Title: Causal effects of genetically determined metabolites and metabolite ratios on esophageal
diseases: A two-sample Mendelian randomization study
Version: 0 Date: 03 Aug 2024
Reviewer's report:
There are several aspects of the manuscript that require clarification and further elaboration to
enhance its scientific rigor and readability.
Methods
GWAS data for esophageal diseases
1. As far as I know, finngen has been updated to R11, may I ask why the author is using the
R9 version of the data?
2. The GWAS data that the authors used for MR study were from European populations,
which might limit the reliability when extrapolating the findings to non-European populations.
I recommend that the authors could use available nonEuropean GWAS data.
Selection of genetic instrumental variables
3. Authors were asked to give a rationale for the choice of p-value (p < 1E-05) or references
4. The author refers to "quality control measures", could you please elaborate on how you
perform quality control on your data?
5. Can the authors please specify for each metabolite the instrument coverage in the outcome
GWAS?
MR statistical analysis
6. May I ask the authors what kind of inverse variance weighting method (fixed effects (IVW-
fixed) and random effects (IVW-random)) they used? Why?
7. Please evaluate statistical power in this study.
8. In most cases, the assumptions of MR are difficult to achieve. I am wondering whether the
authors try to use some alternative methods, like colocalization analysis and PrediXcan?
Results
Selection of genetic instrumental variables
9. How did the authors ensure that this study met the three assumptions mentioned? Please
elaborate in the result.
10. What confounding factors are, the control methods the author used, especially how many
SNPs are excluded accounting for each possible confounders. I suggest all the details should be
mentioned in this Methods part.
Causal effects of metabolites and metabolite ratios on esophageal diseases
11. The section appears to be extraordinarily complex, making it difficult for the reader to read.
Please reorganize the presentation of this section.
12. I think Fig3 could go in the supplemental material.
Discussion
13. The discussion section is too lengthy, and it is recommended that the authors divide the
discussion into subheadings.
Language
14. The manuscript demonstrates a high level of English proficiency overall, with appropriate
use of scientific terminology. However, there are minor grammatical errors and occasional
awkward phrasings that could benefit from careful proofreading and revision. Ensuring
consistent use of technical terms and improving clarity in complex sentences will further enhance
the readability and professionalism of the manuscript.
Title: Causal effects of genetically determined metabolites and metabolite ratios on esophageal
diseases: A two-sample Mendelian randomization study
Version: 0 Date: 03 Aug 2024
Reviewer's report:
There are several aspects of the manuscript that require clarification and further elaboration to
enhance its scientific rigor and readability.
Methods
GWAS data for esophageal diseases
1. As far as I know, finngen has been updated to R11, may I ask why the author is using the
R9 version of the data?
2. The GWAS data that the authors used for MR study were from European populations,
which might limit the reliability when extrapolating the findings to non-European populations.
I recommend that the authors could use available nonEuropean GWAS data.
Selection of genetic instrumental variables
3. Authors were asked to give a rationale for the choice of p-value (p < 1E-05) or references
4. The author refers to "quality control measures", could you please elaborate on how you
perform quality control on your data?
5. Can the authors please specify for each metabolite the instrument coverage in the outcome
GWAS?
MR statistical analysis
6. May I ask the authors what kind of inverse variance weighting method (fixed effects (IVW-
fixed) and random effects (IVW-random)) they used? Why?
7. Please evaluate statistical power in this study.
8. In most cases, the assumptions of MR are difficult to achieve. I am wondering whether the
authors try to use some alternative methods, like colocalization analysis and PrediXcan?
Results
Selection of genetic instrumental variables
9. How did the authors ensure that this study met the three assumptions mentioned? Please
elaborate in the result.
10. What confounding factors are, the control methods the author used, especially how many
SNPs are excluded accounting for each possible confounders. I suggest all the details should be
mentioned in this Methods part.
Causal effects of metabolites and metabolite ratios on esophageal diseases
11. The section appears to be extraordinarily complex, making it difficult for the reader to read.
Please reorganize the presentation of this section.
12. I think Fig3 could go in the supplemental material.
Discussion
13. The discussion section is too lengthy, and it is recommended that the authors divide the
discussion into subheadings.
Language
14. The manuscript demonstrates a high level of English proficiency overall, with appropriate
use of scientific terminology. However, there are minor grammatical errors and occasional
awkward phrasings that could benefit from careful proofreading and revision. Ensuring
consistent use of technical terms and improving clarity in complex sentences will further enhance
the readability and professionalism of the manuscript.
Please review this paper.
user
Title: Causal effects of genetically determined metabolites and metabolite ratios on esophageal
diseases: A two-sample Mendelian randomization study
Version: 0 Date: 03 Aug 2024
Reviewer's report:
There are several aspects of the manuscript that require clarification and further elaboration to
enhance its scientific rigor and readability.
Methods
GWAS data for esophageal diseases
1. As far as I know, finngen has been updated to R11, may I ask why the author is using the
R9 version of the data?
2. The GWAS data that the authors used for MR study were from European populations,
which might limit the reliability when extrapolating the findings to non-European populations.
I recommend that the authors could use available nonEuropean GWAS data.
Selection of genetic instrumental variables
3. Authors were asked to give a rationale for the choice of p-value (p < 1E-05) or references
4. The author refers to "quality control measures", could you please elaborate on how you
perform quality control on your data?
5. Can the authors please specify for each metabolite the instrument coverage in the outcome
GWAS?
MR statistical analysis
6. May I ask the authors what kind of inverse variance weighting method (fixed effects (IVW-
fixed) and random effects (IVW-random)) they used? Why?
7. Please evaluate statistical power in this study.
8. In most cases, the assumptions of MR are difficult to achieve. I am wondering whether the
authors try to use some alternative methods, like colocalization analysis and PrediXcan?
Results
Selection of genetic instrumental variables
9. How did the authors ensure that this study met the three assumptions mentioned? Please
elaborate in the result.
10. What confounding factors are, the control methods the author used, especially how many
SNPs are excluded accounting for each possible confounders. I suggest all the details should be
mentioned in this Methods part.
Causal effects of metabolites and metabolite ratios on esophageal diseases
11. The section appears to be extraordinarily complex, making it difficult for the reader to read.
Please reorganize the presentation of this section.
12. I think Fig3 could go in the supplemental material.
Discussion
13. The discussion section is too lengthy, and it is recommended that the authors divide the
discussion into subheadings.
Language
14. The manuscript demonstrates a high level of English proficiency overall, with appropriate
use of scientific terminology. However, there are minor grammatical errors and occasional
awkward phrasings that could benefit from careful proofreading and revision. Ensuring
consistent use of technical terms and improving clarity in complex sentences will further enhance
the readability and professionalism of the manuscript.
assistant