PONE-D-22-17427Effect of dietary branched chain amino acids on liver related mortality: Results from a large cohort of North American patients with advanced HCV infectionPLOS ONE

Dear Dr. Yu,

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.

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We look forward to receiving your revised manuscript.

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Wan-Long Chuang, M.D., Ph.D.

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: Partly

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

Reviewer #1: No

Reviewer #2: I Don't Know

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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: No

Reviewer #2: Yes

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Reviewer #1: Yes

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: In this retrospective cohort study conducted by using the extended follow-up data from the HALT-C trial, the authors suggested that dietary BCAA intake was not associated with liver-related death or liver transplantation. Besides, incidence of HCC or hepatic encephalopathy was not associated with dietary BCAA level.

Major comments

The authors used the extended data from the HALT-C trial, and the patients enrolled in this trial were with hepatic fibrosis (Ishak score 3-4) or compensated cirrhosis (CTP score < 7). According to the previous studies, the effects on BCAAs, which act as pharmaco-nutrients but not medication, on hepatic outcomes were more suggested in patients who had developed cirrhotic complications. The less severity of liver disease in these patients may contribute to the negative findings in this study.

1. The dietary of BCAA was assessed by the food frequency questionnaire, the cornerstone of this study. The authors have to explain how to deal with the potential response bias and recall bias that would have the major influence in this study.

2. As mentioned in your method, the diet of patients may change overtime, and multiple assessments were applied to calculate the dietary components. However, the detailed information, such as the interval of questionnaire assessment, was not described at all. Considering the long-term follow-up period in your study, the authors have to provide more information about the questionnaire assessment and describe how to ensure the stability of the patients’ dietary habit/ component during the assessment interval. The authors also have to tell how to manage the data if a remarkable change of dietary habit/component was observed in a patient during the long-term follow-up.

3. The BCAA intake is positively correlated with total energy intake, which is closely associated with the whole nutritional status and would have substantial impacts on the clinical outcomes. Besides, the BCAA intake amount was also found significantly associated with the dietary amount of aromatic AA that would also affect the presence of HE and other complications. To reduce the overfitting and multicollinearity of these factors, a regularized regression analysis, such as Ridge regression or Lass regression, is more appropriate to investigate the risk of outcomes in this study.

Minor comments

1. The primary and secondary outcomes of this study included liver-related death, liver transplantation, presence of HCC and HE. Considering the enrolled patients were only with advanced fibrosis or compensated cirrhosis, the incidence of hepatic decompensation, including ascites formation, spontaneous bacterial peritonitis, variceal bleeding, and so on is suggested to investigate. Besides, the definition of liver-related death is needed to be clarified.

2. The crude hazard ratio of each factor that had been input into the regression model for the analyses of the risk of liver-related death, liver transplantation or liver decompensation should be provided in the table. The crude and adjusted risks of each factor to the presence of hepatic decompensation or HCC are also needed to be provided in the separate tables.

Reviewer #2: General comments

The study by Yu, et al. evaluated retrospectively the effect of dietary branch chain amino acids (BACC) on the liver- related outcomes including liver-related death, liver transplantation, hepatoma (HCC) development and hepatic encephalopathy (HE) in a HALT-C cohort of patients with advanced fibrosis or cirrhosis. In a cohort of 656 patients stratified into four groups by BCAA intake, there are no significant differences of the incidences of liver-related death, liver transplantation, HCC development and HE in a median follow-up of 5 years. Contrary to previous studies using BCAA as supplements of diet, this study estimated the BCAA contents of patients’ regular diet to investigate its impact on liver-related outcomes. Although interesting, there are some issues to be clarified.

Major comments

1. It is important to estimate of BCAA amount from the patients’ diet in this study. In the method section, the author might explain briefly how they calculated the BCAA amount from patients’ diet in the food questionnaires.

2. Are the incidences of liver- related outcomes comparable to the similar patient cohorts outside HALT-C trial? This issue might be provided in the discussion section.

3. In addition to liver-related outcomes, the readers might also be interested in the all-cause and non-liver related death. The authors might provide these data.

4. Direct-acting antivirals (DAA) will have a great impact on the liver-related outcomes. Are these patients undergoing DAA for hepatitis C virus treatment?

5. Whether sarcopenia has an impact of the liver-related outcomes in this cohort might be analyzed in this study.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-17427R1Effect of dietary branched chain amino acids on liver related mortality: Results from a large cohort of North American patients with advanced HCV infectionPLOS ONE

Dear Dr. Yu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 13 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,

Wan-Long Chuang, M.D., Ph.D.

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: All comments have been addressed

Reviewer #3: (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: (No Response)

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

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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: (No Response)

Reviewer #3: 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: (No Response)

Reviewer #3: Yes

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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: In the current manuscript, the authors had answered my question and revised the text appropriately.

It is ready to be accepted.

Reviewer #2: (No Response)

Reviewer #3: PONE-D-22-17427R1: statistical reviiew

SUMMARY. This is a retrospective cohort study of the association between dietary BCAA intake and the time up liver-related death or liver transplantation. The effect of BCAA levels on some secondary ouctomes is also investigated. The core statistical analysis correctly relies on a battery of Cox regression models where the effect of interest is estimated, by adjusting for the available confounders. The methods are correct and the limitations of the study are well described in the discussion. I just list below two minor points that the authors should be able to address without too much effort.

MINOR ISSUES

1. Line 159: "There was no significant change in median BCAA intake estimated from the follow-up FFQ (6.4 g/1000 kcal, IQR 5.4 – 7.5) compared to that from baseline (6.4 g, IQR 5.4 – 7.3 g)." I'd welcome a summary of the distribution of the individual differences between baseline and follow-up intakes. This would indicate that dietary behavior is essentially time-constant, motivating its use as a baseline covariate in the Cox model.

2. Line 128: ". Normality for continuous variables were assessed using the Shapiro-Wilk-Test." This sentence can be removed: covariates do not need to be normally distributed.

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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: No

Reviewer #2: No

Reviewer #3: No

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[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.

Effect of dietary branched chain amino acids on liver related mortality: Results from a large cohort of North American patients with advanced HCV infection

PONE-D-22-17427R2

Dear Dr. Yu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice 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,

Wan-Long Chuang, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: 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 #1: Yes

Reviewer #2: (No Response)

Reviewer #3: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

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: (No Response)

Reviewer #3: (No Response)

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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: (No Response)

Reviewer #3: (No Response)

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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 had revised the manuscript well. All the comments I raised had been addressed accordingly. I think it is ready to be accepted.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

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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.

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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

Reviewer #3: No

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