Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data

Nicola Specchio; Paul Gissen; Emily de los Reyes; Andrew Olaye; Charlotte Camp; Tristan Curteis; Annabel Griffiths; Thomas Butt; Jessica Cohen-Pfeffer; Peter Slasor; Zlatko Sisic; Mohit Jain; Angela Schulz

doi:10.1371/journal.pone.0302382

Peer Review History

Original SubmissionAugust 18, 2021
2 Feb 2022 Decision Letter - Rizaldy Taslim Pinzon, Editor PONE-D-21-26733Exploring concurrent validity of the CLN2 Clinical Rating Scale: comparison to PedsQLTM using cerliponase alfa clinical trial dataPLOS ONE Dear Dr. Nicola Spechio 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 follow the input from the reviewers. Please submit your revised manuscript by 10 February 2022. 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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Dr Schulz received grants from the German Federal Ministry of Education and Research (NCL2Treat), European Union's Horizon 2020 Research and Innovation Program (66691), and the European Union Seventh Framework Program (281234) for the Dementia in Childhood consortium which provided data for the historical cohort. Great Ormond Street Hospital and UCL Institute of Child Health Biomedical Research Centre received a grant from the National Institute for Health Research.” Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 4. Thank you for stating the following in the Acknowledgments Section of your manuscript: “This study was funded by BioMarin Europe Ltd. The authors thank the patients and their caregivers in addition to the investigators and their teams who contributed to this study. The authors also acknowledge Bryony Langford, MSc and Chris McDonald, PhD, who worked at Costello Medical, UK at the time of the study, for statistical analysis support. Medical writing and editorial assistance in preparing this manuscript for publication was provided by Costello Medical, UK, based on the authors’ input and direction. The authors acknowledge Eleanor Thurtle, MChem, Costello Medical, Cambridge, for writing and editorial assistance. All costs associated with the development of this manuscript were funded by BioMarin Europe Ltd. PedsQLTM, Copyright © 1998 JW Varni, Ph.D. All rights reserved. PedsQLTM contact information and permission to use: Mapi Research Trust, Lyon, France – Internet: https://eprovide.mapi-trust.org and www.pedsql.org.” We note that you have provided funding information that is not 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 remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “BioMarin Pharmaceutical Inc funded this study, and were involved in the design of the study, analysis and interpretation of data, as well as in preparation of this manuscript and the decision to submit this article for publication. Dr Schulz received grants from the German Federal Ministry of Education and Research (NCL2Treat), European Union's Horizon 2020 Research and Innovation Program (66691), and the European Union Seventh Framework Program (281234) for the Dementia in Childhood consortium which provided data for the historical cohort. Great Ormond Street Hospital and UCL Institute of Child Health Biomedical Research Centre received a grant from the National Institute for Health Research.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. Thank you for stating the following in the Competing Interests section: “PG and NS received no specific funding for this work. AS received compensation from BioMarin Europe as per clinical trial agreement. EdlR received research grants from Amicus Therapeutics, BioMarin Pharmaceuticals Inc, and Giving Back Fund. AO, CC, TB and MJ were employees and shareholders of BioMarin Europe at time of study initiation. ZS was an employee of BioMarin Europe at time of study initiation. JCP and PS were employees and shareholders of BioMarin Pharmaceutical Inc at time of study initiation. TC and AG were employees of Costello Medical at time of study initiation, who provided writing support and editorial assistance which was funded by BioMarin Pharmaceuticals.” 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. 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Additional Editor Comments: This is an interesting topic. Many methodological flaws in your study. Please follow the recommendations and input from the reviewer. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: PONE-D-21-26733: statistical review. SUMMARY. This is a study of a clinical rating scale that evaluates progression of an ultra-rare neurodegenerative disorder (the CLN2 disease) with late infantile onset. It investigates the cross-correlations between the four domains of the scale (motor, language, vision and seizure) and the association between this scale and the domains of the Pediatric Quality of Life PedsQL score. The statistical analysis relies on marginal correlations between the domain-specific scores of the clinincal scale under study and on the estimation of linear mixed models, where PedsQL scores are predicted by clinical scale scores. I have major concerns about the methods employed (see the major issues below), which require a complete revision of the statistical analysis. Appended are further specific points that should be considered by the authors. MAJOR ISSUES 1. Cross-correlations between domain-specific scores are computed by a battery of Spearman correlation indexes. This method is appropriate because the scores are ordinal variables. However, p-values (or standard errors) are not provided, complicating the interpretation of Table 2. P-values must be provided. Due to the small sample size, I wouldn't rely on the asymptotic distributions of the Spearman rho, though. I'd recommend a bootstrap approach to compute p-values. 2. I guess that the computation of the VIF and the Condition index were based on the Pearson correlations (although this was not specified, please clarify). These measures are typical of collinearity analysis in multivariate continuous data, but they are certainly not appropriate here, where the data are multivariate ordinal. This part of the analysis is hence incosistent with the Spearman analysis and should be removed. 3. The association between the CLN2 scale and the domains of the Pediatric Quality of Life PedsQL score is based on the assumption of normally distributed PedsQL scores. The authors should provide evidence that these scores are normally distributed. Fitting a normal linear model to non-normal data could lead to biased p-values. 4. Page 8 "Clinical Rating Scale data were collected every 8 weeks and PedsQL data every 12 weeks, leading to 16 concurrent data for both measures being available every 24 weeks". Please carify whether the analysis (correlations and linear mixed models) has been performed by either using only the concurrent data and discarding the nonoccurrent observations (an unnecessary waste of information...) or including all the data and treating the observations as missing at random (a hypothesis that must be motivated). 5. Page 9 "a selection of random effect structures was considered, including only random intercepts, only random slopes, and both random intercepts and slopes." Two points to be clarified, here. First, the criterion used to select the random effect stucture should be provided. Second, tables 6-8 should indicate which random structure has been selected for each model, to allow replicability of the results (an important requirement of the Journal). SPECIFIC POINTS 1. As remarked in major issue no 1, Spearman correlation is an appropriate method in the paper setting. However, it provides very little information about associations between scores, becuase it does not account for the longitudinal structure of the data. The state-of-the art approach would be a log-linear model that investigates the interations between multiple scores. Log-linear models can be easily estimated by R, which is the software used by the authors. 2. Introduction, line 14. What do the authors mean by "median life expectancy"? Life expectancy is already a mean. Hence I don't understand what is the median of a mean. Please carify how this summary has been computed. 3. It seems that many references in the text went lost during the final compilation of the manuscript ... 4. Although the authors have declared that the data are available without restrictions, data are not provided. Data should be attached as supplementary information, in a publicly available format (txt or xls). This is also an important requirement of the Journal. ****** 6. 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Revision 1
8 Sep 2022 Author Response Dr Nicola Specchio Department of Neuroscience Bambino Gesù Children’s Hospital, IRCCS, Piazza di Sant'Onofrio, 4 Rome, 00165 Italy Email address: nicola.specchio@gmail.com 15 June 2022 Handling Editor: Rizaldy Taslim Pinzon PLOS ONE RE: Exploring concurrent validity of the CLN2 Clinical Rating Scale: comparison to PedsQLTM using cerliponase alfa clinical trial data (Manuscript ID: PONE-D-21-26733) Dear Dr Pinzon, Many thanks for providing us with the peer reviewers’ feedback on the above manuscript. We have now revised the manuscript to implement the comments and have included a detailed point-by-point response to each comment within this letter (see below). We have also prepared the revised manuscript using tracked changes to aid review. We hope that the individual responses below, and revisions to the manuscript, address the concerns raised by the peer reviewers, and that the manuscript is now suitable for publication in PLOS ONE. We look forward to your reply. Yours sincerely, Dr Nicola Specchio, on behalf of all co-authors Major issues Cross-correlations between domain-specific scores are computed by a battery of Spearman correlation indexes. This method is appropriate because the scores are ordinal variables. However, p-values (or standard errors) are not provided, complicating the interpretation of Table 2. P-values must be provided. Due to the small sample size, I wouldn't rely on the asymptotic distributions of the Spearman rho, though. I'd recommend a bootstrap approach to compute p-values. Response: Thank you for your suggestion. The p-values have now been generated to support the results in Table 2 via bootstrapping 1,000 runs as requested. I guess that the computation of the VIF and the Condition index were based on the Pearson correlations (although this was not specified, please clarify). These measures are typical of collinearity analysis in multivariate continuous data, but they are certainly not appropriate here, where the data are multivariate ordinal. This part of the analysis is hence inconsistent with the Spearman analysis and should be removed. Response: Thank you for your feedback. We can confirm that computation of the VIF and the Condition index was based on the Pearson correlations. While we agree that strictly speaking, quality of life measures are indeed ordinal, these tend to be treated as continuous in regression modelling in most literature. Moreover, our two outcomes, CLN2QL and PedsQL total score, spread across a wide range of values between 0 and 100 (i.e. not heavily skewed) hence we believe that treating these as continuous in this context is viable. The association between the CLN2 scale and the domains of the Pediatric Quality of Life PedsQL score is based on the assumption of normally distributed PedsQL scores. The authors should provide evidence that these scores are normally distributed. Fitting a normal linear model to non-normal data could lead to biased p-values. Response: Thank you for your feedback. The normality assumption of linear regression and linear mixed-effects models generally applies to the residuals rather than the dependent variables. We have thus assessed this using diagnostic plots of within-group residuals versus fitted values in the course of our analyses, which by inspection indicate that the assumption of a constant error variance with an approximate normal distribution holds for all analyses, and that it is appropriate to fit linear mixed effects models to these data. We have not included these plots in the manuscript given the large number of plots generated, however we have included the following clarification in the manuscript on page 20, line 30: “However, visual inspection of residual plots across all models indicated no violation of these assumptions (results not shown).” Page 8 "Clinical Rating Scale data were collected every 8 weeks and PedsQL data every 12 weeks, leading to 16 concurrent data for both measures being available every 24 weeks". Please clarify whether the analysis (correlations and linear mixed models) has been performed by either using only the concurrent data and discarding the nonconcurrent observations (an unnecessary waste of information...) or including all the data and treating the observations as missing at random (a hypothesis that must be motivated). Response: Thank you for your suggestion. We can confirm that concurrent data was used here for both correlations and the models. In terms of dealing with missingness, observations have been treated as missing at random. The rationale behind this approach is based on data collection in the trial, where outcomes were reported via proxy (e.g. parent responding on the child’s behalf). Subsequently, likelihood of receiving a response from a parent (as opposed to the child in question) is much more likely to be independent from good/poor health of the child. We evaluated this assumption by comparing clinical rating scale scores immediately before a missing entry with overall clinical rating scores and found no signs of association, suggesting that this assumption is valid. Page 9 "a selection of random effect structures was considered, including only random intercepts, only random slopes, and both random intercepts and slopes." Two points to be clarified, here. First, the criterion used to select the random effect structure should be provided. Second, tables 6-8 should indicate which random structure has been selected for each model, to allow replicability of the results (an important requirement of the Journal). Response: Thank for your suggestion. We can confirm that the Akaike information criterion was used to select the final model and have highlighted this in the manuscript. The model structures for each of the models have been identified for each analysis, and we have updated Table 6, Table 7 and Table 8 in the manuscript to include these. We have described for each model whether a random intercept, random slope for the time variable, random slope for the dependent variable, or a combination of these were used. Specific Points As remarked in major issue no 1, Spearman correlation is an appropriate method in the paper setting. However, it provides very little information about associations between scores, because it does not account for the longitudinal structure of the data. The state-of-the art approach would be a log-linear model that investigates the interactions between multiple scores. Log-linear models can be easily estimated by R, which is the software used by the authors. Response: Thank you for your suggestion. As log-linear models are commonly used for count data, rather than continuous/ordinal data, this would not yield statistics that relay information on the relationships between each domain in this case. Subsequently, we felt that this would not be appropriate for the data presented in the manuscript. We acknowledge that ideally, the longitudinal structure of the data would be accounted for when producing the correlations, and that this is a limitation of this preliminary analysis. However, we consider that the correlations, with the update to include the p-values, adequately indicate which domains capture similar information in the first instance, and in subsequent analyses, the longitudinal structure of the data is accounted for by linear mixed effect models. Introduction, line 14. What do the authors mean by "median life expectancy"? Life expectancy is already a mean. Hence I don't understand what is the median of a mean. Please clarify how this summary has been computed. Response: Many thanks for flagging this. We have now updated the text in the Introduction to align with Nickel et al 2018, which now reads “Ultimately, patients with CLN2 disease experience reduced life expectancy, with a median age at death reported as 10.0 years”. It seems that many references in the text went lost during the final compilation of the manuscript ... Response: Many apologies for this oversight here and thank you for flagging. Unfortunately, during the upload to the manuscript submission site, some reference links were broken. We have ensured that all links are fixed during resubmission of the manuscript. Although the authors have declared that the data are available without restrictions, data are not provided. Data should be attached as supplementary information, in a publicly available format (txt or xls). This is also an important requirement of the Journal. Response: The de-identified individual participant data that underlie the results reported in this article (including text, tables, figures, and appendices) will be made available together with the research protocol and data dictionaries, for non-commercial, academic purposes. Additional supporting documents may be available upon request. Investigators will be able to request access to these data and supporting documents via a data sharing portal beginning 6 months and ending 2 years after publication. Data associated with any ongoing development program will be made available within 6 months after approval of relevant product. Requests must include a research proposal clarifying how the data will be used, including proposed analysis methodology. Research proposals will be evaluated relative to publicly available criteria available at www.biomarin.com/patients/publication-data-request/ to determine whether access will be given, contingent upon execution of a data access agreement with BioMarin Pharmaceutical Inc. Funding statement: Please could the Funding Statement be updated as follows, “BioMarin Pharmaceutical Inc funded this study, and were involved in the design of the study, analysis and interpretation of data, as well as in preparation of this manuscript and the decision to submit this article for publication. Medical writing and editorial assistance in preparing this manuscript for publication was provided by Costello Medical, UK, and funded by BioMarin Pharmaceutical Inc.” Please note that all funding information has been removed from the Acknowledgements section of the manuscript. Competing interests statement: Please could the Competing Interests Statement be updated as follows, “PG, NS: No competing interests to declare; AS: Received compensation from BioMarin Europe as per clinical trial agreement; EdlR: Research grants from Amicus Therapeutics, BioMarin Pharmaceutical Inc., Giving Back Fund; Consultancy: BioMarin Pharmaceuticals Inc.; AO, CC, TB, and MJ: Employees and shareholders of BioMarin Europe; ZS: Employee of BioMarin Europe; TC and AG: Employees of Costello Medical; JCP and PS: Employees and shareholders of BioMarin Pharmaceutical Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.” Attachments Attachment Submitted filename: Peer_Review_Response_15Jun22.docx https://doi.org/10.1371/journal.pone.0302382.r002
21 Sep 2022 Decision Letter - Rizaldy Taslim Pinzon, Editor PONE-D-21-26733R1Exploring concurrent validity of the CLN2 Clinical Rating Scale: comparison to PedsQLTM using cerliponase alfa clinical trial dataPLOS ONE Dear Dr. Specchio 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 improve the quality of the figure. Please make the limitations and conclusion of your study more concise and straightforward. Please submit your revised manuscript by Nov 05 2022 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, Rizaldy Taslim Pinzon Academic Editor PLOS ONE Additional Editor Comments: Thank you for your prompt reply and revisions. Please improve the quality of the figure. Please make the limitations and conclusion of your study more concise and straightforward. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: [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.0302382.r003
Revision 2
28 Nov 2023 Author Response Please improve the quality of the figure. Response: We have now redrawn the figure as requested. Please make the limitations and conclusion of your study more concise and straightforward. Response: We have updated the limitations and conclusion section to make this more concise. Please note, the detailed information regarding the statistical limitations has been moved to a supplementary materials file, should readers still wish to see this information. https://doi.org/10.1371/journal.pone.0302382.r004
2 Apr 2024 Decision Letter - Markus Ries, Editor Exploring concurrent validity of the CLN2 Clinical Rating Scale: comparison to PedsQLTM using cerliponase alfa clinical trial data PONE-D-21-26733R2 Dear Dr. Specchio, 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, Markus Ries, MD PhD MHSc MA FCP Academic Editor PLOS ONE Additional Editor Comments (optional): Please note that some reference links in the text show error codes. 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 ******** 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) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (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: (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: (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: (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 ******** https://doi.org/10.1371/journal.pone.0302382.r005
Formally Accepted
10 May 2024 Acceptance Letter - Markus Ries, Editor PONE-D-21-26733R2 PLOS ONE Dear Dr. Specchio, 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 Professor Markus Ries Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0302382.r006

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