Lipid profiles and risk of major adverse cardiovascular events in CKD and diabetes: A nationwide population-based study

Yeonhee Lee; Sehoon Park; Soojin Lee; Yaerim Kim; Min Woo Kang; Semin Cho; Sanghyun Park; Kyungdo Han; Yong Chul Kim; Seoung Seok Han; Hajeong Lee; Jung Pyo Lee; Kwon Wook Joo; Chun Soo Lim; Yon Su Kim; Dong Ki Kim

doi:10.1371/journal.pone.0231328

Peer Review History

Original SubmissionOctober 22, 2019
27 Nov 2019 Decision Letter - Gregory Shearer, Editor PONE-D-19-29456 Lipid profiles and risk of major adverse cardiovascular events in patients with CKD and diabetes: A nationwide population-based study PLOS ONE Dear Prof. Kim, 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. We would appreciate receiving your revised manuscript by Jan 11 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols 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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Gregory Shearer Academic Editor PLOS ONE Journal Requirements: 1. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. 2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.1093/eurheartj/ehy836 https://doi.org/10.1038/s41598-018-21550-3 https://doi.org/10.1093/ndt/gfv379 https://doi.org/10.1111/ceo.13157 https://doi.org/10.1038/s41598-019-46654-2. In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed. 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: 1) title, please don't use "patients" 2)abstract, please provide numeric values (eg, OR values and 95%CIs) 3) Table 1, please remove P-value due to large sample size 4) The lowest cutoff point for LDL was 79 mg/dL. Please further look at 50 and 30 mg/dL due to the large case number 5) Please discuss the potential limitation for using ICD codes to identify cases. Reviewer #2: Using the Korean National Health Insurance Database in this manuscript the authors have described the association of serum lipid parameters with cardiovascular outcomes in a large population of Korean )patients with mild to severe diabetic nephropathy. They found that patients with advanced CKD (eGFR <30 mL/min/1.73 m2) had lower serum total cholesterol, LDL-c, and HDL-c but higher non-HDL-c levels and triglyceride/HDL-c ratios. They found a positive correlation between serum LDL-c and the major adverse cardiovascular events (MACE) in patients with early and advanced CKD. They further found a U-shaped relationship between serum LDL-c and all-cause mortality. The TG/HDL-c ratio showed a positive association for risk of MACE in patients with early CKD, but not advanced CKD. They found no correlation between serum TG/HDL ratio and all-cause mortality in the study population. The LDL-c level predicted the risk for MACEs and all-cause mortality in diabetic patients with early and advanced CKD, although the patterns of the association differed from each other. The TG/HDL-chol ratio did not predict the risk for either MACEs or all-cause mortality in patients with advanced diabetic nephropathy. However, the TG/HDL-c ratio predicted the risk of MACE in diabetic patients with early CKD. The data presented on a large Korean CKD population in this paper is novel and consistent with those reported on CKD populations of other nationalities. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: ND Vaziri [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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0231328.r001
Revision 1
10 Jan 2020 Author Response Reviewer comments: Reviewer #1: 1) title, please don't use "patients" We agree with the review’s comments. As the reviewer recommended, we have removed “patients” from the title. 2) abstract, please provide numeric values (eg, OR values and 95% CIs) We thank the reviewer for critical comments. We have added P-for-trend for the linear association of LDL-c or TG/HDL-c ratio with HR, and we also added the lowest and highest HR (95% CI) for the U-shape relationship in the revised manuscript. 3) Table 1, please remove P-value due to large sample size Thank you for the reviewer’s thoughtful comments. We have removed P-values in Table 1. 4) The lowest cutoff point for LDL was 79 mg/dL. Please further look at 50 and 30 mg/dL due to the large case number We thank the reviewer for these points. As the reviewer recommended, we have looked further at patients with LDL-c <79 mg/dL (1st octiles). Of 6,564 patients, the number of patients with the categories of LDL-c 50-78 mg/dL and 30-49 mg/dL was 5,343 and 915, respectively. Most of the 1st octile group of baseline LDL-c had LDL-c levels above 50 mg/dL, and those with extremely low LDL-c (<30 mg/dL) accounted for 0.6% of the total (306/51,757), which were very low, resulting in insufficient statistical power. 5) Please discuss the potential limitation for using ICD codes to identify cases. We agree with the reviewer’s comment on this. The International classification of diseases (ICD) data are often used by health researchers to study health services, mortality, and other outcomes. Although validation studies can be carried out to ensure the validity of coding in administrative data, there are still limitations when using ICD information (Izeta Kurbasic et al. Acta Inform Med. 2008; 16(3): 159–161., Jetté et al. Med Care 2010;48: 1105-1110). The ICD classification is not suitable if there is few or no information about the patient. In this case, we can only code symptoms of the disease, which can be caused by several different health conditions that can be coded regularly, if we have enough information to confirm diagnosis. Consequently, ICD-based diagnosis may underestimate the true prevalence of diseases. Also, disease severity can usually not be determined using ICD-coded data alone. In a recent report, it was concluded that the ICD codes alone failed to capture many heart failure (HF) admissions, and that using the hospital codes alone would underestimate the total burden of HF (E. Ingelsson et al. The European Journal of Heart Failure (2005) 787–791). This limitation was also reported in the identification of diabetes (Khokhar B, et al. BMJ Open 2016;6:e009952). We have added this issue as a limitation in the revised manuscript. Reviewer #2: Using the Korean National Health Insurance Database in this manuscript the authors have described the association of serum lipid parameters with cardiovascular outcomes in a large population of Korean patients with mild to severe diabetic nephropathy. They found that patients with advanced CKD (eGFR <30 mL/min/1.73 m2) had lower serum total cholesterol, LDL-c, and HDL-c but higher non-HDL-c levels and triglyceride/HDL-c ratios. They found a positive correlation between serum LDL-c and the major adverse cardiovascular events (MACE) in patients with early and advanced CKD. They further found a U-shaped relationship between serum LDL-c and all-cause mortality. The TG/HDL-c ratio showed a positive association for risk of MACE in patients with early CKD, but not advanced CKD. They found no correlation between serum TG/HDL ratio and all-cause mortality in the study population. The LDL-c level predicted the risk for MACEs and all-cause mortality in diabetic patients with early and advanced CKD, although the patterns of the association differed from each other. The TG/HDL-chol ratio did not predict the risk for either MACEs or all-cause mortality in patients with advanced diabetic nephropathy. However, the TG/HDL-c ratio predicted the risk of MACE in diabetic patients with early CKD. The data presented on a large Korean CKD population in this paper is novel and consistent with those reported on CKD populations of other nationalities. - We appreciate the reviewer for the thoughtful comment. Our study aimed to identify possible associations between lipid profile parameters and MACEs and mortality in CKD patients with diabetes and to evaluate the impact of kidney function on the associations, with large cohort and inclusiveness. Accordingly, we believe that the present data showed the consistence with those reported on CKD with diabetes populations of other nationalities. Again, we would like to thank the reviewer very much. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0231328.r002
5 Feb 2020 Decision Letter - Gregory Shearer, Editor PONE-D-19-29456R1 Lipid profiles and risk of major adverse cardiovascular events in CKD and diabetes: A nationwide population-based study PLOS ONE Dear Prof. Kim, 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. We would appreciate receiving your revised manuscript by Mar 21 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols 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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Gregory Shearer Academic Editor PLOS ONE Additional Editor Comments (if provided): Please be sure to carefully and completely respond to Reviewer 1's questions. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) 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: Partly 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: Yes 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: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thanks for addressing most of my concerns. However, there were still ~1200 participants with LDL <50 and 300 with LDL <30. You may have power to detect a trend or moderate-to-big difference. Statistical significance is not a major issue we should concern about. Even you did not find statistically significant results, it is still worthy to report these results as they could be practically significant. Reviewer #2: The authors have addressed the issues I had raised satisfactorily. I therefore recommend acceptance of their paper for publication. ****** 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: Yes: Nosratola D Vaziri MD, MACP [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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0231328.r003
Revision 2
21 Feb 2020 Author Response #1 Reviewer #1: Thanks for addressing most of my concerns. However, there were still ~1200 participants with LDL <50 and 300 with LDL <30. You may have power to detect a trend or moderate-to-big difference. Statistical significance is not a major issue we should concern about. Even you did not find statistically significant results, it is still worthy to report these results as they could be practically significant. � We thank the reviewer for these points, again. As the reviewer recommended, we have looked further at patients with LDL-c <79 mg/dL (1st octiles) and additionally analyzed subgroups with the categories of LDL-c 50-78 mg/dL, 30-49 mg/dL and <30 mg/dL. Most of the 1st octile group of baseline LDL-c had LDL-c levels above 50 mg/dL, and those with extremely low LDL-c (<30 mg/dL) accounted for 0.6% of the total (306/51,757). When compared with patients with LDL-c 50-78 mg/dL, the relative hazard of MACEs and all-cause mortality in the category of LDL-c 30-49 mg/dL was higher in both baseline and time-varying models (highest HR 1.32; 95% CI 1.13-1.55). Notably, this trend was more prominent in patients with advanced CKD (HR 1.83; 95% CI 1.36-2.45 and HR 1.80; 95% CI 1.34-2.42 in baseline and time-varying models, respectively). These additional results more firmly suggested that the shape of association between serum LDL-c and all-cause mortality is a U-curve, especially in patients with advanced CKD, which is considered to support real-world data. We have added these results in the result section of the revised manuscript. Again, we are really grateful for your consideration. Attachments Attachment Submitted filename: Response to Reviewers_revised2 (1).docx https://doi.org/10.1371/journal.pone.0231328.r004
26 Feb 2020 Decision Letter - Gregory Shearer, Editor PONE-D-19-29456R2 Lipid profiles and risk of major adverse cardiovascular events in CKD and diabetes: A nationwide population-based study PLOS ONE Dear Prof. Kim, 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. We would appreciate receiving your revised manuscript by Apr 11 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols 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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Gregory Shearer Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: 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 ****** 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: Thank you for including additional analysis to look at those with low LDL-c concentration . Results are important for public health and clinical practice. The only suggestion is to add these results into your abstract. This is important because in abstract you stated that "There was a positive linear association between serum LDL-c and MACE risk in both early and advanced CKD patients (P <0.001 for trend)" (Line 42). This may not be true based on your additional analysis :" the relative hazard of MACEs and all-cause mortality in the category of LDL-c 30-49 mg/dL was higher in both baseline and time-varying models " (line 250-251). ****** 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 [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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0231328.r005
Revision 3
27 Feb 2020 Author Response Reviewer #1: Thank you for including additional analysis to look at those with low LDL-c concentration. Results are important for public health and clinical practice. The only suggestion is to add these results into your abstract. This is important because in abstract you stated that "There was a positive linear association between serum LDL-c and MACE risk in both early and advanced CKD patients (P <0.001 for trend)" (Line 42). This may not be true based on your additional analysis: "the relative hazard of MACEs and all-cause mortality in the category of LDL-c 30-49 mg/dL was higher in both baseline and time-varying models" (line 250-251). -> Thank you for the reviewer’s thoughtful comments. We have added these results in the abstract. The sentences added in the abstract are the following. There was a positive linear association between serum LDL-c and MACE risk in both early and advanced CKD patients (P <0.001 for trend), except for the category of LDL-c 30-49 mg/dL in extremely low LDL-c subgroup analyses. Attachments Attachment Submitted filename: Response to Reviewers_revised3.docx https://doi.org/10.1371/journal.pone.0231328.r006
23 Mar 2020 Decision Letter - Gregory Shearer, Editor Lipid profiles and risk of major adverse cardiovascular events in CKD and diabetes: A nationwide population-based study PONE-D-19-29456R3 Dear Dr. Kim, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, Gregory Shearer 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: 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 ****** 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: The authors have adequately addressed your comments for previous version. No further comments. Suggest to accept. ****** 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.0231328.r007
Formally Accepted
25 Mar 2020 Acceptance Letter - Gregory Shearer, Editor PONE-D-19-29456R3 Lipid profiles and risk of major adverse cardiovascular events in CKD and diabetes: A nationwide population-based study Dear Dr. Kim: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Gregory Shearer Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0231328.r008

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