Cohort profile: Celiac disease genomic, environmental, microbiome and metabolome study; a prospective longitudinal birth cohort study of children at-risk for celiac disease

Maureen M. Leonard; Victoria Kenyon; Francesco Valitutti; Rita Pennacchio-Harrington; Pasqua Piemontese; Ruggiero Francavilla; Lorenzo Norsa; Tiziana Passaro; Marco Crocco; Mariella Baldassarre; Chiara Maria Trovato; Alessio Fasano; the CDGEMM working group

doi:10.1371/journal.pone.0282739

Peer Review History

Original SubmissionJanuary 4, 2023
8 Feb 2023 Decision Letter - Brenda A Wilson, Editor PONE-D-23-00282Cohort Profile: Celiac Disease Genomic, Environmental, Microbiome and Metabolome Study; a prospective longitudinal birth cohort study of children at-risk for celiac diseasePLOS ONE Dear Dr. Leonard, 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. Both reviewers noted a number of minor issues that must be adequately addressed in a revised manuscript.Please submit your revised manuscript by Mar 25 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. 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[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: N/A Reviewer #2: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: An interesting and well written cohort profile manuscript re the development of CD from birth in an at risk population of new births from two geographical areas. 1. Given the high rate of CD development by age 3 years, what proportion of cases correlated with an early or late-on transition from breast milk / formula / or both to solid foods irrespective of gluten introduction? That is was the introduction of solid foods on a similar time-line for all the cases irrespective of geographical location of the participants? Clarify. 2. Also from 1 above and a related query. Are the authors recording the types of overall foods and gluten consumed by the participants? As this reviewer understands it unless gluten content of foods has changed...the expectation is that the majority of wheat grown in the US tends to be high in protein content this being in the form of gluten, whereas in Europe where the majority of wheat grown has lower levels of proteins and as a consequence has a decreased gluten content. Clarify. 3. I agree with the authors that questionnaire data can be difficult to assess in terms of reliable parent reporting and missing data. 4. As a final comment I would like to add that employing the intestinal microbiome as a surrogate marker may have limitations, especially in the absence of samples from healthy children, yet this data could provide information on the progression of intestinal dysbiosis and possible deficits in SCFAs cross feeding that occurs between microbes to trigger pro-inflammatory actions in CD. Reviewer #2: This manuscript is an update of the status of the CDGEMM cohort study that summarizes the current number of patients and their characteristics, and reviews the scientific papers previously published from the data. The methodology employed to achieve their successful cohort is presented in accessible language and abundant detail, such that others seeking to create patient cohorts could adopt aspects of this approach. The success of the effort to date is clear. Three publications deriving from collected data are described as well as the future investigative agenda. The authors are to be congratulated for achieving longitudinal retention of upwards of 82% of families over 5-10 years. The stated purpose of this descriptive presentation is to invite collaborations. Therefore, the detailed presentation of available samples and data is appropriate. Minor comments: Abstract: I think you mean 80% of the 31 who developed CD developed it by age 3. Right now, it reads as if 80% of all participants (554) developed CD. Development of CD: Is there any speculation as to why more children in the Italian cohort (37 vs 17 US) developed positive TTG? Is that a statistically significant difference? Is it related to specific HLA type? Can you speculate as to the reason and meaning of transient TTG positivity that then disappears? More details would be interesting (ages, duration of positivity, etc.). Please provide a reference for the paragraph on page 12 line 290 “In other work . . . .” Do you want to be more specific in your goal of inviting collaborators into the work? I have not seen this discussed in a scientific paper before, but you may want to end with a sentence on that since it is the stated goal of this descriptive paper. ****** 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: Luis Vitetta 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.0282739.r001
Revision 1
20 Feb 2023 Author Response Responses to Reviewer’s Questions Reviewer #1: An interesting and well written cohort profile manuscript re the development of CD from birth in an at risk population of new births from two geographical areas. 1. Given the high rate of CD development by age 3 years, what proportion of cases correlated with an early or late-on transition from breast milk / formula / or both to solid foods irrespective of gluten introduction? That is was the introduction of solid foods on a similar time-line for all the cases irrespective of geographical location of the participants? Clarify. We thank the reviewer of this comment. An analysis of dietary factors that may contribute to CD onset was outside the scope of this paper. We are currently analyzing the data you mention as part of a larger study examining dietary and environmental factors in the first 15 months of age that may influence CD onset. 2. Also from 1 above and a related query. Are the authors recording the types of overall foods and gluten consumed by the participants? As this reviewer understands it unless gluten content of foods has changed...the expectation is that the majority of wheat grown in the US tends to be high in protein content this being in the form of gluten, whereas in Europe where the majority of wheat grown has lower levels of proteins and as a consequence has a decreased gluten content. Clarify. We are recording the types of foods and types of gluten consumed to try to understand how the amount and type may influence CD onset. We agree that there may be differences in wheat protein content between the US and Europe and will explore this in future studies. 3. I agree with the authors that questionnaire data can be difficult to assess in terms of reliable parent reporting and missing data. Thank you for this comment. 4. As a final comment I would like to add that employing the intestinal microbiome as a surrogate marker may have limitations, especially in the absence of samples from healthy children, yet this data could provide information on the progression of intestinal dysbiosis and possible deficits in SCFAs cross feeding that occurs between microbes to trigger pro-inflammatory actions in CD. We agree with your statement. We hope this cohort profile will help us to develop relationships with collaborators who have samples from healthy children which may be used in order to better understand our findings. We have added the following sentence to the end of the paper “We welcome collaborations with those interested in efforts to prevent chronic inflammatory disease.” Reviewer #2: This manuscript is an update of the status of the CDGEMM cohort study that summarizes the current number of patients and their characteristics, and reviews the scientific papers previously published from the data. The methodology employed to achieve their successful cohort is presented in accessible language and abundant detail, such that others seeking to create patient cohorts could adopt aspects of this approach. The success of the effort to date is clear. Three publications deriving from collected data are described as well as the future investigative agenda. The authors are to be congratulated for achieving longitudinal retention of upwards of 82% of families over 5-10 years. The stated purpose of this descriptive presentation is to invite collaborations. Therefore, the detailed presentation of available samples and data is appropriate. We thank the reviewer for these comments. Minor comments: 1. Abstract: I think you mean 80% of the 31 who developed CD developed it by age 3. Right now, it reads as if 80% of all participants (554) developed CD. We have updated the abstract to read: “Approximately 80% of the 54 participants with CD have developed it by 3 years of age. 2. Development of CD: Is there any speculation as to why more children in the Italian cohort (37 vs 17 US) developed positive TTG? Is that a statistically significant difference? Is it related to specific HLA type? We are also intrigued by this result as children from the US and Italy all have an increased risk of developing CD due to the family history of CD yet as of now there is a higher incidence in Italy. It is a statistically significant difference. We have not identified why more children in Italy have developed CD. It will be interesting to see once the study is complete if this difference remains. We are currently analyzing environmental and dietary factors as well as looking at serum markers that may contribute to this difference. These studies are ongoing. Our completed studies to date did not identify differences in the microbiome of subjects in the US compared to Italy. 3.Can you speculate as to the reason and meaning of transient TTG positivity that then disappears? More details would be interesting (ages, duration of positivity, etc.). We have provided data about these subjects with transient CD in the supplement. As stated in the paper 4 of the 8 subjects are undergoing work-up for CD, while the other 4 subjects are still on a gluten-containing diet, no symptoms and tTG IgA has not since been elevated except for that one instance. Since the study is ongoing, we expect some of these subjects will have CD. However, transient tTG IgA elevations have been described in other prospective cohort studies of children at risk of CD. For example, Lionetti et al developed a cohort of 832 children at-risk for CD and described a total of 5 children with low titer tTG IgA from their cohort and 26 children with potential CD that had different outcomes such as development of CD, normalization of antibodies on a gluten containing diet, or fluctuating tTG. (PMID: 25271602). Vriezinga et al followed a cohort of 963 children at risk for celiac disease and describe 8 subjects with transient elevats of celiac-disease associated antibodies for which a diagnosis was never confirmed. (PMID: 25271603). Thus are findings are in line with previous work. 4. Please provide a reference for the paragraph on page 12 line 290 “In other work . . . .” Thank you for pointing out this omission. We have provided a reference within the manuscript, which is also below: Olshan KL, Zomorrodi AR, Pujolassos M, et al. Microbiota and Metabolomic Patterns in the Breast Milk of Subjects with Celiac Disease on a Gluten-Free Diet. Nutrients. 2021;13(7). 5. Do you want to be more specific in your goal of inviting collaborators into the work? I have not seen this discussed in a scientific paper before, but you may want to end with a sentence on that since it is the stated goal of this descriptive paper. Thank you for this comment. We have added the following to the end of the paper “We welcome collaborations with those interested in efforts to prevent chronic inflammatory disease.” Attachments Attachment Submitted filename: ResponseToReviewers.docx https://doi.org/10.1371/journal.pone.0282739.r002
22 Feb 2023 Decision Letter - Brenda A Wilson, Editor Cohort Profile: Celiac Disease Genomic, Environmental, Microbiome and Metabolome Study; a prospective longitudinal birth cohort study of children at-risk for celiac disease PONE-D-23-00282R1 Dear Dr. Leonard, 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, Brenda A Wilson, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0282739.r003
Formally Accepted
27 Feb 2023 Acceptance Letter - Brenda A Wilson, Editor PONE-D-23-00282R1 Cohort Profile: Celiac Disease Genomic, Environmental, Microbiome and Metabolome Study; a prospective longitudinal birth cohort study of children at-risk for celiac disease Dear Dr. Leonard: I'm 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 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 plosone@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. Brenda A Wilson Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0282739.r004

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