The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study

Zeyu Wang; Tangyi Liu; Dan Cao; Hui Luo; Ze Yang; Xiaoyu Kang; Yanglin Pan

doi:10.1371/journal.pone.0302809

Peer Review History

Original SubmissionFebruary 20, 2024
2 Apr 2024 Decision Letter - Jorge Cervantes, Editor PONE-D-24-04501The associations between possible risk factors and functional dyspepsia: A comprehensive Mendelian randomization study.PLOS ONE Dear Dr. Pan, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by May 17 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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: Dear Dr. Pn, You manuscript has undergone careful review, and some revisions are needed before it can be suitable for publication. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I have carefully reviewed your manuscript titled "The associations between possible risk factors and functional dyspepsia: A comprehensive Mendelian randomization study." and would like to provide you with some constructive feedback to improve the quality and impact of your work. Overall, I find your study to be interesting and potentially valuable in understanding the causal relationship between human metabolites and functional dyspepsia.However, there are several areas that require attention. 1.supplementry figure 4：The text of the plot overlaps, so I recommend to draw it separately. 2.The duration of MR Exposure is lifelong, and the effect may be larger than that of clinical RCT studies.The results of MR Analysis do not indicate that the RCT study is necessarily valid.The conclusions should be interpreted with caution. 3.Figure1's MRII assumes that the location table notes should be accurate.Just next to this sentence"Genetic instruments are independent of confounding factors" 4.Please provide an explanation for the predominance of NA values in table 2 as a result of MR-PRESSO. Overall, this paper is methodologically rigorous and meticulous, providing new insights into the causes of functional dyspepsia. Reviewer #2: Overall, it is an interesting and relevant study (design / MR analyses is unique, considering the condition). Functional dyspepsia is a common and difficult to treat entity. Understanding the risk factors (other than psychological) is important to provide better therapies (treat the underlying factors). The conclusion is supported by the data - I greatly enjoyed the recommendations brought forth by the authors - it's pertinent in clinical practice. Recommend accepting for publication after making revisions (English / correcting grammar) - I made a few recommendations but there are additional sections that I did not mark (too many). I recommend an English editor for additional proofreading (this will make it easier on the reader and avoid distraction from the very interesting study / results). Consider changing the title to include function dyspepsia first (the studied condition), and avoid the use of ‘possible’ in titles - consider ‘potential’ (i.e., The associations between functional dyspepsia and potential risk factors: a comprehensive Mendelian randomization study). Under ‘Abstract / Background’ - change ‘identified many possible risk factors’ to ‘identified multiple potential risk factors.’ Change ‘between the factors and FD’ to ‘between these factors and FD.’ Under ‘Abstract / Methods’ - remove the first word ‘Totally’ - consider ‘A total of 53 possible.’ Change ‘obtained through comprehensive literature reviewing’ to ‘obtained through a comprehensive literature review.’ Don’t use the word ‘Totally’ in the manuscript - change to ‘A total of.’ Change ‘involved’ to ‘available’ (320387 controls were available for analysis). Under ‘Abstract / Results’ - Change ‘was significantly associated with the risk for FD in univariate MR analyses’ to ‘were associated with risk for FD in univariate MR analyses.’ Change ‘alcohol drinking’ to ‘alcohol consumption.’ Change ‘diabetes type 1’ to ‘type 1 diabetes.’ 'Systolic blood pressure' requires additional details - I believe it should mention 'elevated' systolic blood pressure.’ Change ‘lower health ratings’ to ‘lower overall health rating.’ Under ‘Abstract / Conclusions’ - Consider re-wording it to ‘Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.’ Under ‘Introduction’ - Change ‘However, up to date, no studies performed MR analyses to explore the associations between modifiable risk factors and FD’ to ‘However, no study has been performed that uses MR analyses to explore the associations between modifiable risk factors and FD.’ Under ‘Methods / MR design’ - Change ‘published after 1989 Since Rome criteria was initially established’ to ‘published after 1989, when Rome criteria was initially established.’ There are multiple misspelled words in the ‘Discussion’ - at least ‘depression,’ ‘demonstrate.’ Under ‘Discussion’ - Re-word / grammatically correct the following ‘In our study, genetically predicted alcohol drinking and diabetes type 1 are suggested to have suggestive higher odds for FD. However, Up to date, no studies have verified causal relationships between excessive alcohol consumption, and diabetes with FD.’ Consider ‘In our study, genetically predicted alcohol consumption and type 1 diabetes are suggestive of higher odds for FD. However, prior studies have failed to verify a causal relationship between excessive alcohol consumption or diabetes with FD.’ Using the words ‘Up to date’ is not required - if needed, a sentence can be started with “To date,.” ****** 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 ******** [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.0302809.r001
Revision 1
11 Apr 2024 Author Response Dear editor, We thank the reviewers and editors for reviewing our Manuscript ID PONE-D-24-04501 entitled “The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study”. We have revised the manuscript according to the constructive suggestions. A point-by-point response is included below. In response to the comments of the editor and reviewers, additional information has been added to the revised manuscript. These are marked by yellow highlights in the version with tracked changes. The version with all changes accepted (clean version) are also provided. Deleted text no longer appears in the final clean version. Reviewer #1 1.supplementry figure 4：The text of the plot overlaps, so I recommend to draw it separately. Response: Thank you for your suggestion. The text of 3 plots overlapped in the supplementary figure 4. To make it clearer, we re-drew the three pictures and uploaded the three figures as separate supplementary materials. The new figures were presented as supplementary figures 4.1-4.4. 2.The duration of MR Exposure is lifelong, and the effect may be larger than that of clinical RCT studies. The results of MR Analysis do not indicate that the RCT study is necessarily valid. The conclusions should be interpreted with caution. Response: Thank you for your suggestion. Your comments make us understand the longer and larger effect of the MR analysis. Therefore, based on your suggestion, we added the following sentences as “To our knowledge, the current study was the first study to demonstrate the causal effects of depression and education attainment on FD. The duration of MR exposure to those risk factors is lifelong and the effects of the factors on FD may be profound. Therefore, the identification, follow-up and psychotherapy for individuals with depression were of vital importance for superior prevention and treatment of FD. In addition, our study also revealed the lifelong effect of education status on FD and reinforced the importance of education for FD.” in the first paragraph of Discussion Section with yellow highlighted. We hoped that the above discussions could make the audiences understand the clinical importance of our findings deeply. 3. Figure1's MRII assumes that the location table notes should be accurate. Just next to this sentence" Genetic instruments are independent of confounding factors". Response: Thank you for your suggestion. According to your suggestion, we have placed the description of “MRII” next to the description of "Genetic instruments are independent of confounding factors" in Figure 1. 4.Please provide an explanation for the predominance of NA values in table 2 as a result of MR-PRESSO. Response: Thank you for your question. To make it clearer, we added the following explanations as “The MR-PRESSO approach was used to identify pleiotropic outliers in summary-level multi-instrumental MR analysis, and to obtain causal effect estimates using the IVW model after removing these pleiotropic outliers.” in the sixth paragraph of the methods section with yellow highlighted. “NA” indicated that the instrumental variables for this exposure did not have these pleiotropic outliers. The MR-PRESSO approach and the IVW method had the same result. To make it clearer, we added the following contents as ““NA” in the MR-PRESSO form indicated that the instrumental variables for this exposure did not have these pleiotropic outliers. The MR-PRESSO approach and the IVW method had the same result.” in the Notes section below table 2 with yellow highlighted. Reviewer #2 Consider changing the title to include function dyspepsia first (the studied condition), and avoid the use of ‘possible’ in titles - consider ‘potential’ (i.e., The associations between functional dyspepsia and potential risk factors: a comprehensive Mendelian randomization study). Response: Thank you for your suggestion. According to your suggestion, we have modified this title as “The associations between functional dyspepsia and potential risk factors: a comprehensive Mendelian randomization study”. This new title will enable the audience to understand the aim of this article better. The modified contents were also marked with yellow highlighted in the updated version. Under ‘Abstract / Background’ - change ‘identified many possible risk factors’ to ‘identified multiple potential risk factors.’ Change ‘between the factors and FD’ to ‘between these factors and FD.’ Response: Thank you for your suggestion. We have changed “identified many possible risk factors” to “identified multiple potential risk factors”. We have changed “between the factors and FD” to “between these factors and FD” in the Abstract Section. The modified contents were also marked with yellow highlighted. Under ‘Abstract / Methods’ - remove the first word ‘Totally’ - consider ‘A total of 53 possible.’ Change ‘obtained through comprehensive literature reviewing’ to ‘obtained through a comprehensive literature review.’ Don’t use the word ‘Totally’ in the manuscript - change to ‘A total of.’ Change ‘involved’ to ‘available’ (320387 controls were available for analysis). Response: Thank you for your suggestion. According to your suggestion, we have changed “Totally” to “A total of”, “obtained through comprehensive literature reviewing” to “obtained through a comprehensive literature review”, and “involved” to “available” in the Methods section of Abstract with yellow highlighted. Under ‘Abstract / Results’ - Change ‘was significantly associated with the risk for FD in univariate MR analyses’ to ‘were associated with risk for FD in univariate MR analyses.’ Change ‘alcohol drinking’ to ‘alcohol consumption.’ Change ‘diabetes type 1’ to ‘type 1 diabetes.’ 'Systolic blood pressure' requires additional details - I believe it should mention 'elevated' systolic blood pressure.’ Change ‘lower health ratings’ to ‘lower overall health rating.’ Response：Thank you for your suggestion. According to your suggestion, we have changed “was significantly associated with the risk for FD in univariate MR analyses” to “were associated with risk for FD in univariate MR analyses”, “alcohol drinking” to “alcohol consumption”, “diabetes type 1” to “type 1 diabetes”, “Systolic blood pressure” to “elevated systolic blood pressure”, and “lower health ratings” to “lower overall health rating” in the Results section of Abstract with yellow highlighted. Under ‘Abstract / Conclusions’ - Consider re-wording it to ‘Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.’ Response：Thank you for your suggestion. According to your suggestion, we have changed “Our comprehensive MR study demonstrated that depression and less years of education were the causal factors for FD at the genetic levels.” to “Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.” in the Conclusions section of Abstract with yellow highlighted. Under ‘Introduction’ - Change ‘However, up to date, no studies performed MR analyses to explore the associations between modifiable risk factors and FD’ to ‘However, no study has been performed that uses MR analyses to explore the associations between modifiable risk factors and FD.’ Response：Thank you for your suggestion. According to your suggestion, we have changed” However, up to date, no studies performed MR analyses to explore the associations between modifiable risk factors and FD.” to “However, no study has been performed that uses MR analyses to explore the associations between modifiable risk factors and FD.” in the third paragraph of the Introduction section with yellow highlighted. Under ‘Methods / MR design’ - Change ‘published after 1989 Since Rome criteria was initially established’ to ‘published after 1989, when Rome criteria was initially established.’ Response：Thank you for your suggestion. According to your suggestion, we have changed” published after 1989 Since Rome criteria was initially established” to “published after 1989, when Rome criteria was initially established” in the MR design of Methods section with yellow highlighted. There are multiple misspelled words in the ‘Discussion’ - at least ‘depression,’ ‘demonstrate.’ Response：Thank you for your suggestion. We have made corrections to the misspelled words in the first paragraph of the Discussion section with yellow highlighted. Under ‘Discussion’ - Re-word / grammatically correct the following ‘In our study, genetically predicted alcohol drinking and diabetes type 1 are suggested to have suggestive higher odds for FD. However, Up to date, no studies have verified causal relationships between excessive alcohol consumption, and diabetes with FD.’ Consider ‘In our study, genetically predicted alcohol consumption and type 1 diabetes are suggestive of higher odds for FD. However, prior studies have failed to verify a causal relationship between excessive alcohol consumption or diabetes with FD.’ Using the words ‘Up to date’ is not required - if needed, a sentence can be started with “To date,.” Response: Thank you for your suggestion. According to your suggestion, we have changed” In our study, genetically predicted alcohol drinking and diabetes type 1 are suggested to have suggestive higher odds for FD. However, Up to date, no studies have verified causal relationships between excessive alcohol consumption, and diabetes with FD.” to “In our study, genetically predicted alcohol consumption and type 1 diabetes are suggestive of higher odds for FD. However, prior studies have failed to verify a causal relationship between excessive alcohol consumption or diabetes with FD.” in the fifth paragraph of the Discussion section with yellow highlighted. Sincerely, Yanglin Pan Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0302809.r002
15 Apr 2024 Decision Letter - Jorge Cervantes, Editor The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study. PONE-D-24-04501R1 Dear Dr. Pan, 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. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Jorge Cervantes Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0302809.r003
Formally Accepted
26 Apr 2024 Acceptance Letter - Jorge Cervantes, Editor PONE-D-24-04501R1 PLOS ONE Dear Dr. Pan, 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. Jorge Cervantes Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0302809.r004

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