Anemia-driven heterogeneity in TG-UA Association: A DDML approach to precision management of hyperuricemia in hospitalized patients aged 50–65

Tong Zhi; Jin Song; Shuai Zhang; Qi Li; Mingrui Li; Huaxin Zhang

doi:10.1371/journal.pone.0321554

Peer Review History

Original SubmissionSeptember 17, 2024
17 Sep 2024 Author Response https://doi.org/10.1371/journal.pone.0321554.r001
21 Jan 2025 Decision Letter - Shengqian Sun, Editor PONE-D-24-33617Anemic Patients are Unable to Reduce Uric Acid Levels by Lowering Triglyceride Level Based on Double Debiased Machine LearningPLOS ONE Dear Dr. Zhang, 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 Mar 07 2025 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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Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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). 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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: Zhi et al. present an intriguing research titled: “Anemic Patients are Unable to Reduce Uric Acid Levels by Lowering Triglyceride Levels Based on Double Debiased Machine Learning.” However, to further enhance their study, I recommend incorporating the following edits: • Page 9, Lines 53-54: The sentence "hyperuricemia’s association with dyslipidemia underscores the interconnected" is incomplete and does not clearly establish the link being discussed. The authors should elaborate on the significance of this connection and explain how it might affect clinical management. Expanding on these points will help strengthen the rationale for the study. • Page 9, Lines 48-50: The prevalence rates of hyperuricemia mentioned in different countries are based on outdated statistics, with the most recent being 13 years old. Please provide current or more recent statistics on hyperuricemia prevalence rates in various countries to make the comparison more relevant. Additionally, the prevalence rate of hyperuricemia in China has not been mentioned and should be included for completeness. • Page 10, Lines: 66-67: The current sentence is grammatically incorrect. Consider rephrasing it to “These factors need to be fully explored in relation to this association.” • Pages 14-15, Lines 148-155: I would recommend that the authors move this content to the Introduction or Discussion sections of the study, as it effectively highlights the novelty and robustness of the statistical methods employed in this research. This would allow the authors to effectively elaborate on their choice to use DDML and how it addresses limitations in traditional models. In contrast, the Methods section should largely focus on providing a clear, step-by-step explanation of the specific techniques applied to the data, while remaining brief and directly relevant to the research process. • Page 11, Line 79: There appears to be an error in the dates for data collection. The statement indicates that data was collected for patients from “August 1, 2016, to June 31, 2023.” However, June only has 30 days. Please verify and correct this discrepancy. • Page 15, Line 160: The use of the word "curse" in this context appears informal. I recommend the authors to adopt a more formal academic tone throughout the manuscript. • Pages 24-25, Lines 266-282: The authors’ explanation for the lack of association between triglycerides (TG) and uric acid (UA) levels in anemic patients could benefit from further clarity and coherence. While the authors mention various metabolic disruptions caused by anemia—such as shifts from aerobic to anaerobic metabolism, impacts on kidney function, and hormonal changes—they fail to explicitly connect these disruptions to the study's findings. To strengthen their argument, the authors should provide more specific references to how these mechanisms resulted in the observed nonsignificant association. Clear articulation of the relationship between these metabolic disruptions and the absence of correlation between TG and UA levels in anemic patients aged 50-65 is essential for enhancing the clarity and rigor of the discussion. • Page 24, Line 266: Please rephrase the statement "anemia contributes to the TG-UA relation," as it implies an association exists, which contradicts the study's findings that no such association was observed. • Page 23-25: In the discussion section, there is a lack of emphasis on the implications of the findings. The authors should address how these results can improve public health, outline their potential clinical significance, and discuss their broader medical importance. Highlighting these aspects will enhance the overall impact of the discussion. Reviewer #2: It seems the title only covers one aspect of the research conclusion but neglected the other one. The research is interesting and provides some new insights. But minors have to been addressed. Line 137. The formula should be noted with each nomenclature. How was the data partitioned into training and test. Is there any k-ford method used? Line 141. data sets or datasets? Line 212. By which data and how? Line 217. By which data and how? Table 1. Was it very odd that TG and UA values were the same? UA values cannot be found in Tables 2 3 4 5. ****** 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. 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Revision 1
17 Feb 2025 Author Response Reviewer 1 1.Page 9, Lines 53-54: The sentence "hyperuricemia’s association with dyslipidemia underscores the interconnected" is incomplete and does not clearly establish the link being discussed. The authors should elaborate on the significance of this connection and explain how it might affect clinical management. Expanding on these points will help strengthen the rationale for the study. Thank you for your constructive feedback. We sincerely apologize for the incomplete sentence and have restructured the text to explicitly clarify the mechanistic and clinical significance of the hyperuricemia-dyslipidemia association. Besides, according to your suggestion, the revised Abstract (Lines 54–59) are as follow: Substantial evidence suggests that hyperuricemia is mechanistically associated with dyslipidemia, particularly through shared pathways involving insulin resistance, oxidative stress, and lipid metabolism dysregulation. This bidirectional relationship implies that targeted management of dyslipidemia—via lifestyle interventions or lipid-lowering therapies—could synergistically mitigate hyperuricemia progression, thereby reducing associated cardiovascular and renal risks. 2.Page 9, Lines 48-50: The prevalence rates of hyperuricemia mentioned in different countries are based on outdated statistics, with the most recent being 13 years old. Please provide current or more recent statistics on hyperuricemia prevalence rates in various countries to make the comparison more relevant. Additionally, the prevalence rate of hyperuricemia in China has not been mentioned and should be included for completeness. Thank you for your insightful feedback. We agree that updating the prevalence statistics strengthens the relevance of the comparison. In the revised manuscript (Lines 49–54 in the Introduction), we have incorporated the most recent nationally representative data available for mainland USA and China. We acknowledge the challenge of obtaining uniformly recent global data and have emphasized this as a limitation in the Discussion (Line 323-325). Future studies could further address this gap. 3.Page 10, Lines: 66-67: The current sentence is grammatically incorrect. Consider rephrasing it to “These factors need to be fully explored in relation to this association.” Thank you for your valuable feedback. We appreciate your careful reading and constructive suggestion. The sentence has been revised as recommended to "These factors need to be fully explored in relation to this association" (now in Line 69 of the revised manuscript). This modification improves the clarity and grammatical accuracy of the statement while preserving its intended meaning. 4.Pages 14-15, Lines 148-155: I would recommend that the authors move this content to the Introduction or Discussion sections of the study, as it effectively highlights the novelty and robustness of the statistical methods employed in this research. This would allow the authors to effectively elaborate on their choice to use DDML and how it addresses limitations in traditional models. In contrast, the Methods section should largely focus on providing a clear, step-by-step explanation of the specific techniques applied to the data, while remaining brief and directly relevant to the research process. Thank you for your valuable feedback. We appreciate your suggestion to move the content discussing the novelty and robustness of the statistical methods to the Introduction or Discussion sections of the manuscript. In response to your recommendation, we have relocated the relevant content to the Introduction, where we elaborate on the choice to use DDML and how it addresses the limitations of traditional models. This adjustment allows us to better highlight the significance of the statistical approach and its contributions to the research. We have also ensured that the Methods section now focuses primarily on providing a clear, step-by-step explanation of the techniques applied to the data, remaining concise and directly relevant to the research process. We believe these revisions enhance the structure and clarity of the manuscript, and we thank you again for your insightful suggestions. 5.Page 11, Line 79: There appears to be an error in the dates for data collection. The statement indicates that data was collected for patients from “August 1, 2016, to June 31, 2023.” However, June only has 30 days. Please verify and correct this discrepancy. •Page 15, Line 160: The use of the word "curse" in this context appears informal. I recommend the authors to adopt a more formal academic tone throughout the manuscript. Thank you for your constructive feedback. We appreciate your attention to detail and your suggestions for improving the manuscript. Regarding the discrepancy in the data collection dates, we have verified the dates and corrected the error. The data collection period is now accurately stated as "August 1, 2016, to June 30, 2023," in line with the correct number of days in June. In response to your comment about the use of the word "curse," we have replaced it with a more formal and academic expression. We have revised the relevant sections to ensure the tone throughout the manuscript is consistent with the standards of academic writing. We believe these revisions address your concerns and improve the clarity and formal tone of the manuscript. Thank you again for your valuable suggestions. 6.Pages 24-25, Lines 266-282: The authors’ explanation for the lack of association between triglycerides (TG) and uric acid (UA) levels in anemic patients could benefit from further clarity and coherence. While the authors mention various metabolic disruptions caused by anemia—such as shifts from aerobic to anaerobic metabolism, impacts on kidney function, and hormonal changes—they fail to explicitly connect these disruptions to the study's findings. To strengthen their argument, the authors should provide more specific references to how these mechanisms resulted in the observed nonsignificant association. Clear articulation of the relationship between these metabolic disruptions and the absence of correlation between TG and UA levels in anemic patients aged 50-65 is essential for enhancing the clarity and rigor of the discussion. Thank you for your valuable feedback. We appreciate your suggestion to provide further clarity and coherence in our explanation regarding the lack of association between TG and UA levels in anemic patients. In response to your comment, we have revised the manuscript to connect the various metabolic disruptions caused by anemia—such as shifts from aerobic to anaerobic metabolism, kidney dysfunction, and hormonal changes—to the observed nonsignificant association between TG and UA levels. We have also provided more specific references to how these mechanisms may impact lipid and purine metabolism, and why these complex interactions could result in the lack of a direct correlation between TG and UA in the study population. We believe these revisions clarify the relationship between the metabolic disruptions associated with anemia and the absence of a significant TG-UA association, strengthening the overall argument in the manuscript. Thank you again for your thoughtful and constructive suggestions. 7.Page 24, Line 266: Please rephrase the statement "anemia contributes to the TG-UA relation," as it implies an association exists, which contradicts the study's findings that no such association was observed. Thank you for your insightful feedback. We appreciate your suggestion to rephrase the statement regarding the role of anemia in modulating the relationship between TG and UA levels, as it implied an association that contradicts the study's findings. In response to your comment, we have revised the sentence to clarify that while anemia may influence various metabolic functions, it does not lead to a significant correlation between TG and UA levels in our study population. We have reworded the text to better reflect the absence of a significant association and to more accurately describe the potential metabolic disruptions caused by anemia without implying a direct relationship. We believe these revisions strengthen the clarity and accuracy of the manuscript, ensuring it aligns with the study's findings. Thank you once again for your constructive suggestion 8.Page 23-25: In the discussion section, there is a lack of emphasis on the implications of the findings. The authors should address how these results can improve public health, outline their potential clinical significance, and discuss their broader medical importance. Highlighting these aspects will enhance the overall impact of the discussion. Thank you for your valuable feedback and suggestion to emphasize the implications of our findings in the discussion section. In response to your comment, we have added a new paragraph that outlines the potential public health, clinical, and broader medical significance of our results. Specifically, we highlight the importance of managing TG levels to reduce the risk of hyperuricemia and related complications, particularly in individuals aged 50-65. Additionally, we emphasize the gender-specific variations in the TG-UA relationship and propose more personalized clinical approaches based on these findings. We also discuss how our results may inform preventive strategies and improve patient outcomes, particularly in the context of metabolic and cardiovascular diseases. We believe these additions address your concerns and enhance the overall impact of the discussion, providing greater clarity on how our findings can be applied in clinical practice and public health strategies. Thank you again for your constructive feedback. Reviewer 2 1.It seems the title only covers one aspect of the research conclusion but neglected the other one. Thank you for your valuable feedback. I appreciate your observation regarding the title and its coverage of the research conclusion. In response to your comment, I have revised the title to better reflect both aspects of the study. The new title, "Anemia-Driven Heterogeneity in TG-UA Association: A DDML Approach to Precision Management of Hyperuricemia in Hospitalized Patients Aged 50-65," now more comprehensively encapsulates the key themes of the research, including the focus on anemia and its impact on the TG-UA association, as well as the application of DDML in precision management of hyperuricemia. I hope the revised title meets your expectations and provides a clearer representation of the study's scope and findings. Thank you again for your constructive suggestions. 2.Line 137. The formula should be noted with each nomenclature. How was the data partitioned into training and test. Is there any k-fold method used? Line 212. By which data and how? Line 217. By which data and how? Thank you for your thoughtful questions. In response to your comment on Line 137, I have added detailed explanations of the variables in each part of the formula beneath the result tables for the analytical models. This change aims to enhance the clarity of the tables for readers. Regarding your query on how the data was partitioned into training and test sets, we utilized 5-fold cross-validation (the default k=5 is aligned with prior DDML-related researches), where both the test and validation sets were automatically determined in each fold. This process ensures that the partitioning is done independently without manual control, allowing for a more objective and robust model evaluation. Our approach follows the methodology outlined by Victor Chernozhukov and his colleagues in 2018, ensuring alignment with established practices. For your questions on Lines 212 and 217, I have clarified the data used and the methodologies applied. The observational data we aim to obtain corresponds to the TG levels in the models that show statistical significance, as noted earlier. We trust that these clarifications address your concerns, and we sincerely appreciate your careful review. 3.Line 141. data sets or datasets? Thank you for your insightful comment. In response to your question regarding the use of "data sets" versus "datasets," we have revised the manuscript to use "datasets" (as a single word) consistently throughout, including in line 78. We believe this aligns with the current convention in the field. We appreciate your careful review and believe this change enhances the manuscript's consistency. 4.Table 1. Was it very odd that TG and UA values were the same? UA values cannot be found in Tables 2 3 4 5. Thank you for your careful review and insightful comments. With regard to variables such as gender, age,UA and TG, we excluded cases with missing data. This is the reason why the sample size of TG and UA are the same. For other control variables, missing values were addressed using mean imputation. In Table 1, we present the original sample size of the control variables such as GLU, Sodiumion, CHE and etc. As for your comment about the absence of UA values in Table 2 3 4 5, we appreciate your attention to this detail. UA, being the dependent variable in each model, was not listed in the table, which could potentially cause confusion for readers. To address this, we have added explanations below each table to improve clarity and facilitate better understanding for the readers. Thank you again for your valuable feedback Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0321554.r003
9 Mar 2025 Decision Letter - Shengqian Sun, Editor Anemia-Driven Heterogeneity in TG-UA Association: A DDML Approach to Precision Management of Hyperuricemia in Hospitalized Patients Aged 50-65 PONE-D-24-33617R1 Dear Dr. Zhang, 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, Shengqian Sun Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 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: Thank for the authors revising the manuscript, and it has been greatly improved. I have no more questions. Cheers, ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0321554.r004
Formally Accepted
Acceptance Letter - Shengqian Sun, Editor PONE-D-24-33617R1 PLOS ONE Dear Dr. Zhang, 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 Dr. Shengqian Sun Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0321554.r005

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