Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community

Roberta Forlano; Tijana Stanic; Sahan Jayawardana; Benjamin H. Mullish; Michael Yee; Elias Mossialos; Robert D. Goldin; Salvatore Petta; Emmanouil Tsochatzis; Mark R. Thursz; Pinelopi Manousou

doi:10.1371/journal.pone.0307500

Peer Review History

Original SubmissionApril 30, 2024
4 Jun 2024 Decision Letter - Ashraf Elbahrawy, Editor PONE-D-24-15954Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community.PLOS ONE Dear Dr. Manousou, 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 Jul 19 2024 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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Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 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: I reviewed your manuscript titled “Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community.”. This study is well written, nicely designed and highly boosted with illustrative figures. Actually, this study provides a novel, simple and cheap method for easy prediction of the MASLD and its prognosis in diabetics, particularly at the primary care level, which will greatly affect clinical practice. However, some clarifications and revisions would help to better understand and put in perspective your findings: - By reading the previous work of the authors, Reference 13 (attached file); I think the same dataset of the previous publication was used for the current derivation of the developed BIMAST score, and even some figures are the same. However, no clear statement that the same dataset was used in both publications, and I think the same figures may need a copyright agreement for re-publication. Moreover, both papers have the same research ethics committee approval no. (REC approval 18/LO/1742, IRAS 251274)). So, this needs clarification and clear statements in the manuscript. - Methods of the diagnosis of MASLD, which you have already mentioned that it is challenging, were defined clearly in the supplementary files, however, missed from the main manuscript. I think it is crucial to be mentioned as part of the study design and methodology. - In the methodology you mentioned that Standard of care (abnormal LFTs or no screening), rather than the gold standard liver histology, was used as a standard test for different methods including BIMAST score in prediction of fibrosis stage. Nonetheless, diagnosing MASLD relying only on abnormal liver enzymes carry the risk for false negative cases which may carry advanced fibrosis. Moreover, In both external validation cohorts, you mentioned that, MASLD was diagnosed based on either US or histology. So, clarification may be needed on this point. Another point, in the discussion you mentioned that one of the limitations was using TE rather than liver biopsy as a gold standard! while TE was one of the different methods used for comparison with the standard test! this contradiction needs clarification. - Lastly, all figures are hazy and overlying data are not clear (especially figure 5). Reviewer #2: The study by Forlano et al. is an intriguing validation study of a new score to non-invasively diagnose MASLD and fibrosis in patients with diabetes. The aim and the findings of this study represent a hot topic in the field of hepatology, and it is well documented in both the introduction and discussion. From a statistical point of view, the investigation is rigorously performed. however, I recommend a deep English revision and to address some issues. - Line 94: please explain what does ELF stands for - In material and methods section: please explain how does MASLD was diagnosed. According to 2024 consensus statement MASLD diagnosis required the presence of cardiometabolic risk factors in addiction to liver steatosis. - Line 226: what does “significant liver disease” mean? - What about antidiabetic therapy? Since GLP1-RA have been shown to improve liver steatosis, were there any patients undergoing antidiabetic therapy with these drugs? - In the abstract: please clarify to which cohort the percentages presented in the results section are referred to. ****** 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: Yes: Hassan Atalla, MD 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.] 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. Attachments Attachment Submitted filename: renamed_7adce.pdf https://doi.org/10.1371/journal.pone.0307500.r001
Revision 1
12 Jun 2024 Author Response Re: PONE-D-24-15954. Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community. Dear Editorial Team, Thank you for giving us the opportunity to submit a revised draft of the manuscript “Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community” for publication in PLOS one. We appreciate the time and effort that yourself and the peer reviewers dedicated to providing feedback on our manuscript and are grateful for the insightful comments on and valuable improvements to our paper. We have made considerable changes in light of the reviewer comments, which we feel address their queries, and which strengthen the manuscript; we hope as such that it is now acceptable for publication. Please see below for a point-by-point response to the reviewers’ comments and concerns. Reviewer n. 1: I reviewed your manuscript titled “Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community.”. This study is well written, nicely designed and highly boosted with illustrative figures. Actually, this study provides a novel, simple and cheap method for easy prediction of the MASLD and its prognosis in diabetics, particularly at the primary care level, which will greatly affect clinical practice. However, some clarifications and revisions would help to better understand and put in perspective your findings: - By reading the previous work of the authors, Reference 13 (attached file); I think the same dataset of the previous publication was used for the current derivation of the developed BIMAST score, and even some figures are the same. However, no clear statement that the same dataset was used in both publications, and I think the same figures may need a copyright agreement for re-publication. Moreover, both papers have the same research ethics committee approval no. (REC approval 18/LO/1742, IRAS 251274)). So, this needs clarification and clear statements in the manuscript. Response: We thank the reviewer for their comment. We have made clearer the use of the same dataset as previous publication within the text (page 7, line 118): “Of note, this study population was previously published”. With regards to figures, we thank the reviewer for raising the issue. As previous publication was open access and granted Creative Commons CC BY license, there is no need for permission to re-use the article contents. - Methods of the diagnosis of MASLD, which you have already mentioned that it is challenging, were defined clearly in the supplementary files, however, missed from the main manuscript. I think it is crucial to be mentioned as part of the study design and methodology. Response: We agree with the reviewer for their comment. We have included how MASLD was diagnosed in the main text (page 7, line 119 to 121). “MASLD was defined as presence of steatosis with at least one cardiometabolic risk factor and in absence of other causes of liver disease.” Of note, all patients have a cardiometabolic risk factors as they suffer from Type-2 Diabetes Mellitus. - In the methodology you mentioned that Standard of care (abnormal LFTs or no screening), rather than the gold standard liver histology, was used as a standard test for different methods including BIMAST score in prediction of fibrosis stage. Nonetheless, diagnosing MASLD relying only on abnormal liver enzymes carry the risk for false negative cases which may carry advanced fibrosis. Moreover, In both external validation cohorts, you mentioned that, MASLD was diagnosed based on either US or histology. So, clarification may be needed on this point. Response: We agree with the reviewer that MASLD diagnosis cannot rely on abnormal liver function tests as these are not sensitive. Nevertheless, MASLD screening among general practitioners still relies on abnormal liver function tests and/or no screening at all. We have clarified this in the main manuscript (page 8, line 127-129): “Definition of standard of care for MASLD screening in primary care was obtained from previously published economic evaluations on MASLD screening (Tanajewski et al., 2017; Thavorn & Coyle, 2015), and defined based on what is routinely performed in the community (either abnormal LFTs or no screening)” Finally, external cohorts used in this study, include patients already screened and seen by the specialist, whereby MASLD was diagnosed as per guidelines (i.e. based on either US or histology). - Another point, in the discussion you mentioned that one of the limitations was using TE rather than liver biopsy as a gold standard! while TE was one of the different methods used for comparison with the standard test! this contradiction needs clarification. Response: We agree with the reviewer for their comment. We have emphasized this concept as limitation of the study (page 21, line 417 to 419): “Nevertheless, applying TE as reference for the economic model might be translated into an overestimation of the cost-effectiveness of the TE in this scenario.” - Lastly, all figures are hazy and overlying data are not clear (especially figure 5). Response: We agree with the reviewer for their comment. We have submitted a better version of the figures. Reviewer n. 2: The study by Forlano et al. is an intriguing validation study of a new score to non-invasively diagnose MASLD and fibrosis in patients with diabetes. The aim and the findings of this study represent a hot topic in the field of hepatology, and it is well documented in both the introduction and discussion. From a statistical point of view, the investigation is rigorously performed. However, I recommend a deep English revision and to address some issues. - Line 94: please explain what does ELF stands for Response: We agree with the reviewer for their comment. We have clarified the acronym in “Enhanced liver fibrosis” - In material and methods section: please explain how does MASLD was diagnosed. According to 2024 consensus statement MASLD diagnosis required the presence of cardiometabolic risk factors in addiction to liver steatosis. Response: We agree with the reviewer for their comment. We have modified the methods as per reviewer n.1 comment. - Line 226: what does “significant liver disease” mean? Response: We have included a definition in the methods (page 7, line 119): “Significant liver disease was defined as LSM≥8.1 kPa.” - What about antidiabetic therapy? Since GLP1-RA have been shown to improve liver steatosis, were there any patients undergoing antidiabetic therapy with these drugs? Response: We agree with the reviewer that antidiabetic therapy is an important point to consider when analysing risk for MASLD in diabetics. In this cohort, 37 (13%) patients were on a GLP-1R agonist with a median length of disease of 11 (4-16) years. There was no difference in terms of anti-diabetic treatment as well as length of the disease between those with and without significant liver disease. Results were also shown in our previously published paper (Forlano et al., 2023). - In the abstract: please clarify to which cohort the percentages presented in the results section are referred to. Response: We have clarified the population used for descriptive statistic (page 3, line 59): “In the whole population, …” REFERENCES Forlano, R., Stanic, T., Jayawardana, S., Mullish, B. H., Yee, M., Mossialos, E., Goldin, R., Petta, S., Tsochatzis, E., Thursz, M., & Manousou, P. (2023). A prospective study on the prevalence of MASLD in people with type-2 diabetes in the community. Cost effectiveness of screening strategies. Liver Int. https://doi.org/10.1111/liv.15730 Tanajewski, L., Harris, R., Harman, D. J., Aithal, G. P., Card, T. R., Gkountouras, G., Berdunov, V., Guha, I. N., & Elliott, R. A. (2017). Economic evaluation of a community-based diagnostic pathway to stratify adults for non-alcoholic fatty liver disease: a Markov model informed by a feasibility study. BMJ Open, 7(6), e015659. https://doi.org/10.1136/bmjopen-2016-015659 Thavorn, K., & Coyle, D. (2015). Transient Elastography and Controlled Attenuation Parameter for Diagnosing Liver Fibrosis and Steatosis in Ontario: An Economic Analysis. Ont Health Technol Assess Ser, 15(19), 1-58. https://www.ncbi.nlm.nih.gov/pubmed/26664666 Attachments Attachment Submitted filename: PLOS one_Response to reviewers.docx https://doi.org/10.1371/journal.pone.0307500.r002
8 Jul 2024 Decision Letter - Ashraf Elbahrawy, Editor Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community. PONE-D-24-15954R1 Dear Dr. Manousou, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: 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 #3: 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 #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thanks for addressing all the raised revision points and I think that all required questions have been answered. The topic of this paper is interesting and would add an easy method for prediction of MASLD particularly within the hands of GPs. Reviewer #3: (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: Yes: Hassan Atalla, MD Reviewer #3: Yes: Mohammed El-Fayoumie ******** https://doi.org/10.1371/journal.pone.0307500.r003
Formally Accepted
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