Creatinine versus cystatin C for renal function-based mortality prediction in an elderly cohort: The Northern Manhattan Study

Joshua Z. Willey; Yeseon Park Moon; S. Ali Husain; Mitchell S. V. Elkind; Ralph L. Sacco; Myles Wolf; Ken Cheung; Clinton B. Wright; Sumit Mohan

doi:10.1371/journal.pone.0226509

Peer Review History

Original SubmissionJuly 23, 2019
19 Aug 2019 Decision Letter - Tatsuo Shimosawa, Editor PONE-D-19-20793 Creatinine versus Cystatin C for Renal Function-Based Mortality Prediction in an Elderly Cohort: the Northern Manhattan Study PLOS ONE Dear Dr Willey, 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 Oct 03 2019 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, Tatsuo Shimosawa, M.D., Ph.D. 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 http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 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: I Don't Know 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: The manuscript by Willey et al. investigated the role of estimated GFR based on creatinine (eGFRcr) or cystatin-C (eGFRcys) for mortality risk prediction in an elderly, ethnically diverse cohort, and found that eGFRcys was superior in predicting the risk of all-cause mortality. The topic may be of scientific interest, and might give some impact on clinical practice. I feel, however, there are still some unclear and unconvincing points that should be clarified from a scientific viewpoint. My major concerns are as follows: 1. Although there was a slight but significant difference in a predicting power between the two measures, the reason is not clear. As the authors state in Discussion, the most important point must be whether eGFRcys is superior in accurately measuring GFR in their cohort. This point should be clarified at least in a small number of subjects in their cohort, using iohexol or inulin as an exogenous marker. 2. Also, the dot plot between eGFRcr (mean, 74.7) and eGFRcys (mean, 51.7) should be presented to know the correlation between the two. As the CKD stage progresses, does the discrepancy become larger? 3. It is also important and should be analyzed whether the predicting power of eGFRcys was influenced by the severity of CKD, i.e., CKD stage 1-2 (eGFR > 60), stage 3, or stage 4-5 (eGFR < 30). Mortality incidence should have been more often in advanced CKD stages. This point should be clearly presented. 4. In Figure 3, the ROC curve of eGFRcys seemed much better than eGFRcr among the subjects under 70. Why? 5. It is not clear what are critical conditions where eGFRcys is superior to eGFRcr in mortality risk prediction. Males? Younger age? Caucasians? Subgroup analysis should be performed in order to specify the factors which have impact in favor of eGFRcys for risk prediction. Reviewer #2: The authors compared creatinine and cystatin C as factor of eGFR. I think that the aim of this study is very interesting to nephrologist, and felt old. 1. I believe that authors knew serum cystatin C concentration is influenced by many factors, hyper/hypo thyroid, HIV infection, and so on. I could not find in the manuscript about exclusion of these patient from cohort. 2. Main finding of this study may be “eGFRcys predicted all-cause mortality better than eGFRcre”. However, this fact is already reported indirectly as the authors cited in Ref 24, 33,34, and Astor BC et al 2011, Peralta CA et al 2011 ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files 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.0226509.r001
Revision 1
5 Nov 2019 Author Response We appreciate the reviewer’s comments on our manuscript. We have included the comments by the reviewers below and have modified the manuscript as requested in the appropriate sections and included below are responses to the reviews. Reviewer #1: 1. Although there was a slight but significant difference in a predicting power between the two measures, the reason is not clear. As the authors state in Discussion, the most important point must be whether eGFRcys is superior in accurately measuring GFR in their cohort. This point should be clarified at least in a small number of subjects in their cohort, using iohexol or inulin as an exogenous marker. Response: We agree with the reviewer that having a gold-standard measure of GFR would be ideal. Unfortunately the serum measures were collected at the time of initial enrollment in the Northern Manhattan Study between 1993 to 2001 such that we do not have the ability to measure GFR concomitantly. We currently do not have funding to measure GFR objectively in NOMAS but this is a planned future study if funded. We have acknowledged this is a limitation of our study. 2. Also, the dot plot between eGFRcr (mean, 74.7) and eGFRcys (mean, 51.7) should be presented to know the correlation between the two. As the CKD stage progresses, does the discrepancy become larger? Response: We agree and have included the following figure to outline the raw data with a dot and Bland&Altman plot. From our data it seems the discrepancy between eGFRCys and eGFRCr is higher at the higher ranges of GFR estimation than in the lower end. We have included this as the new figure 1 and added a comment in the results section. Dot plot (left) and the Bland & Altman plot (right) (figure 1) In results section: “The mean eGFRcr (74.68±18.8 ml/min/1.73m2) was higher than eGFRcys (51.72±17.2 ml/min/1.73m2); there was a greater difference in GFR estimations at the upper rather than lower ranges (figure 1).” 3. It is also important and should be analyzed whether the predicting power of eGFRcys was influenced by the severity of CKD, i.e., CKD stage 1-2 (eGFR > 60), stage 3, or stage 4-5 (eGFR < 30). Mortality incidence should have been more often in advanced CKD stages. This point should be clearly presented. Response: We agree with the reviewer than analyzing by CKD stages would have been ideal in our analyses. Unfortunately the proportion of participants with stages 4-5 in our cohort was small and chose to collapse stages 3-5 together. We were nonetheless concerned that severity of CKD would be important and performed our analyses using GFR in a continuous manner (per 10 ml/min/1.73m2) and noted there was a significant association with all-cause mortality. 4. In Figure 3, the ROC curve of eGFRcys seemed much better than eGFRcr among the subjects under 70. Why? Response: We thank the reviewer for highlighting this finding in our study. We were concerned that in the older participants in our study serum creatinine would be less predictive due to loss of muscle mass in the elderly, as well as less validated GFR estimation formulae for multi-ethnic populations such as ours. The discussion has been modified as follows: “The results, particularly in the participants older than age 70, related to eGFRcys are consistent with findings from other studies suggesting that eGFRcys may be a more accurate estimate of GFR than a serum creatinine-based formula, and extend those findings to an elderly multiethnic population where GFRcr may be confounded by loss of muscle mass which would attenuate the association. The inability to accurately estimate GFR disproportionately affects blacks and Hispanic elderly patients creating significant challenges for prognostication for outcomes, decline of renal function, and management (particularly for medication dosing) of these individuals.” 5. It is not clear what are critical conditions where eGFRcys is superior to eGFRcr in mortality risk prediction. Males? Younger age? Caucasians? Subgroup analysis should be performed in order to specify the factors which have impact in favor of eGFRcys for risk prediction. Response: We performed analyses examining GFR estimates by sex, age, and race-ethnicity and noted that for predicting 5 year mortality risk, eGFRcys was better than eGFRcr among those age under 70 years old (p for difference=0.047, compared to age>70) or men (p for difference=0.049, compared to woman). No race-ethnicity differences were found. We have included this in the results section. For predicting 10 year mortality risk, there were no statistically interactions. We have included the following table for reference for the reviewer but not in the manuscript since the results were outlined in text. 5 year mortality 10 year mortality NRI (%) 95% CI of NRI p for difference NRI (%) 95% CI of NRI p for difference age<70 22.3 (10.6, 34.0) 0.047 4.6 (-2.5,11.8) 0.654 age>=70 9.3 ( 4.2, 14.4) 2.9 ( 0.3, 5.4) Women 7.4 (1.4, 13.4) 0.049 4.4 ( 1.2 ,7.6) 0.965 Men 16.9 (9.6, 24.3) 4.5 (-0.2, 9.2) White 8.8 (0.7, 16.9) 0.977 0.8 (-3.5, 5.2) 0.187 Black 12.1 (4.1, 20.0) 6.5 ( 1.9,11.2) Hispanic 14.9 (6.6, 23.2) 4.9 ( 0.2, 9.7) We have included the AUC’s in our figures to describe overall model fit in these groups. In conclusion serum cystatin-C based GFR estimated performed better in those under age 70 and in men. Overall however the AUC was low for both cystatin-C and creatinine based GFR estimations emphasizing the need for further better data in diverse populations such as the elderly and women. We have now included this as an additional comment in the results and discussion. “Interestingly in our cohort the predictive ability of eGFR (regardless of serum measure) appeared higher in the younger participants and men who were most likely to be included in prior cohort that derived GFR estimation formulae. These results highlight the importance of improved accuracy in measurement of GFR in diverse populations will help better understand how CKD is associated with CVD mortality related disparities.” Reviewer #2: 1. I believe that authors knew serum cystatin C concentration is influenced by many factors, hyper/hypo thyroid, HIV infection, and so on. I could not find in the manuscript about exclusion of these patient from cohort. Response: We thank the reviewer for this comment. We did not collect information on thyroid and HIV status is NOMAS, but these conditions were not exclusion criteria for the Northern Manhattan Study. Participants were excluded from a medical condition perspective only if they already had a stroke. 2. Main finding of this study may be “eGFRcys predicted all-cause mortality better than eGFRcre”. However, this fact is already reported indirectly as the authors cited in Ref 24, 33,34, and Astor BC et al 2011, Peralta CA et al 2011 Response: We agree with the reviewer, however this topic has not been explored to the same degree in diverse, multi-ethnic, and more predominantly older populations such as the Northern Manhattan Study. Attachments Attachment Submitted filename: Reviewers comments-PLOS ONE final.docx https://doi.org/10.1371/journal.pone.0226509.r002
15 Nov 2019 Decision Letter - Tatsuo Shimosawa, Editor PONE-D-19-20793R1 Creatinine versus Cystatin C for Renal Function-Based Mortality Prediction in an Elderly Cohort: the Northern Manhattan Study PLOS ONE Dear Dr Willey, 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. As a reviewer pointed out, cystatin C is affected by multiple conditions. It is a limitation of this study that you can not exclude those cohort with thyroid dysfunction, HIV infection and others. The authors should describe the limitation on this point. We would appreciate receiving your revised manuscript by Dec 30 2019 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, Tatsuo Shimosawa, M.D., Ph.D. 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: All comments have been addressed Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ****** 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: The revised manuscript by Wiiley et al. responded well to the points raised. I have no further critique. Reviewer #2: At least authors should refer in manuscript about my previous comment 1. Because it must exist and affect on the results. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files 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.0226509.r003
Revision 2
26 Nov 2019 Author Response We appreciate the reviewer’s comments on our manuscript. We have included the comments by the reviewers below and have modified the manuscript as requested in the appropriate sections and included below are responses to the reviews. Reviewer: 1. As a reviewer pointed out, cystatin C is affected by multiple conditions. It is a limitation of this study that you can not exclude those cohort with thyroid dysfunction, HIV infection and others. The authors should describe the limitation on this point. and At least authors should refer in manuscript about my previous comment 1. Because it must exist and affect on the results. Response: We agree with the reviewer and editor that the lack of this kind of medical comorbidity information is a limitation of our study and have included the following sentence in the limitation sections: “Cystatin-C levels can be affected by several medical conditions including thyroid dysfunction44 and human immunodeficiency virus infection45 which unfortunately we did not collect in NOMAS.” We have also added the very helpful references by the reviewer on other studies that have studied creatinine and cystatin as predictors (Astor BC et al 2011, Peralta CA et al 2011). Attachments Attachment Submitted filename: Reviewers comments-PLOS ONE v2.docx https://doi.org/10.1371/journal.pone.0226509.r004
2 Dec 2019 Decision Letter - Tatsuo Shimosawa, Editor Creatinine versus Cystatin C for Renal Function-Based Mortality Prediction in an Elderly Cohort: the Northern Manhattan Study PONE-D-19-20793R2 Dear Dr. Willey, 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, Tatsuo Shimosawa, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0226509.r005
Formally Accepted
2 Jan 2020 Acceptance Letter - Tatsuo Shimosawa, Editor PONE-D-19-20793R2 Creatinine versus Cystatin C for Renal Function-Based Mortality Prediction in an Elderly Cohort: the Northern Manhattan Study Dear Dr. Willey: 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 Prof. Tatsuo Shimosawa Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0226509.r006

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