Impact of patients’ age and comorbidities on prostate cancer overdiagnosis in clinical practice

Abraham Beltrán; Lucy Parker; Irene Moral-Pérez; Juan Pablo Caballero-Romeu; Elisa Chilet-Rosell; Ildefonso Hernández-Aguado; Pablo Alonso-Coello; Elena Ronda; Luis Gómez-Pérez; Blanca Lumbreras

doi:10.1371/journal.pone.0315979

Peer Review History

Original SubmissionAugust 30, 2024
6 Nov 2024 Decision Letter - Jan Philipp Radtke, Editor PONE-D-24-35992Impact of patients' age and comorbidities on prostate cancer overdiagnosis in clinical practicePLOS ONE Dear Dr. Lumbreras, 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 Dec 21 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Prof. Jan Philipp Radtke, MBA Academic Editor PLOS ONE Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following financial disclosure: Research funded by the research project of the Instituto de Salud Carlos III, code PI20/01334, Principal Investigator Dr. Blanca Lumbreras, co-financed with FEDER funds from 631 the European Union “A way of doing Europe”. 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. 3. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. 4. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. Additional Editor Comments: General comments: The study focuses on assessing the probability of overdiagnosis in the early detection of prostate cancer (PCa) using the PSA test. The study primarily investigates how the age of the patient and concomitant diseases affect overdiagnosis. The authors argue that most previous studies on PSA-based PCa screening have focussed on healthier populations, mainly from clinical trials, and want to provide a more relevant context by examining real-world clinical data. The aim of the study was to assess the likelihood of overdiagnosis based on PSA levels, Gleason scores and patients' comorbidities. The study is based on a retrospective cohort analysis of 1,070 asymptomatic men over 40 who were diagnosed with PCa between 2004 and 2022. The primary outcome is the probability of overdiagnosis assessed by life expectancy adjusted for comorbidities using the Charlson Comorbidity Index. Lead times of 5, 10 and 15 years are considered in the study. Statistical comparisons are made between the groups stratified by PSA values and Gleason scores. The paper contains several important results: Higher PSA levels (>10 ng/dL) and Gleason scores (≥8) are associated with an increased likelihood of overdiagnosis, particularly in older patients with significant comorbidities. Patients with lower PSA levels (4-10 ng/dL) and Gleason scores (≤7) were less likely to be overdiagnosed. Radiation exposure was higher in patients with higher PSA levels, and pharmacological treatment was more common in patients with elevated PSA levels. Most patients (71.7%) did not receive pharmacological treatment, highlighting the likelihood of overdiagnosis without active treatment. In total, this is a retrospective observational study measure methods in a double center setting. Idea fine. Specific comments: 1. Real-world data: The study’s use of real-world clinical data provides valuable insights, especially considering older and more comorbid patients who are often underrepresented in clinical trials. Very good. 2. Incorporation of comorbidities: The use of the Charlson Comorbidity Index to adjust life expectancy is a strong methodological approach, as it emphasizes the importance of considering a patient’s overall health, not just age. Well, done. 3. Comprehensive analysis: The inclusion of different lead times (5, 10, and 15 years) provides a thorough examination of overdiagnosis probabilities. Well, done 4. Follow-up duration: The median follow-up of 5.7 years, though reasonable, may not be sufficient to capture long-term outcomes or fully assess the impact of overdiagnosis on patient health. � Extension of the follow-up if necessary 5. Unknown Gleason scores: A considerable portion of patients did not have their Gleason scores recorded, which could have affected the robustness of the statistical comparisons. � severely limits the significance of the study 6. Overdiagnosis estimation: The estimation of overdiagnosis relies on external lead-time data from the literature rather than patient-specific lead-time information, which introduces potential biases.The study's findings may be less applicable to younger or healthier populations, limiting the external validity. The study emphasises the importance of considering both age and comorbidities when assessing the risk of overdiagnosis in prostate cancer screening. The study shows that older patients with significant comorbidities are more likely to be overdiagnosed, often without receiving active treatment. The results underline the need for personalised screening strategies and caution in the general use of PSA testing without consideration of patients' individual health profiles. The study addresses an important issue in PCa screening and provides useful clinical insights. The limitations regarding the data on Gleason scores and follow-up duration should be re-examined as they significantly limit the statistical power. The paper could also benefit from further clarification of the impact of overdiagnosis on patient management and treatment decisions. Overall, the research findings are solid and relevant, especially for clinicians looking to adjust PSA testing strategies based on individual patient risk factors. [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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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: General comments: The study focuses on assessing the probability of overdiagnosis in the early detection of prostate cancer (PCa) using the PSA test. The study primarily investigates how the age of the patient and concomitant diseases affect overdiagnosis. The authors argue that most previous studies on PSA-based PCa screening have focussed on healthier populations, mainly from clinical trials, and want to provide a more relevant context by examining real-world clinical data. The aim of the study was to assess the likelihood of overdiagnosis based on PSA levels, Gleason scores and patients' comorbidities. The study is based on a retrospective cohort analysis of 1,070 asymptomatic men over 40 who were diagnosed with PCa between 2004 and 2022. The primary outcome is the probability of overdiagnosis assessed by life expectancy adjusted for comorbidities using the Charlson Comorbidity Index. Lead times of 5, 10 and 15 years are considered in the study. Statistical comparisons are made between the groups stratified by PSA values and Gleason scores. The paper contains several important results: Higher PSA levels (>10 ng/dL) and Gleason scores (≥8) are associated with an increased likelihood of overdiagnosis, particularly in older patients with significant comorbidities. Patients with lower PSA levels (4-10 ng/dL) and Gleason scores (≤7) were less likely to be overdiagnosed. Radiation exposure was higher in patients with higher PSA levels, and pharmacological treatment was more common in patients with elevated PSA levels. Most patients (71.7%) did not receive pharmacological treatment, highlighting the likelihood of overdiagnosis without active treatment. In total, this is a retrospective observational study measure methods in a double center setting. Idea fine. Specific comments: 1. Real-world data: The study’s use of real-world clinical data provides valuable insights, especially considering older and more comorbid patients who are often underrepresented in clinical trials. Very good. 2. Incorporation of comorbidities: The use of the Charlson Comorbidity Index to adjust life expectancy is a strong methodological approach, as it emphasizes the importance of considering a patient’s overall health, not just age. Well, done. 3. Comprehensive analysis: The inclusion of different lead times (5, 10, and 15 years) provides a thorough examination of overdiagnosis probabilities. Well, done 4. Follow-up duration: The median follow-up of 5.7 years, though reasonable, may not be sufficient to capture long-term outcomes or fully assess the impact of overdiagnosis on patient health. � Extension of the follow-up if necessary 5. Unknown Gleason scores: A considerable portion of patients did not have their Gleason scores recorded, which could have affected the robustness of the statistical comparisons. � severely limits the significance of the study 6. Overdiagnosis estimation: The estimation of overdiagnosis relies on external lead-time data from the literature rather than patient-specific lead-time information, which introduces potential biases.The study's findings may be less applicable to younger or healthier populations, limiting the external validity. The study emphasises the importance of considering both age and comorbidities when assessing the risk of overdiagnosis in prostate cancer screening. The study shows that older patients with significant comorbidities are more likely to be overdiagnosed, often without receiving active treatment. The results underline the need for personalised screening strategies and caution in the general use of PSA testing without consideration of patients' individual health profiles. The study addresses an important issue in PCa screening and provides useful clinical insights. The limitations regarding the data on Gleason scores and follow-up duration should be re-examined as they significantly limit the statistical power. The paper could also benefit from further clarification of the impact of overdiagnosis on patient management and treatment decisions. Overall, the research findings are solid and relevant, especially for clinicians looking to adjust PSA testing strategies based on individual patient risk factors. ****** 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 ******** [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.0315979.r001
Revision 1
18 Nov 2024 Author Response Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Done 2. Thank you for stating the following financial disclosure: Research funded by the research project of the Instituto de Salud Carlos III, code PI20/01334, Principal Investigator Dr. Blanca Lumbreras, co-financed with FEDER funds from 631 the European Union “A way of doing Europe”. 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. Done 3. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. We have added this statement in the manuscript and in the system: We will make our data fully accessible in a public repository upon acceptance of this manuscript (https://fairsharing.org/), in accordance with PLOS ONE’s open access requirements. We understand that all data, except data restricted by ethics protocol compliance, must be freely accessible upon publication. 4. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. With this expression we wanted to express that there was no table related to the results. We did not mean that there were data not shown in the article (this was an error). All results described in the text are reflected in figure 3 (figure 3A and figure 3B), so we have deleted this expression and rearranged the results (page 18). For the results on page 19, all data are described in the text. Additional Editor Comments: General comments: The study focuses on assessing the probability of overdiagnosis in the early detection of prostate cancer (PCa) using the PSA test. The study primarily investigates how the age of the patient and concomitant diseases affect overdiagnosis. The authors argue that most previous studies on PSA-based PCa screening have focussed on healthier populations, mainly from clinical trials, and want to provide a more relevant context by examining real-world clinical data. The aim of the study was to assess the likelihood of overdiagnosis based on PSA levels, Gleason scores and patients' comorbidities. The study is based on a retrospective cohort analysis of 1,070 asymptomatic men over 40 who were diagnosed with PCa between 2004 and 2022. The primary outcome is the probability of overdiagnosis assessed by life expectancy adjusted for comorbidities using the Charlson Comorbidity Index. Lead times of 5, 10 and 15 years are considered in the study. Statistical comparisons are made between the groups stratified by PSA values and Gleason scores. The paper contains several important results: Higher PSA levels (>10 ng/dL) and Gleason scores (≥8) are associated with an increased likelihood of overdiagnosis, particularly in older patients with significant comorbidities. Patients with lower PSA levels (4-10 ng/dL) and Gleason scores (≤7) were less likely to be overdiagnosed. Radiation exposure was higher in patients with higher PSA levels, and pharmacological treatment was more common in patients with elevated PSA levels. Most patients (71.7%) did not receive pharmacological treatment, highlighting the likelihood of overdiagnosis without active treatment. In total, this is a retrospective observational study measure methods in a double center setting. Idea fine. Specific comments: 1. Real-world data: The study’s use of real-world clinical data provides valuable insights, especially considering older and more comorbid patients who are often underrepresented in clinical trials. Very good. Thank you very much for your comment. Indeed, the use of real-world clinical data in the study allows us to capture perspectives that are often not considered in controlled clinical trials, especially in populations such as older adults or people with multiple conditions. 2. Incorporation of comorbidities: The use of the Charlson Comorbidity Index to adjust life expectancy is a strong methodological approach, as it emphasizes the importance of considering a patient’s overall health, not just age. Well, done. Thank you for your comment. This approach recognises that a patient's comorbidities can significantly influence his life expectancy and, consequently, the likelihood of overdiagnosis. 3. Comprehensive analysis: The inclusion of different lead times (5, 10, and 15 years) provides a thorough examination of overdiagnosis probabilities. Well done. Thank you very much. The use of multiple time periods (5, 10 and 15 years) in the study allows for a more in-depth analysis of the probabilities of overdiagnosis, providing information on how the probability of overdiagnosis changes over time. 4. Follow-up duration: The median follow-up of 5.7 years, though reasonable, may not be sufficient to capture long-term outcomes or fully assess the impact of overdiagnosis on patient health. � Extension of the follow-up if necessary As noted in the limitations section, the median follow-up duration of 5.7 years provides valuable information, but may be insufficient for a full analysis of the long-term effects of overdiagnosis on patient health and mortality. We have included in the limitation section the following sentence: ‘A longer follow-up would allow a clearer assessment of the progression of indolent cancers, which could improve both the understanding of the risks of overdiagnosis and the applicability of findings to inform clinical decisions and long-term patient care strategies’ (page 24, lines 654-657). 5. Unknown Gleason scores: A considerable portion of patients did not have their Gleason scores recorded, which could have affected the robustness of the statistical comparisons. � severely limits the significance of the study The absence of recorded Gleason scores for a significant number of patients is a limitation that could have affected the robustness and significance of the study results. This data gap highlights the challenge of conducting analyses in real-world practice where not all variables are consistently documented, and this could limit the applicability of the study to larger clinical populations. Nevertheless, we conducted a sensitivity analysis by assessing subgroups of patients with known Gleason scores. This analysis allowed for a more specific assessment of the likelihood of overdiagnosis in this subset. The results remained similar to those performed with the whole group. We have added this explanation in the limitation section (page 24, lines 646-649). 6. Overdiagnosis estimation: The estimation of overdiagnosis relies on external lead-time data from the literature rather than patient-specific lead-time information, which introduces potential biases. The study's findings may be less applicable to younger or healthier populations, limiting the external validity. As discussed in the study limitations, the study's approach to estimating overdiagnosis uses waiting time data from the literature, rather than patient-specific waiting times. This may have introduced potential biases by assuming uniform waiting times across diverse patient profiles. Consequently, the results may have limited external validity. Incorporating individualised waiting time estimate could improve the precision and applicability of the results across broader demographic groups. We have expanded the limitation in the discussion section to clarify this point (pages 23-24, lines 634-638). The study emphasises the importance of considering both age and comorbidities when assessing the risk of overdiagnosis in prostate cancer screening. The study shows that older patients with significant comorbidities are more likely to be overdiagnosed, often without receiving active treatment. The results underline the need for personalised screening strategies and caution in the general use of PSA testing without consideration of patients' individual health profiles. The reviewer is right. The study highlights the critical role of assessing both age and comorbidities to more accurately gauge the risk of overdiagnosis in prostate cancer screening. By demonstrating that older patients with significant comorbidities are more likely to be overdiagnosed - often leading to diagnoses that do not result in active treatment - the results reinforce the importance of tailoring screening methods with more personalised screening strategies to optimise care and avoid overtreatment. We have remarked this idea in the conclusion section (page 25, lines 677-679). The study addresses an important issue in PCa screening and provides useful clinical insights. The limitations regarding the data on Gleason scores and follow-up duration should be re-examined as they significantly limit the statistical power. The paper could also benefit from further clarification of the impact of overdiagnosis on patient management and treatment decisions. Overall, the research findings are solid and relevant, especially for clinicians looking to adjust PSA testing strategies based on individual patient risk factors. The reviewer is right. Limitations related to missing Gleason scores and the relatively short duration of follow-up warrant further attention, as they limit statistical power and the ability to observe long-term results. As we mentioned previously, we have extended the explanation for both limitations in the discussion section to further characterise their potential impact on the study results. In addition, we have included a paragraph to detail the impact of overdiagnosis on patient management and treatment decisions in the Implication for clinical practice section (page 23, lines 613-628): ‘Overdiagnosis in PCa screening can have significant implications for patient management and treatment decisions. When a diagnosis identifies an indolent or slow-growing cancer that may never cause symptoms or affect the patient's life expectancy, it often leads to unnecessary clinical interventions. These include frequent monitoring, invasive procedures or even treatments such as surgery or radiotherapy. These interventions can lead to adverse effects, such as incontinence and sexual dysfunction, with no clear benefit to the patient's survival or quality of life. We have shown in our study that older patients, or those with multiple comorbidities, are more likely to be overdiagnosed. This may mean that they are subjected to the psychological burden of a cancer diagnosis and the potential harms of overtreatment, rather than receiving the management of more relevant health problems. This underscores the need for a balanced approach to PSA testing, with clinicians carefully weighing the risks and benefits and potentially opting for active surveillance or less aggressive interventions in patients with low-risk profiles. Personalising patient care in this way not only minimises the impact of overdiagnosis, but also aligns treatment decisions with each patient's overall health goals and quality of life’. https://doi.org/10.1371/journal.pone.0315979.r002
4 Dec 2024 Decision Letter - Jan Philipp Radtke, Editor Impact of patients' age and comorbidities on prostate cancer overdiagnosis in clinical practice PONE-D-24-35992R1 Dear Dr. Lumbreras, 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, Jan Philipp Radtke, MBA Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0315979.r003
Formally Accepted
21 Dec 2024 Acceptance Letter - Jan Philipp Radtke, Editor PONE-D-24-35992R1 PLOS ONE Dear Dr. Lumbreras, 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 Dr. Jan Philipp Radtke Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0315979.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 .