Peer Review History
Original SubmissionDecember 27, 2019 |
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PONE-D-19-35347 Improved Residual Fat Malabsorption and Growth in Children with Cystic Fibrosis Treated with a Novel Oral Structured Lipid Supplement: A Randomized Controlled Trial PLOS ONE Dear Dr. Tindall, 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 Apr 11 2020 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. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript:
Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Maret G Traber, PhD Academic Editor PLOS ONE Additional Editor Comments (if provided): Your manuscript describes an interesting approach to the continuing problem of fat malabsorption in patients with cystic fibrosis. The three reviewers were positive in their comments, but asked for some clarifications. One asked for a new statistical approach. Please address these comments and either justify your approach, or revise your statistical analysis. Journal Requirements: When submitting your revision, we need you to address these additional requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for including your ethics statement: This study was approved by the Children's Hospital of Philadelphia Institutional Review Board and each CF center (#4611). Verbal assent was obtained from subjects 6 to <18 years and written consent from parents/legal guardians of subjects <18 years. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research. 3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified whether written consent was informed (line 25). 4. Please add sub-sections to each part of your Methods section to aid in the reading of the manuscript. 5. Thank you for stating the following in the Acknowledgments Section of your manuscript: "Supported by NIDDK (R44DK060302), and the Nutrition Center at the Children’s Hospital of Philadelphia. The project described was supported by the National Center for Research Resources, Grant UL1RR024134, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000003." 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Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ 8. Please include a separate caption for each figure in your manuscript. [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 Reviewer #3: Yes ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes Reviewer #3: 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 Reviewer #3: 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 Reviewer #3: 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: An team of nutrition investigators conducted a 2007-2011 double-blind placebo controlled dietary supplement study using LYM-X-SORBTM (LXS), a readily absorbable structured lipid technology developed to increase dietary fat absorption, in CF subjects with pancreatic insufficiency ages 5-18. The overall 12 month study demonstrated that the oral LXS supplementation was safe and more effective than the energy and micronutritent-matched placebo supplement and resulted in increase daily fat absorption and fasting plasma fatty acid status and growth as published in ref 9, related parts of the study being published in refs 8, 10 &11. In the present report the authors have harvested data gathered at baseline and the three month visit from 40 LXS supplemented and 46 placebo supplemented subjects. Findings in this secondary analysis showed LXS to be most effective in subjects with more severe baseline malabsorption of fat. The authors present solid data supporting their conclusions, the findings are of translational value to clinical medicine and the discussion is both informative and relevant. A story case is made for more widespread use of LXS in CF patients with continuing fat malabsorption after optimizations for dosing of PERT. Comments 1. A major issue needing to be addressed by the authors concerns the modifying effects of CFTR modulator therapies on fat malabsorption. Unlike the subjects of a decade ago, most CF patients are now receiving CFTR corrector and potentiator therapies known to be modifiers of intestinal absorption... and this significantly impacts the translational value of this paper. There are now publications addressing this issue. 2. It would be useful if the authors could mention the effects of LXS to increase 20:5 and 22:6 absorption. To what extent are these values low in CF because of absorption issues vs. deficiencies in desaturases? 3. Line 127 and 180, what is CP? 4. Do the authors have any information on the effects of LXS on carotenoid absorption? Reviewer #2: Stallings et al. performed a secondary analysis of a multicenter RCT focusing on the effects of 3-month supplementation with a readily absorbable structured lipid versus placebo in 66 patients with cystic fibrosis aged 10.3±3.0 years, which has been reported previously to be well tolerated and exert beneficial effects on fat absorption, growth and nutritional and essential fatty acid status. In the present manuscript the effects in patients with coefficient of fat absorption (CFA) below versus above 88%, the median baseline CFA of the study group, were analyzed. Patients with lower than median CFA receiving the supplement showed improved CFA, anthropometry (weight, BMI z scores) and plasma essential fatty acids (linoleic, α-linolenic acid) and those receiving placebo only showed improved weight z scores (due to additional energy intake from the supplement), while patients with higher than median CFA (both treatment and placebo groups) had improvements in weight z scores and some plasma fatty acids. The authors concluded that the supplement provided greater benefits to CF patients with more severe baseline residual dietary fat malabsorption and that it enhanced dietary energy absorption, weight gain and fatty acid status. Overall, the RCT has been well designed and conducted using state-of-the-art methodologies and complying with human intervention study standards. However, this study has a few strong limitations: (1) The main difficulty arises from the fact that the RCT was not designed and powered for detecting a difference in the treatment effects between patients with CFA below versus above the median CFA of the entire study group. (2) The threshold of CFA 88% is not clinically or pathophysiology based, but determined by group characteristics and data distribution. (3) There is an unbalanced distribution of 63% of the treatment group showing CFA <88%, while only 39% did so in the placebo group. (4) Improvement of fat absorption at the level of the mean changes in CFA (7.5 � 7.2 %) and stool fat excretion (5.7 �7.2 g/d) reported for the group with CFA <88% receiving the supplement are clinically relevant, but the standard deviations are very high, suggesting that only a few patients may have responded that well. (5) In the absence of dietary fatty acid intake data changes in plasma fatty acid concentrations are difficult to explain by improved intestinal fatty acid absorption. Given that fat malabsorption-associated improvements are clinically relevant in CF patients, it is suggested that the authors address the following recommendations for further exploration of the results: As a consequence of (1) some real differences might not have been detected while others could have been observed by chance. For instance, there were significant changes in plasma linoleic and alpha-linolenic acid in the CFA>88% group receiving placebo, which is difficult to explain. Student’s paired tests were applied for testing time effects within treatment groups. When using for instance 2-way repeated measures ANOVA across the treatment groups, the likelihood to observe significant changes by chance could be minimized. To overcome (2) the limitation of an arbitrary threshold rather than one supported by clinical or pathophysiological criteria, it is suggested that differences in the treatment effects are studied across the entire range of baseline CFA instead of splitting the group by the median CFA and/or as an additional approach. It is suggested that the authors visualize and analyze the data in that way. This could possibly even help detect a real clinically relevant threshold (if such exists in this study). Regarding (3), even though the differences in baseline CFA were not significant between treatment and placebo group, the impact of this imbalance on the results should be taken care of by additional statistical analysis. Given (4) the high standard deviations of 7.5÷7.2 % for CFA and 5.7÷7.2 g/d for stool fat excretion in the CFA <88% and treatment group, a closer look at the data of this subgroup is suggested, including, for instance, the impact of absence versus presence of CF-associated cholestatic liver disease – which may have been more (or even exclusively) prevalent in CFA<88%. (5) Even though the 3-day weighed dietary records performed before and after the intervention may be too short in duration to definitely exclude possible effects of changes in dietary intake, they could be helpful in this regard. It is therefore suggested to include fatty acid intake data in the present manuscript. Studying the improvements in plasma FA in relation to improvements in CFA by using regression analysis could help support a mechanistic explanation of improved intestinal absorption proposed in the manuscript. Minor point: λ-linolenic acid should read γ-linolenic acid. Reviewer #3: This article is certainly very interesting and useful as it proposes to investigate whether the effect of 3 months of LXS treatment varied by the participants degree of dietary fat malabsorption at baseline. The paper is well written and highly readable, however they some minor comments worth addressing. Minor Perhaps not essential but it would it be good to include a rationale for looking at 3 month time-point. Clinical reason?, or more to do with immediate effects of the intervention? It would perhaps be more clear and transparent that this was a subgroup analysis. Calling it a secondary analysis might imply that the analysis is based on one of the secondary objectives from the main RCT, but it isn’t. In the methods section, it would be help if the sections were labelled clearly or made distinguishable, ‘outcomes’, ‘statistical analysis’ Result section, it’s worth mentioning that 86 participants completed 3 months (according to the Fig 1), however 66 children had data available for the ‘subgroup’ analysis. Lines 118 – 121 (page 9), also give actual numbers as you have done for low CFA group. ********** 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 Reviewer #3: 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. |
Revision 1 |
PONE-D-19-35347R1 Improved Residual Fat Malabsorption and Growth in Children with Cystic Fibrosis Treated with a Novel Oral Structured Lipid Supplement: A Randomized Controlled Trial PLOS ONE Dear Dr. Tindall, 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 May 24 2020 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. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript:
Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Maret G Traber, PhD Academic Editor PLOS ONE Additional Editor Comments (if provided): Please address the outstanding concerns from one of the reviewers, or provide a rationale why you think this action is unnecessary. [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 #2: (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 #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: 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 #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 #2: 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 #2: The authors have addressed the concerns raised by this reviewer in their point-by-point reply and have added corresponding additions to their manuscript. In contrast to the statement in the reply "As suggested, we added the total, saturated, monounsaturated and polyunsaturated dietary fat intake data to Table 2" and "There were no significant differences in intake between groups for total, monounsaturated fat, polyunsaturated fat, or saturated fat classes." these additional data do not appear in this table. These data should be added as described. While it was proposed that "Regarding the unbalanced distribution of 63% of the treatment group showing CFA <88%, while only 39% did so in the placebo group ... this is related to the original (Encala/placebo group) randomization procedure for all subjects with sex/age blocks ... It did not include CFA, as CFA was an outcome variable ... We have included this in the limitations section", this explanation is still missing in the limitations section and should be appropriately addressed in a re-revised version of the manuscript. Even though the inclusion/exclusion criteria have been previously reported (refs. 10-12), it would be helpful for the readers to include information regarding "Significant liver disease and any other significant diagnosis that might impact dietary intake, growth or body composition were exclusion criteria for subjects to participate in this study. There were no subjects with cholestatic liver disease" provided in the reply also in the manuscript as this is highly relevant for the present study. ********** 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 #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. |
Revision 2 |
Improved Residual Fat Malabsorption and Growth in Children with Cystic Fibrosis Treated with a Novel Oral Structured Lipid Supplement: A Randomized Controlled Trial PONE-D-19-35347R2 Dear Dr. Stallings, 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, Maret G Traber, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): The authors have responded acceptably. Reviewers' comments: |
Formally Accepted |
PONE-D-19-35347R2 Improved Residual Fat Malabsorption and Growth in Children with Cystic Fibrosis Treated with a Novel Oral Structured Lipid Supplement: A Randomized Controlled Trial Dear Dr. Stallings: 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 Professor Maret G Traber Academic Editor PLOS ONE |
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