Increasing metabolic co-morbidities are associated with higher risk of advanced fibrosis in nonalcoholic steatohepatitis

Robert J. Wong; Tram Tran; Harvey Kaufman; Justin Niles; Robert Gish

doi:10.1371/journal.pone.0220612

Peer Review History

Original SubmissionMay 23, 2019
18 Jun 2019 Decision Letter - Ming-Lung Yu, Editor PONE-D-19-14625 Increasing Metabolic Co-Morbidities are Associated with Higher Risk of Advanced Fibrosis in Nonalcoholic Steatohepatitis PLOS ONE Dear Dr Wong, 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 Aug 02 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. 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Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [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: Partly ******** 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: This study was performed by a group of experts, aiming to utilize a nationally representative U.S. clinical laboratory database to evaluate prevalence of advanced fibrosis using a systematic algorithm of non-invasive fibrosis biomarker (FIB-4) and to evaluate the impact of metabolic co-morbidities on odds of advanced fibrosis. The findings are important. It would be even nice to improve the quality of figures by using colour figures of higher resolution. Reviewer #2: The Authors conducted the retrospective study aiming to evaluate prevalence of advanced fibrosis and to evaluate the impact of metabolic co-morbidities on odds of advanced fibrosis based on a large-scale database. They found that the prevalence of advanced fibrosis ranged from 6.18% - 9.07%, and the prevalence of F4 fibrosis/cirrhosis ranged from 3.91% – 5.35%. They concluded that co-morbid metabolic abnormalities were associated with higher risk of advanced fibrosis among NASH patients. Although the study touched the important issue indicating the parallel association between disease severity and metabolic abnormalities in NAFLD patients, some points need clarification. 1. The definition of NAFLD/NASH in the current study was based on the ICD 9/10 diagnosis coding. The validation of the diagnosis should at least be performed to its best. The exclusion of alcoholism, pregnancy-related fatty change could be the confounding factors. 2. The Authors used FIB-4 as the non-invasive serum panel for fibrosis assessment. The performance could be validated by APRI. 3. Hypertension is one of the main components of metabolic abnormalities. How come the results if the diagnosis coding of hypertension were added to enhance the accuracy of metabolic syndrome in the current study. 4. The conclusion depicted "prevalence of NASH ..., representing 6.80 million and 4.01 million, respectively." , which could not be sufficiently supported by the results. A mild form is suggested. ****** 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.0220612.r001
Revision 1
2 Jul 2019 Author Response To: Dr. Joerg Heber Editor-in-Chief, PLOS ONE Dr. Ming-Lung Yu Academic Editor, PLOS ONE RE: Manuscript (PONE-D-19-14625) " Increasing Metabolic Co-Morbidities are Associated with Higher Risk of Advanced Fibrosis in Nonalcoholic Steatohepatitis" Dear Dr. Yu and Dr. Heber My co-authors and I are grateful of the reviewers’ comments and your continued consideration of our manuscript for publication in PLOS ONE. Please find below our point-by-point responses to the reviewers’ comments and suggestions. We have also made revisions in the manuscript text to incorporate the changes resulting from these reviewer comments. We have included two versions of our revised manuscript – track changes and clean version - as per your instructions. Comments to the Author(s): Reviewer #1: This study was performed by a group of experts, aiming to utilize a nationally representative U.S. clinical laboratory database to evaluate prevalence of advanced fibrosis using a systematic algorithm of non-invasive fibrosis biomarker (FIB-4) and to evaluate the impact of metabolic co-morbidities on odds of advanced fibrosis. The findings are important. It would be even nice to improve the quality of figures by using colour figures of higher resolution. Response: Thank you for this suggestion – we have revised our figures to be of color and improved the resolution of our submitted figure files. Reviewer #2: The Authors conducted the retrospective study aiming to evaluate prevalence of advanced fibrosis and to evaluate the impact of metabolic co-morbidities on odds of advanced fibrosis based on a large-scale database. They found that the prevalence of advanced fibrosis ranged from 6.18% - 9.07%, and the prevalence of F4 fibrosis/cirrhosis ranged from 3.91% – 5.35%. They concluded that co-morbid metabolic abnormalities were associated with higher risk of advanced fibrosis among NASH patients. Although the study touched the important issue indicating the parallel association between disease severity and metabolic abnormalities in NAFLD patients, some points need clarification. 1. The definition of NAFLD/NASH in the current study was based on the ICD 9/10 diagnosis coding. The validation of the diagnosis should at least be performed to its best. The exclusion of alcoholism, pregnancy-related fatty change could be the confounding factors. Response: Thank you for this very important question. This is one of the stated limitations of this database in that our diagnosis and identification of NAFLD/NASH relies on the data that we have available in the current dataset. We tried to utilize a systematic algorithm, and agree with this reviewer that even among the cohort of patients with ICD-9/10 codes, we were not able to perfectly exclude all other potential concurrent disease states. For example, we did not have data on alcohol consumption and thus were not able to accurately capture this. However, based on this reviewer’s very insightful feedback, we did go back and incorporate two additional levels of exclusion criteria to further validate our study findings. We implemented exclusion criteria of any patients with ICD-9/10 codes for alcohol use/abuse or alcoholic liver disease. We further reviewed the Quest Diagnostics database and were able to exclude any individual with evidence if pregnancy. We have completely revised our entire study, which is reflected in an updated figure 1 flow chart as well as updated all of the results and relevant methods section. Thank you again for this feedback as we feel that the revisions arising out of this suggestion has truly strengthened our manuscript. Reviewer #2: 2. The Authors used FIB-4 as the non-invasive serum panel for fibrosis assessment. The performance could be validated by APRI. Response: Thank you for this suggestion. While we did in fact perform similar analyses using APRI, we chose not to include this in our analyses. Firstly, when evaluating the performance characteristics of different non-invasive methods for assessing hepatic fibrosis, FIB-4 has significantly better performance characteristics (higher AUROC) than APRI, and thus our analyses focused on FIB-4 given the better sensitivity and specificity (Xiao, et al. Hepatology 2017;66:1486-1501). Furthermore, recent studies demonstrated that the performance characteristics of these non-invasive markers are affected by age, and a recent study by McPherson et al. (Am J Gastroenterol 2017;112:740-51) developed a revised cut-off of FIB-4>2.67, which we were able to incorporate into our analyses. However, no such analyses have been evaluated with APRI, and thus the performance characteristics may be worse than originally thought. Secondly, our analysis was specifically focused on evaluating patients with F3 or greater fibrosis, which can be done with the FIB-4 based algorithm that we illustrated. However, currently validated cutpoints for APRI are only validated for assessing at the F2 and F4 levels, and have not specifically been validated for the F3 fibrosis level. For these reasons and limitations, we felt strongly about not including the APRI data in our manuscript. However, the data that we did analyze demonstrated similar trends, such that increasing number of metabolic co-morbidities also correlated with increasing risk of hepatic fibrosis when using APRI-based cutpoints. Reviewer #2: 3. Hypertension is one of the main components of metabolic abnormalities. How come the results if the diagnosis coding of hypertension were added to enhance the accuracy of metabolic syndrome in the current study. Response: Thank you for this comment. This is a great suggestion. We have completely revised our entire analysis and updated our manuscript to include hypertension as a fourth metabolic co-morbidity analyzed. Given that blood pressure measurements and medication data were not available for analysis, we utilized ICD=9/10 coding to identify patient with hypertension. Thank you for this important suggestion as you can see by adding hypertension, it actually strengthened our analysis of the correlation between metabolic co-morbidities and the presence of advanced fibrosis in the multivariate model. Reviewer #2: 4. The conclusion depicted "prevalence of NASH ..., representing 6.80 million and 4.01 million, respectively." , which could not be sufficiently supported by the results. A mild form is suggested. Response: Thank you for raising this important point. These estimates were based on a estimated national NAFLD prevalence of 75 million based on a recent systematic review (Rinella ME. JAMA. 2015;313(22):2263-73). We neglected to mention this 75 million estimate as our basis. We have revised our conclusion section incorporate this. We thank the editors and reviewers for the helpful comments and suggestions that have improved our manuscript significantly and have made our manuscript more valuable to the readers of PLOS ONE. We hope that you will find the response to the above comments and the corresponding manuscript revisions acceptable. Thank you again for the opportunity to revise our manuscript for your continued consideration. Sincerely, Robert J. Wong, M.D., M.S., F.A.C.G. Assistant Clinical Professor of Medicine Division of Gastroenterology and Hepatology Alameda Health System – Highland Hospital Highland Care Pavilion – 5th Floor, Endoscopy Unit 1411 East 31st Street Oakland, CA 94602 Phone: 510-437-6531 Email: rowong@alamedahealthsystem.org Attachments Attachment Submitted filename: Response to Reviewers_PLOS One_final.docx https://doi.org/10.1371/journal.pone.0220612.r002
22 Jul 2019 Decision Letter - Ming-Lung Yu, Editor Increasing Metabolic Co-Morbidities are Associated with Higher Risk of Advanced Fibrosis in Nonalcoholic Steatohepatitis PONE-D-19-14625R1 Dear Dr. Wong, 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, Ming-Lung Yu, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (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) ****** 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) ****** 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: I have no additional comments. Reviewer #2: (No Response) ****** 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: Jee-Fu Huang https://doi.org/10.1371/journal.pone.0220612.r003
Formally Accepted
24 Jul 2019 Acceptance Letter - Ming-Lung Yu, Editor PONE-D-19-14625R1 Increasing Metabolic Co-Morbidities are Associated with Higher Risk of Advanced Fibrosis in Nonalcoholic Steatohepatitis Dear Dr. Wong: 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. Ming-Lung Yu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0220612.r004

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