has been added to a table in the supplementary appendix (Supplementary table 1). We have added a sentence to the manuscript in order to refer readers to the table on page 11 line 207. Changes made to the manuscript: The mean TBK and p-K in each study group at baseline, six weeks, and six months are shown in S1 Table. #2.The authors’ idea about the sample size calculation is questionable. The reviewer agree with the idea that the study was powered to detect an increase in TBK of 5%. However, as shown in Supplemental Figure 2, the mean difference between measurements in the same sample was 0.024 g/kg body weight, which may up-to 1.6% of the absolute value. Considering the measurement error, the reviewer can not believe that the sample size calculation is sufficient to interpret the results. The sample size calculation should definitely be revised. I guess more number of samples should be included to lead a conclusion. Response: Thank you for this comment. The sample size calculation was performed prior to the initiation of the study and thus, naturally holds estimations of the study outcome. As no prior trial has been made on the same study population some assumptions had to be made. Thus, we assumed that …… and standard deviations for the sample size calculation were achieved from …. We all prefer large studies – but we also have to acknowledge the ethics - that it is considered un-ethical to expose more patients to trial examinations than what has been shown to be necessary to reach a conclusion in the specific study. The observed changes came quite close to the estimated changes. TBK increased slightly more than estimated (0.083 g/kg) while the standard deviation of the paired differences was 0.05. A future study with a sample size calculation based on these numbers would need 6 patients in each group. Attachments Attachment Submitted filename: Response to Reviewers.docx* https://doi.org/10.1371/journal.pone.0288756.r002
27 Jun 2023 Decision Letter - Yoshihiro Fukumoto, Editor PONE-D-23-02299R1Treatment-induced increase in total body potassium in patients at high risk of ventricular arrhythmias; a randomized POTCAST substudyPLOS ONE Dear Dr. Winsløw, 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 11 2023 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, Yoshihiro Fukumoto Academic Editor PLOS ONE Journal Requirements: 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: This academic editor considers that the authors well performed the present study, and that they well responded to the reviewers’ comments. This editor has an additional comment as described below. Major comment: 1. The authors should add why they performed this study in this sample size in the “Ethics”, as responded in comment #2 of Reviewer #2 (that it is considered un-ethical to expose more patients to trial examinations than what has been shown to be necessary to reach a conclusion in the specific study). [Note: HTML markup is below. Please do not edit.] 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: (No Response) ******** 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: (No Response) Reviewer #2: No ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: (No Response) Reviewer #2: No ****** 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: (No Response) Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: Many of the reviewers' comments and requests have not been addressed. The revision made by the authors is not sufficient to overcome the fundamental problems of the study. ****** 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 ******** [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.0288756.r003
Revision 2
30 Jun 2023 Author Response In this revision we have responded to the editor's advice to add a comment on the ethics behind the chosen sample size. We have added the following to the manuscript's ethics section (page 7 line 160): “The limited size of the study was solely based on the sample size calculation as it is, due to ethical considerations, recommended to avoid exposing more patients to trial examinations than what has been shown to be necessary to reach a conclusion.“ Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0288756.r004
5 Jul 2023 Decision Letter - Yoshihiro Fukumoto, Editor Treatment-induced increase in total body potassium in patients at high risk of ventricular arrhythmias; a randomized POTCAST substudy PONE-D-23-02299R2 Dear Dr. Winsløw, 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, Yoshihiro Fukumoto Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0288756.r005
Formally Accepted
10 Jul 2023 Acceptance Letter - Yoshihiro Fukumoto, Editor PONE-D-23-02299R2 Treatment-induced increase in total body potassium in patients at high risk of ventricular arrhythmias; a randomized POTCAST substudy Dear Dr. Winsløw: 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. Yoshihiro Fukumoto Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0288756.r006

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