PONE-D-22-26854Assessment of severity scoring systems for predicting mortality in critically ill patients receiving continuous renal replacement therapyPLOS ONE

Dear Dr. Chun,

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.

The manuscript focuses as a topic of potential interest. The study, however, has major shortcomings that preclude sound conclusions, and should be addressed. To mention some of them, i) concern about the fact that many of the scores being compared have used in their developmental cohort patients only with AKI needing CRRT unlike author study here where CKD patients needed dialysis is also included; ii) need to mention what percent of their patients had CKD among survivors vs non-survivors; iii) there is no mention of timing of scoring with respect to CRRT start; iv) concern about the fact that the authors overstate how good any of the models are; v) need to further explain that none of these tests are particularly good, and therefore they should more strongly emphasize that the primary conclusion of this study is that additional research is needed to develop better scoring systems; vi) unclear why the mortality of the cohort was so high; vii) need to include this high mortality as a potential limitation of the study, because these results may not be as relevant to centers with different patient selection and/or better CRRT outcomes, viii) need to report the results of the Hosmer-Lemeshow tests by simply providing the terms “significant” or “not significant”; ix) unclear if this is a secondary analysis of a cohort which was generated for a prior study; x) concern about Table 3, which is somewhat confusing; xi) need to review some statements in the Introduction that are somewhat misleading; xii) need to provide the distribution of baseline creatinine or eGFR and the proportion of patients with advanced CKD (stage 4 or 5); xiii) need to provide the relative number of patients with de novo AKI, AKI on CKD, and progressive CKD.

Please submit your revised manuscript by Mar 26 2023 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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We look forward to receiving your revised manuscript.

Kind regards,

Giuseppe Remuzzi

Academic Editor

PLOS ONE

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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: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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: No

Reviewer #2: Yes

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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 study by Chun et al is an original research to attempt using well validated scoring systems to predict 7 day and in hospital mortality in patients on CRRT. The study does follow the necessary statistical requirement to compare scoring systems and uses the standard metrics to judge prognostic scoring systems including discrimination and calibration. Unfortunately the conclusions are not valid since there are methodological flaws. Firstly many of the scores being compared have used in their developmental cohort patients only with AKI needing CRRT unlike authors study where CKD patients needing dialysis is also included. Additionally, they do not mention what percentage of their patients had CKD among survivors vs non-survivors. Besides this there is no mention of timing of scoring with respect to CRRT start.

Minor issues: Sentences need to structured for more clarity: for instance

Line 71 : which study is mentioned here

Line 72: Another several studies is grammatically incorrect. I think authors want to say that other studies have compared predictive power of disease severity scoring systems

Line 74 : needs clarification

Other than that the research meets all applicable standards for the ethics of experimentation and research integrity and seems to adhere to appropriate reporting guidelines and community standards for data availability.

Reviewer #2: Chun and colleagues present a single-center retrospective study from Korea of the ability of a variety of general and kidney-specific disease severity scores to predict mortality in patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). In short, though they somewhat overstate the utility of the kidney-specific scores, they found no single score performs that well (i.e., none had excellent discrimination nor calibration), though overall the kidney-specific scores performed somewhat better. Though the study has a lot of limitations, it is a relevant topic and reasonably thought provoking. The methods used appear appropriate and straightforward, and the data are presented clearly. However, the manuscript needs significant editing to improve the quality and clarify of the English language. In addition, I have the following recommendations, questions, and concerns:

1. The authors overstate how good any of these models are. For example, in the results the authors state that, "The AUROC revealed high discrimination ability of Demirjian’s score followed by Liano's score." In the discussion, they state that, "The AUROC for in-hospital mortality revealed high discrimination ability of Demirjian’s score (0.770) followed by Liano's score (0.728) and APACHE II score (0.710)." I would not agree with these statements. Though it's somewhat arbitrary, most would consider AUROC of 0.7-0.8 to have "moderate" or "acceptable" predictive ability. For example, a frequently cited interpretation of AUROC is as follows:

0.5 = No discrimination

0.5-0.7 = Poor discrimination

0.7-0.8 = Acceptable discrimination

0.8-0.9= Excellent discrimination

>0.9 = Outstanding discrimination

[From: Hosmer, D.W., Jr., Lemeshow, S. and Sturdivant, R.X. (2013). Assessing the Fit of the Model. In Applied Logistic Regression (eds D.W. Hosmer, S. Lemeshow and R.X. Sturdivant). https://doi.org/10.1002/9781118548387.ch5]

Overall, the results of this study are disappointing -- only 1 test was had borderline good AUC (Demirjian’s), but even that test had poor fit. I think the authors needs to do a better job of explaining that none of these tests are particularly good, and therefore they should more strongly emphasize that the primary conclusion of this study is that additional research is needed to develop better scoring systems.

2. Why was the mortality of the cohort so high? The authors should try to better address this. The authors suggest that AKI treated specifically with CRRT has higher mortality than AKI patients overall, which is true, but even for AKI requiring CRRT this is high. In most studies, the mortality of AKI requiring CRRT is closer to 50%. Comparing it to the BEST study (reference 6) -- which reported data from patients treated >20 years -- doesn't seem to adequate address the extremely high mortality seen here. To the degree that these authors are looking to evaluate mortality prediction tools, analyzing a cohort that has a much higher mortality than other centers could make the findings less generalizable. To help address this, they should report the mean or median and distribution of the disease severity scores of this cohort, particularly those that are a reflection of overall disease severity (i.e., SOFA, SAPS 3, APACHE 2, MODS). Regardless of whether they are able to somehow justify such a high mortality, this high mortality should be included as a potential limitation of the study, because these results may not be as relevant to centers with different patient selection and/or better CRRT outcomes.

3. This is extremely poorly worded: "Except for Liano's score (χ2=7.555, 166 p=0.478) and PICARD score (χ2=14.835, p=0.062), the Hosmer-Lemeshow test for in-hospital mortality demonstrated that calibration ability of all scores was not significant." Essentially, the authors are misusing the word significant here. The term "significant" when describing a statistical test indicates you reject the null hypothesis because the observed findings are unlikely to be due to change (i.e., p is <0.05). Technically, for Liano and PICARD in this study, the results of the Hosmer-Lemeshow test are *not* statistically significant (i.e., the null hypothesis that the predicted and observed outcomes are the same is not rejected). For Hosmer-Lemeshow test, a significant test indicates that the model is *not* a good fit, and a non-significant test indicates a good fit. I would suggest the authors report the results of the Hosmer-Lemeshow tests by simply providing the appropriate interpretation and avoiding the terms "significant" or "not significant", which are confusing in general for this type of test. For example, the authors could state, "Except for Liano's score (χ2=7.555, 166 p=0.478) and PICARD score (χ2=14.835, p=0.062), the Hosmer-Lemeshow test for in-hospital mortality demonstrated poor fit of the prediction models (p <0.05)." Similarly, this statement, "The APACHE II score was more discriminative compared to other general scores, but the results of the fitness test were not significant" could be changed to "The APACHE II score was more discriminative compared to other general scores, but the results of the fitness test showed poor calibration." Similarly, the abstract should state, "The Hosmer-Lemeshow test demonstrated good fit of Liano's score and PICARD scores." Likely, in the discussion I suggest, "The Hosmer-Lemeshow test on Demirjian’s score showed poor fit in our analysis, but it was more acceptable compared to the general severity scores."

4. Why are the authors publishing retrospective data from 2016-2018 in 2023? That seems odd. It certainly takes time to do this research, but a 4-year interval seems much. Is this a secondary analysis of a cohort which was generated for a prior study? If so, the authors should cite the prior work. Otherwise, at least a brief explanation as to why these patients from a cohort that is >4y old at publication seems warranted.

5. Table 3, as written, is somewhat confusing. It is hard to follow the directionality of comparisons. To help make it easier to follow, I suggest putting the score with the highest AUC first (Demirjian), followed by the second highest (Liano), etc. That should make it a little easier to read.

6. In the introduction, I found this statement to be somewhat misleading: "This is because the therapy is hemodynamically more stable than the intermittent hemodialysis therapy, and it is easy to control fluid balance and to correct metabolic acidosis or electrolyte imbalance and to correct nutritional deficiency [9]." In general, intermittent HD corrects acidosis and electrolytes just as well as CRRT. I also don't understand what is meant by "correct nutritional deficiency". I would simply end the sentence after "...control fluid balance." If they want to claim that CRRT is better for acidosis or electrolytes, a much more complicated discussion about instantaneous clearance vs. today daily dose of RRT (i.e., equilibrated Kt/V) would be needed, but it’s just best to avoid suggesting that CRRT is better than IHD for acidosis or electrolytes.

7. For the calibration tests, why did the author present results for only 5 of the 7 scoring systems? They should present them all or explain why they excluded SOFA and MODS.

8. In the discussion, for all the other prediction scores used (e.g., Mehta, Chertow, Paganini, SHARF II, and VELLORE), the authors should cite the original publications describing these scoring systems.

9. Do the authors have the distribution of baseline creatinine or eGFR? Or do they have the proportion of patients with advanced (e.g., stage 4 or 5) CKD? The authors suggest some patients with advanced CKD were included in the cohort. These patients (which many of which may be better classified as new ESKD rather than AKI) could be vastly different than patients with AKI. To better understand this cohort, more information about the relative number of patients with de novo AKI, AKI on CKD, and progressive CKD would be good.

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Reviewer #1: Yes: Anirban Ganguli

Reviewer #2: Yes: J. Pedro Teixeira

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PONE-D-22-26854R1Assessment of severity scoring systems for predicting mortality in critically ill patients receiving continuous renal replacement therapyPLOS ONE

Dear Dr. Chun,

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.

The revised manuscript is significantly improved. Most of the reviewer’s comments have been addressed. However, the authors need to further consider the few remaining minor recommendations by Reviewer 2 dealing with the conclusions. Moreover, additional English language editing of the manuscript is required.

Please submit your revised manuscript by May 29 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Giuseppe Remuzzi

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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)

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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

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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

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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: (No Response)

Reviewer #2: I think the manuscript is significantly improved. I have few additional minor recommendations:

1. In the discussion [lines 263-265 in the clean version] I once again suggest , "The Hosmer-Lemeshow test on Demirjian’s score showed poor fit in our analysis, but it was more acceptable compared to the general severity scores."

2. The term suitability is vague. In the conclusions, I recommend changing, "However, none of those evaluated in this study showed both excellent differentiation and suitability" to a more precise statement, "However, none of those evaluated in this study showed both excellent differentiation and calibration."

3. In the conclusion I also suggest being a bit less extreme by stating, "In conclusion, all severity scoring systems included in this study had limited ability to predict mortality of critically ill patients requiring CRRT."

4. As I commented in my first review, I think the manuscript could significantly benefit from additional English language editing.

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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: Yes: Anirban Ganguli

Reviewer #2: Yes: J. Pedro Teixeira

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Assessment of severity scoring systems for predicting mortality in critically ill patients receiving continuous renal replacement therapy

PONE-D-22-26854R2

Dear Dr. Chun,

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.

The re-revised version of the manuscript is definitely improved. The authors have properly addressed all the remaining issues raised by the Reviewer 2, and previously all comments from Reviewer 1. Thus, the manuscript is now suitable for publication.

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 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,

Giuseppe Remuzzi

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 #2: All comments have been addressed

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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 #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

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 #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 #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 #2: The manuscript is significantly improved with the changes made. I have no additional comments to make at this point.

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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 #2: Yes: J. Pedro Teixeira

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