The Diabetes Remission in India (DiRemI) study: Protocol for a prospective matched-control trial

Pramod Tripathi; Nidhi Kadam; Diptika Tiwari; Thejas Kathrikolly; Anagha Vyawahare; Baby Sharma; Malhar Ganla; Banshi Saboo

doi:10.1371/journal.pone.0306394

Peer Review History

Original SubmissionApril 18, 2024
21 May 2024 Decision Letter - Patricia Khashayar, Editor PONE-D-24-12706The Diabetes Remission in India (DiRemI) Study: Protocol for a Prospective Matched-Control TrialPLOS ONE Dear Dr. Kadam, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers have raised some concerns regarding the design and analysis of the study. Please address the comments and resubmit the article. Please submit your revised manuscript by Jul 05 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. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Line 178 was a two sample t-test used to calculate the sample size? Clarify primary and secondary endpoints. For multiple endpoints, better adjust p values. How are outliers defined? Line 427, how can you perform analyses with inclusion of missing data? In linear regression, records with missing will be automatically excluded. How will non-random missing be handled. Reviewer #2: Dear Authors, I am pleased to review your submitted manuscript which attempts to demonstrate the weight loss effects of a comprehensive treatment in patients with type 2 diabetes. The results are intriguing and could undoubtedly be clinically useful. However, there appear to be some significant concerns. 1. The lower BMI limit for study entry is 25. If subjects in this range are enrolled, achieving significant weight loss could also lead to excessive thinness, which cannot be completely ruled out. What are your thoughts on this? 2. Because the intervention is comprehensive, interpreting the results may be challenging even if the outcome measures show a significant difference. Please consider including refinements that allow for specific discussion of the results obtained. ****** 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 ******** [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.0306394.r001
Revision 1
31 May 2024 Author Response RESPONSE TO REVIEWERS We sincerely thank the editor and reviewers for their valuable and insightful comments, which helped improve the quality of our manuscript. Please find below the detailed response to the reviewers’ comments for your kind perusal and necessary consideration. Reviewer Comments Reviewer #1: Comments: Line 178 was a two sample t-test used to calculate the sample size? Response: Thank you for your comment. Yes. A two-sample t-test was used to calculate the sample size based on the difference between two independent sample means, as reported in a previous study by Lean et al. (Ref. 18). Clarify primary and secondary endpoints. Response: Thank you for your comment. We have added details on both the primary and secondary outcomes in the ‘Outcome Measures’ section. Page 18, Lines. 386-396 For multiple endpoints, better adjust p values. We acknowledge your suggestion in this regard. We have recalculated the sample size for both weight and HbA1c with adjusted p-values. The same has been added to the manuscript as below- in Page 9, Lines 175-184. “We calculated the sample size for our study using Bonferroni correction to adjust for two primary outcome measures: weight and HbA1c. With an overall alpha level of 0.05, the adjusted significance level for each outcome was set to 0.025. Assuming a power of 95%, the required sample sizes were determined based on Cohen's d effect sizes of 0.445 for weight and 0.635 for HbA1c, based on a previous study by Lean et al. (2018) [18]. The calculations indicated a sample size of 132 participants per group for weight and 65 participants per group for HbA1c level. To ensure adequate power for both outcomes, we selected the larger sample size requirement, resulting in a total sample size of 132 participants per group. To account for the potential dropout and loss to follow-up of 30%, the final sample size was estimated at 360 (180 in each group).” How are outliers defined?` Response: Thank you for your comment. All values greater than +/- 3 times the standard deviation will be considered outliers. We have added the same to the ‘Statistical Analyses’ section as below- in Page 20, Line 433. “For outliers (± 3 standard deviation), efforts will be made to cross-check and obtain the correct values.” Line 427, how can you perform analyses with inclusion of missing data? In linear regression, records with missing will be automatically excluded. Response: Thank you for your comment. We agree that in linear or any other regression analysis, records with missing data will automatically be excluded. However, we would like to clarify that, by including missing values, we mean not deleting the entire case for analysis, where other parameters for the case are available. We have clarified this in the text under the Statistical Analyses section as below in Page 20, Line 435-436. “ In the case of random missing values, two separate analyses will be performed: one including the cases with missing data by choosing pairwise deletion and the other excluding it using listwise or case-wise deletion.” How will non-random missing be handled. Response: Thank you for your comment. Using the data imputation method, we will replace the missing value with the mean of that variable for non-random missing values. We have added the same to the ‘Statistical Analyses’ section as below- in Page 20, Line. 438-439 “In case of non-random missing values, the imputation method may be used by replacing the missing value with the mean for that variable.” Reviewer #2: Dear Authors, I am pleased to review your submitted manuscript which attempts to demonstrate the weight loss effects of a comprehensive treatment in patients with type 2 diabetes. The results are intriguing and could undoubtedly be clinically useful. However, there appear to be some significant concerns. Comments 1. The lower BMI limit for study entry is 25. If subjects in this range are enrolled, achieving significant weight loss could also lead to excessive thinness, which cannot be completely ruled out. What are your thoughts on this? Response: Thank you for your comment. We acknowledge the significance of ensuring that participants did not undergo extreme weight loss. Based on the Asian WHO cutoffs, a BMI of 25 or higher is categorized as obese and 23-24.9 as overweight (WHO Expert Consultation (2004). Lancet (London, England), 363(9403), 157–163. https://doi.org/10.1016/S0140-6736(03)15268-3.; Mishra et al. 2009 https://pubmed.ncbi.nlm.nih.gov/19582986/). Consequently, in our study, we included participants who met the obesity criteria of BMI ≥25 kg/m2. To support this, the "Personal Fat Threshold" (PFT) hypothesis proposed by Dr. Roy Taylor suggests that all individuals have a specific fat threshold, and losing weight below this threshold can help regain normal glycemic control regardless of BMI. The ReTUNE trial also supports this finding, showing improvements in HbA1c levels, even in those with normal or near-normal BMI with weight loss. (Taylor, R., & Holman, R. R. (2015). https://doi.org/10.1042/CS20140553(Clinical science (London, England: 1979), 137(16), 1333–1346. https://doi.org/10.1042/CS20230586). Additionally, since the intervention is personalized, the assigned nutritionist and physician will closely monitor the participants during the weight loss phase to prevent any adverse events due to weight loss. Comments 2. Because the intervention is comprehensive, interpreting the results may be challenging even if the outcome measures show a significant difference. Please consider including refinements that allow for specific discussion of the results obtained. Response: Thank you for your comment. The intervention combines four main aspects, as mentioned in the protocol: diet, exercise, psychological support, and medical management. Our hypothesis for the current study is that a holistic approach to managing diabetes and its related comorbidities would be more beneficial than isolating these protocols. We agree that their individual effects are difficult to isolate. We have also acknowledged the same in the limitations section of the Discussion section. However, previous studies combining diet and exercise have also reported a combined effect of the interventions. Similarly, we will also report the effects of holistic interventions rather than isolating them. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0306394.r002
17 Jun 2024 Decision Letter - Patricia Khashayar, Editor The Diabetes Remission in India (DiRemI) study: protocol for a prospective matched-control trial PONE-D-24-12706R1 Dear Dr. Kadam, 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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Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: All my concerns are addressed. The statistical section is acceptable. Reviewer #2: To the authors, Thank you for your thoughtful responses to my questions. I am satisfied that you have adequately addressed all of my concerns regarding the study protocol. I do not have any further questions or comments. ****** 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 ******** https://doi.org/10.1371/journal.pone.0306394.r003
Formally Accepted
21 Jun 2024 Acceptance Letter - Patricia Khashayar, Editor PONE-D-24-12706R1 PLOS ONE Dear Dr. Kadam, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Patricia Khashayar Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0306394.r004

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