Health-related quality of life in non-alcoholic fatty liver disease: A cross-cultural study between Spain and the United Kingdom

Jesús Funuyet-Salas; Agustín Martín-Rodríguez; María Ángeles Pérez-San-Gregorio; Luke Vale; Tomos Robinson; Quentin M. Anstee; Manuel Romero-Gómez

doi:10.1371/journal.pone.0300362

Peer Review History

Original SubmissionDecember 14, 2022
6 Jan 2023 Decision Letter - Ashraf Elbahrawy, Editor PONE-D-22-34276Health-related quality of life in non-alcoholic fatty liver disease: A cross-cultural study between Spain and the United KingdomPLOS ONE Dear Dr. Funuyet-Salas, 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. ============================== Dear Dr. Jesús Funuyet-Salas, this manuscript was reviewed by 2 independent reviewers and the editor. The major concerns were the lack of matching between the two patients’ groups (Spanish and UK) regarding BMI, education level and employment activity. In addition, the two patient groups were not compared regarding the severity of liver fibrosis and the presence of associated comorbidities (like diabetes mellitus, hypertension, etc..). Indeed, these concerns need major revision, please review the reviewers' comments. ============================== Please submit your revised manuscript by Feb 20 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'. 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In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. Additional Editor Comments: Dear Dr. Jesús Funuyet-Salas, this manuscript was reviewed by 2 independent reviewers and the editor. The major concerns were the lack of matching between the two patients’ groups (Spanish and UK) regarding BMI, education level and employment activity. In addition, the two patient groups were not compared regarding the severity of liver fibrosis and the presence of associated comorbidities (like diabetes mellitus, hypertension, etc..). Indeed, these concerns need major revision, please review the reviewers' comments. [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: No ****** 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: Title is very relevant for holistic management of NAFLD as HRQoL is underestimated issue. Introduction covers background knowledge, knowledge gap and specific objectives of the study clearly. In Methodology patient reported outcome CLDQ followed to search HRQoL but need to exclude other chronic functional illness associated with NAFLD eg diabetes, hypertension and these may be confounder. These confounding effect was not removed Definition of NAFLD done only Biopsy, possibly these patients are more advanced NAFLD so quality of life more disrupted Result and abstract of manuscript were concordant. Reviewer #2: Thanks for inviting me to review this manuscript. Funuyet-Salas et al., described Health-related quality of life in non-alcoholic fatty liver disease patients from Spain and the United Kingdom. I have the following comments: 1- Although interesting, however it is not novel. The same research question was addressed in a similar study from different European countries including Spain and UK (https://pubmed.ncbi.nlm.nih.gov/30580090/ ). Another recent review confirmed the same (https://pubmed.ncbi.nlm.nih.gov/32435754/ ). 2- The manuscript needs language editing (e.g., “Methods: HRQoL (CLDQ) was measure in both Southern” should be written as “measured”). 3- In the sentence “In general, the negative impact of MODERATORS on Harmol was reported to a greater degree in UK than in Spanish participants” what does moderator means? 4- Page 10 line 99 the expression “and liver severity” is not appropriate “liver diseases severity” is more suitable. 5- It is preferred to add S1 and S2 Tables to the main document. 6- Please add ethics committee approval number 7- Page 13 line 189: the sentence “There were no important between-group differences” needs rephrasing. ****** 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: Shahinul Alam Reviewer #2: Yes: Prof. Mohamed Alboraie ******** [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. https://doi.org/10.1371/journal.pone.0300362.r001
Revision 1
17 Feb 2023 Author Response Response to Editor Comments Point 1: Dear Dr. Jesús Funuyet-Salas, this manuscript was reviewed by 2 independent reviewers and the editor. The major concerns were the lack of matching between the two patients’ groups (Spanish and UK) regarding BMI, education level and employment activity. In addition, the two patient groups were not compared regarding the severity of liver fibrosis and the presence of associated comorbidities (like diabetes mellitus, hypertension, etc..). Indeed, these concerns need major revision, please review the reviewers' comments. Response 1: Dear editor, thank you for your review. The lack of matching between the two patient cohorts regarding BMI and liver fibrosis was discussed as a study limitation. Differences in education and employment were statistically significant but not important (small effect sizes). Effect sizes were defined as: null (d < 0.2; w < 0.1), small (d > 0.2; w > 0.1), medium (d > 0.5; w > 0.3) or large (d > 0.8; w > 0.5). Only statistically significant differences with medium or large effect sizes were considered important in this manuscript. This is discussed in Page 8 lines 158-160. In addition, the two patient cohorts were compared with respect to BMI as obesity is the metabolic condition most closely linked to NAFLD. The fact that we did not consider the effects of other metabolic comorbidities such as diabetes or hypertension has been discussed as a study limitation in Page 23 line 420. We hope the editor finds this explanation sufficient. Response to Reviewer 1 Comments Point 1: Title is very relevant for holistic management of NAFLD as HRQoL is underestimated issue. Introduction covers background knowledge, knowledge gap and specific objectives of the study clearly. Response 1: Thank you for your review and your encouraging comments on our manuscript. Point 2: In Methodology patient reported outcome CLDQ followed to search HRQoL but need to exclude other chronic functional illness associated with NAFLD eg diabetes, hypertension and these may be confounder. These confounding effect was not removed. Response 2: Thank you for this suggestion. The two patient cohorts were compared with respect to BMI. This is because obesity is the metabolic condition most closely linked to NAFLD. The fact that we did not consider the effects of other metabolic comorbidities such as diabetes or hypertension was discussed as a study limitation in Page 23 line 420. Point 3: Definition of NAFLD done only Biopsy, possibly these patients are more advanced NAFLD so quality of life more disrupted. Response 3: Thank you for your comment. Liver biopsy is currently considered as the gold standard for the diagnosis and histological assessment of NAFLD. All the participants were biopsy-proven NAFLD patients, which provides added value to the validity of the study results. In terms of liver severity, we recruited patients with no or mild fibrosis as well as those with moderate or severe fibrosis. However, this has been discussed as a study limitation in Page 23 line 419. Point 4: Result and abstract of manuscript were concordant. Response 4: Thank you for your positive comment on our manuscript. Response to Reviewer 2 Comments Point 1: Funuyet-Salas et al., described Health-related quality of life in non-alcoholic fatty liver disease patients from Spain and the United Kingdom. I have the following comments: 1- Although interesting, however it is not novel. The same research question was addressed in a similar study from different European countries including Spain and UK (https://pubmed.ncbi.nlm.nih.gov/30580090/). Another recent review confirmed the same (https://pubmed.ncbi.nlm.nih.gov/32435754/). Response 1: Thank you for your review and your precise helpful suggestions that contributed to the improvement of the manuscript. As suggested in the introduction of the manuscript, the study by Huber et al., (2019) is the only one that has so far compared the quality of life of NAFLD patients in different European countries. Indeed, whilst the study included Spain, it only reported on 17 participants from Spain. Our manuscript is substantially larger and included 513 Spanish participants. We therefore believe that our study provides more accurate results on the comparison between Spain and other countries. In addition, cross-cultural comparisons were only addressed minor component of Huber et al., (2019). In order to understand this issue better, we sought to go deeper into the differences in HRQoL between Spanish and UK participants as is described in Page 4 line 98. For McSweeney et al., (2020), which was led by members of our team was a review of extant literature, it focused mainly on the impact of NASH-associated cirrhosis from a humanistic perspective. The literature it considered whilst useful was very different in term of design to the current study and was designed to support the development of a patient reported outcome measure suitable for use in trials of treatments for NAFLD. The study was not in any way quantitative and sought to identify issues and themes relevant to the assessment of HRQoL. Given our focus on HRQoL in NAFLD patients from a cross-cultural and quantitative approach we strongly argue that the current study and McSweeney et al., (2020) do not overlap at all but are complementary in terms of adding to the evidence base for NAFLD. Point 2: 2- The manuscript needs language editing (e.g., “Methods: HRQoL (CLDQ) was measure in both Southern” should be written as “measured”). Response 2: Thank you for this correction. Change made. Point 3: 3- In the sentence “In general, the negative impact of MODERATORS on HRQoL was reported to a greater degree in UK than in Spanish participants” what does moderator means? Response 3: "Moderator" means the mediating and moderating variables in the moderated mediation model (third study objective). Specifically, the negative effects of gender on quality of life through emotional function, BMI and fatigue were higher in UK than in Spanish participants. This has been edited to put the text in plain language (Page 2 line 42). Point 4: 4- Page 10 line 99 the expression “and liver severity” is not appropriate “liver diseases severity” is more suitable. Response 4: Thank you for this correction. Change made. Point 5: 5- It is preferred to add S1 and S2 Tables to the main document. Response 5: Thank you for this suggestion. Change made. Point 6: 6- Please add ethics committee approval number. Response 6: Thank you. We have now added this information. Point 7: 7- Page 13 line 189: the sentence “There were no important between-group differences” needs rephrasing. Response 7: Thank you for this suggestion. Change made. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0300362.r002
22 Mar 2023 Decision Letter - Ashraf Elbahrawy, Editor PONE-D-22-34276R1 Health-related quality of life in non-alcoholic fatty liver disease: A cross-cultural study between Spain and the United Kingdom PLOS ONE Dear Dr. Funuyet-Salas, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected. I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision. Kind regards, Ashraf Elbahrawy Academic Editor PLOS ONE Additional Editor Comments: Dear Dr. Jesús Funuyet-Salas There are still some major issues related to the lack of matching between groups and the absence of comparison regarding some potential confounding factors that might affect the final results. Please revise the reviewers comments [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: All comments have been addressed Reviewer #4: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #3: Yes Reviewer #4: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes Reviewer #4: N/A ****** 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 #3: Yes Reviewer #4: 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 #3: Yes Reviewer #4: 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 #3: Patient-reported outcome is an important but often neglected topic. The authors have addressed previous Reviewers' comments adequately. I do not have anything else to add. Reviewer #4: There are still some major issues related to the lack of matching between the Spanish and the UK groups, the absence of comparison regarding some potential confounding factors such as diabetes mellitus, and other stated limitations that might affect the results and the resulting conclusions. ****** 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 #3: No Reviewer #4: 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.] - - - - - For journal use only: PONEDEC3 https://doi.org/10.1371/journal.pone.0300362.r003
Revision 2
16 May 2023 Author Response Response to Academic Editor Comments: Dear Academic Editor, thank you for your review and the decision to reconsider our manuscript. All changes to the manuscript have been highlighted in yellow. The lack of matching between the two patient cohorts regarding BMI and liver fibrosis has now been extensively discussed (page 24, lines 429-444). We understand that this could affect the validity of our results. We argue that although a formal matching procedure (using a technique such as propensity score matching) has not been conducted, we did use a consistent regression analytical framework across both data sets. This allowed us to highlight the impact of a common set of effect modifiers which included BMI and fibrosis. If the aim of our paper was to compare differences in quality of life between countries, then a formal matching procedure would have been appropriate. However, the aim of our paper was to specifically look at the mediating and predictor factors. A formal matching procedure would have prevented the indirect exploration of the differential impact of mediating and predictor factors such as liver fibrosis, BMI, age or gender between the two countries (as they would be equalised in a matched cohort). The analysis as it stands allows us to consider if these confounders could have a differential impact between countries. As noted above, the two patient cohorts were compared with respect to BMI, with obesity being the most common metabolic condition in NAFLD patients. As the reviewers have noted this approach will not have considered other potential confounding factors such as diabetes, as it can only explore the impact of effect modifiers that are consistent across both data sets. Nevertheless, several potential confounders were consistently explored in the two data sets (page 8, lines 170-175). The fact that we did not consider the effects of other metabolic comorbidities such as diabetes or hypertension has been discussed as a study limitation (page 24, lines 424-429) and highlighted as an area for further research. We hope the editor finds this explanation sufficient. Response to Reviewer 3 Comments: Thank you for your review and your positive comment. Response to Reviewer 4 Comments: Thank you for your review and your comments. Reviewer 4 raised issues relating to the control of BMI and fibrosis. We cross refer to our response to the editor above on these issues. We trust that reviewer 4 finds this response satisfactory. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0300362.r004
11 Oct 2023 Decision Letter - Mohamed El-Kassas, Editor PONE-D-22-34276R2 Health-related quality of life in non-alcoholic fatty liver disease: A cross-cultural study between Spain and the United Kingdom PLOS ONE Dear Dr. Funuyet-Salas, 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. ============================== ACADEMIC EDITOR: Please insert comments here and delete this placeholder text when finished. Be sure to: Indicate which changes you require for acceptance versus which changes you recommend Address any conflicts between the reviews so that it's clear which advice the authors should follow Provide specific feedback from your evaluation of the manuscript Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. For Lab, Study and Registered Report Protocols: These article types are not expected to include results but may include pilot data. ============================== Please submit your revised manuscript by Nov 10 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, Mohamed El-Kassas Academic Editor PLOS ONE Journal Requirements: 1. We notice that your manuscript file was uploaded on February 17, 2023. Please can you upload the latest version of your revised manuscript as the main article file, ensuring that does not contain any tracked changes or highlighting. This will be used in the production process if your manuscript is accepted. Please follow this link for more information: http://blogs.PLOS.org/everyone/2011/05/10/how-to-submit-your-revised-manuscript/ 2. 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. Additional Editor Comments (if provided): [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: All comments have been addressed Reviewer #5: 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 #3: Yes Reviewer #5: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes Reviewer #5: 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 #3: Yes Reviewer #5: 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 #3: Yes Reviewer #5: 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 #3: 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. Response: I do not have further suggestions. Reviewer #5: 1-Methodology: You made the NAFLD diagnosis by taking liver biopsy. Why did you do liver biopsy? Is it for your study or indicated otherwise? it should be addressed in the manuscript. 2- their was a statistical significant difference between the 2 groups regarding their education level and occupation. As you know, the socioeconomic level of the patients could greatly affect their HRQoL. How could you prove that the difference you found in the HRQoL is not due to the difference in socioeconomic level? 3-You chose Spain and UK as a distinct geographical areas. Do you think they are distinct? why didn't you choose 2 so far areas especially from 2 different continents? 4. Please consider grammatical reversion of some errors. ****** 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 #3: Yes: Vincent Wong Reviewer #5: Yes: Mohamed Elbadry ******** [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. https://doi.org/10.1371/journal.pone.0300362.r005
Revision 3
19 Oct 2023 Author Response Response to Reviewer 3 Comments Point 1: I do not have further suggestions. Response 1: Thank you for your review that contributed to the improvement of the manuscript. Response to Reviewer 5 Comments Point 1: Methodology: You made the NAFLD diagnosis by taking liver biopsy. Why did you do liver biopsy? Is it for your study or indicated otherwise? it should be addressed in the manuscript. Response 1: Thank you for your review and your helpful suggestions that contributed to the improvement of the manuscript. The 513 Spanish participants were part of Hepamet, the Spanish registry, which diagnoses NAFLD by liver biopsy. The 224 UK participants were part of the European NAFLD Registry, which also uses liver biopsy to diagnose NAFLD. Liver biopsy is part of the standard of care for the diagnosis of NAFLD in both Spanish and UK patient cohorts, which allowed comparison of the data from Spanish and UK participants in this cross-cultural study. This has been addressed in the manuscript (page 24, lines 423-425). Point 2: There was a statistical significant difference between the 2 groups regarding their education level and occupation. As you know, the socioeconomic level of the patients could greatly affect their HRQoL. How could you prove that the difference you found in the HRQoL is not due to the difference in socioeconomic level? Response 2: Thank you for this comment. There was indeed a statistically significant difference between the two groups in terms of education and employment. However, the effect sizes were not important (w = 0.194 and -0.102, respectively), as you can see in Table 1. Effect sizes are defined as: null (d < 0.2; w < 0.1), small (d > 0.2; w > 0.1), medium (d > 0.5; w > 0.3) or large (d > 0.8; w > 0.5). Only statistically significant differences with medium or large effect sizes were considered important in this manuscript (page 8, lines 158-160). Point 3: You chose Spain and UK as distinct geographical areas. Do you think they are distinct? why didn't you choose 2 so far areas especially from 2 different continents? Response 3: The aim of this study was to compare and explore quality of life in both Southern European and Northern European cohorts of patients with NAFLD. For this reason, Spain and the United Kingdom were selected for this cross-cultural study. We believe that both countries are different not only in relation to lifestyle, socio-cultural issues or estimates of obesity, but also in terms of awareness and strategies for approaching NAFLD from a public health policy perspective, as suggested in the manuscript (see Lazarus et al., 2021). Point 4: Please consider grammatical reversion of some errors. Response 4: Thank you for this comment. The manuscript has been grammatically revised again. All changes have been highlighted in yellow. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0300362.r006
27 Feb 2024 Decision Letter - Matias A Avila, Editor Health-related quality of life in non-alcoholic fatty liver disease: A cross-cultural study between Spain and the United Kingdom PONE-D-22-34276R3 Dear Dr. Funuyet-Salas, 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, Matias A Avila, 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 #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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #3: Thanks a lot for your thoughtful revision. I do not have anything else to add. Congratulations on the publication! ****** 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 #3: No ******** https://doi.org/10.1371/journal.pone.0300362.r007

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