Title: Unveiling the Influence of Lipidomes on Inflammatory Bowel Disease: A Bidirectional
Mendelian Randomization Study
Version: 1 Date: 28 Mar 2025
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors have made substantial revisions in response to the
reviewers' comments. Key methodological concerns were addressed, including the validity of
instrumental variables in the Mendelian randomization (MR) framework. The authors have now
provided p-values for SNPs in the IBD GWAS to support the exclusion of variants that might
violate MR assumptions. In addition, both unadjusted and Bonferroni-corrected p-values are
now included in the main figures, improving the transparency of the statistical findings.
The discussion section has been expanded to address biological mechanisms linking
lipidome dysregulation to IBD pathogenesis, particularly via endoplasmic reticulum stress
and inflammatory signaling. The potential role of lipid species such as phosphatidylcholine,
cholesteryl esters, and lysophosphatidylethanolamine is now more clearly outlined. Besides, the
authors have acknowledged pleiotropy as a limitation, noting that while MR-PRESSO did not
detect global pleiotropy, some MR-Egger intercepts were significant.
REQUESTED REVISIONS:
While the manuscript is now largely suitable for publication, a few minor revisions are
recommended.
First, consider emphasizing MR limitations (e.g., residual pleiotropy and population specificity)
more clearly in the conclusion.
Second, refine the discussion to better differentiate the roles of individual lipid species, such as
LPC 18:1 vs LPC 20:4, in clinical terms.
Finally, if feasible, a multivariable MR approach or a brief phenome-wide sensitivity check
would provide additional reassurance against potential pleiotropic bias.
These enhancements would further improve the manuscript’s clarity and impact."
Title: Unveiling the Influence of Lipidomes on Inflammatory Bowel Disease: A Bidirectional
Mendelian Randomization Study
Version: 1 Date: 28 Mar 2025
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors have made substantial revisions in response to the
reviewers' comments. Key methodological concerns were addressed, including the validity of
instrumental variables in the Mendelian randomization (MR) framework. The authors have now
provided p-values for SNPs in the IBD GWAS to support the exclusion of variants that might
violate MR assumptions. In addition, both unadjusted and Bonferroni-corrected p-values are
now included in the main figures, improving the transparency of the statistical findings.
The discussion section has been expanded to address biological mechanisms linking
lipidome dysregulation to IBD pathogenesis, particularly via endoplasmic reticulum stress
and inflammatory signaling. The potential role of lipid species such as phosphatidylcholine,
cholesteryl esters, and lysophosphatidylethanolamine is now more clearly outlined. Besides, the
authors have acknowledged pleiotropy as a limitation, noting that while MR-PRESSO did not
detect global pleiotropy, some MR-Egger intercepts were significant.
REQUESTED REVISIONS:
While the manuscript is now largely suitable for publication, a few minor revisions are
recommended.
First, consider emphasizing MR limitations (e.g., residual pleiotropy and population specificity)
more clearly in the conclusion.
Second, refine the discussion to better differentiate the roles of individual lipid species, such as
LPC 18:1 vs LPC 20:4, in clinical terms.
Finally, if feasible, a multivariable MR approach or a brief phenome-wide sensitivity check
would provide additional reassurance against potential pleiotropic bias.
These enhancements would further improve the manuscript’s clarity and impact."
Please review this paper.
user
Title: Unveiling the Influence of Lipidomes on Inflammatory Bowel Disease: A Bidirectional
Mendelian Randomization Study
Version: 1 Date: 28 Mar 2025
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors have made substantial revisions in response to the
reviewers' comments. Key methodological concerns were addressed, including the validity of
instrumental variables in the Mendelian randomization (MR) framework. The authors have now
provided p-values for SNPs in the IBD GWAS to support the exclusion of variants that might
violate MR assumptions. In addition, both unadjusted and Bonferroni-corrected p-values are
now included in the main figures, improving the transparency of the statistical findings.
The discussion section has been expanded to address biological mechanisms linking
lipidome dysregulation to IBD pathogenesis, particularly via endoplasmic reticulum stress
and inflammatory signaling. The potential role of lipid species such as phosphatidylcholine,
cholesteryl esters, and lysophosphatidylethanolamine is now more clearly outlined. Besides, the
authors have acknowledged pleiotropy as a limitation, noting that while MR-PRESSO did not
detect global pleiotropy, some MR-Egger intercepts were significant.
REQUESTED REVISIONS:
While the manuscript is now largely suitable for publication, a few minor revisions are
recommended.
First, consider emphasizing MR limitations (e.g., residual pleiotropy and population specificity)
more clearly in the conclusion.
Second, refine the discussion to better differentiate the roles of individual lipid species, such as
LPC 18:1 vs LPC 20:4, in clinical terms.
Finally, if feasible, a multivariable MR approach or a brief phenome-wide sensitivity check
would provide additional reassurance against potential pleiotropic bias.
These enhancements would further improve the manuscript’s clarity and impact."
assistant