Title: Unraveling the link between Inflammatory Bowel Disease and Perianal Abscess: Insights
from Bidirectional and Multivariable Mendelian Randomization Study
Version: 3 Date: 11 May 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: Overall, my previous comments were addressed comprehensively,
with critical technical concerns receiving methodologically sound justifications and appropriate
revisions. However, further improvements are warranted, including more cautious interpretation
of exploratory findings and enhanced reproducibility to ensure broader accessibility. I give my
detailed comments below.
REQUESTED REVISIONS:
Although the instruments used in the reverse MR analysis demonstrated adequate strength
(F-statistic > 20), the small number of SNPs still imposes a significant constraint on the
statistical power of these analyses. The authors should clearly acknowledge in the limitations
section that non-significant findings in the reverse MR may reflect limited power rather than
definitive evidence against a causal effect. Additionally, future studies could consider alternative
approaches such as Bayesian Mendelian randomization to enhance inference reliability in
settings with sparse instruments.
The analysis of ulcerative ileocolitis and other site-specific IBD subtypes was presented as
hypothesis-generating; however, the observed marginal statistical significance (e.g., p=0.0417)
requires a more cautious interpretative tone. It is recommended that these subgroup analyses be
explicitly labeled as exploratory not only in the discussion but also in the conclusion sections,
in order to prevent overstatement of their implications and to maintain alignment with best
practices for reporting secondary analyses.
While the manuscript presents robust causal findings, the translation of these results into
clinical practice could be more clearly articulated. The discussion would benefit from specific
suggestions on how genetic risk profiling or early detection of perianal abscess might inform IBD
screening protocols or therapeutic decisions. Additionally, clarifying whether perianal abscess
could feasibly serve as a trigger for early IBD evaluation—given current diagnostic tools—
would improve the clinical relevance and applicability of the study’s conclusions.
Despite prior revisions, the manuscript still contains numerous instances of overly long
sentences and dense, jargon-heavy phrasing that may impair readability for a broader audience.
For example, terms like “pleiotropy-robust analytical approaches” or “orthogonalization of
genetic instrument effects” could be rephrased using clearer, more accessible language. Further
revision by a native English-speaking scientific editor is strongly recommended.
Finally, although the provided R code includes the essential components of the Mendelian
Randomization (MR) analysis pipeline described in the manuscript, issues such as variable
overwriting, omission of reverse MR analyses, and the absence of MR-Steiger filtering limit
its completeness and reproducibility. These shortcomings raise concerns about the transparency
and robustness of the reported statistical analysis. I strongly recommend that the authors
provide a complete, well-annotated version of the R code to ensure methodological clarity and
reproducibility.
Title: Unraveling the link between Inflammatory Bowel Disease and Perianal Abscess: Insights
from Bidirectional and Multivariable Mendelian Randomization Study
Version: 3 Date: 11 May 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: Overall, my previous comments were addressed comprehensively,
with critical technical concerns receiving methodologically sound justifications and appropriate
revisions. However, further improvements are warranted, including more cautious interpretation
of exploratory findings and enhanced reproducibility to ensure broader accessibility. I give my
detailed comments below.
REQUESTED REVISIONS:
Although the instruments used in the reverse MR analysis demonstrated adequate strength
(F-statistic > 20), the small number of SNPs still imposes a significant constraint on the
statistical power of these analyses. The authors should clearly acknowledge in the limitations
section that non-significant findings in the reverse MR may reflect limited power rather than
definitive evidence against a causal effect. Additionally, future studies could consider alternative
approaches such as Bayesian Mendelian randomization to enhance inference reliability in
settings with sparse instruments.
The analysis of ulcerative ileocolitis and other site-specific IBD subtypes was presented as
hypothesis-generating; however, the observed marginal statistical significance (e.g., p=0.0417)
requires a more cautious interpretative tone. It is recommended that these subgroup analyses be
explicitly labeled as exploratory not only in the discussion but also in the conclusion sections,
in order to prevent overstatement of their implications and to maintain alignment with best
practices for reporting secondary analyses.
While the manuscript presents robust causal findings, the translation of these results into
clinical practice could be more clearly articulated. The discussion would benefit from specific
suggestions on how genetic risk profiling or early detection of perianal abscess might inform IBD
screening protocols or therapeutic decisions. Additionally, clarifying whether perianal abscess
could feasibly serve as a trigger for early IBD evaluation—given current diagnostic tools—
would improve the clinical relevance and applicability of the study’s conclusions.
Despite prior revisions, the manuscript still contains numerous instances of overly long
sentences and dense, jargon-heavy phrasing that may impair readability for a broader audience.
For example, terms like “pleiotropy-robust analytical approaches” or “orthogonalization of
genetic instrument effects” could be rephrased using clearer, more accessible language. Further
revision by a native English-speaking scientific editor is strongly recommended.
Finally, although the provided R code includes the essential components of the Mendelian
Randomization (MR) analysis pipeline described in the manuscript, issues such as variable
overwriting, omission of reverse MR analyses, and the absence of MR-Steiger filtering limit
its completeness and reproducibility. These shortcomings raise concerns about the transparency
and robustness of the reported statistical analysis. I strongly recommend that the authors
provide a complete, well-annotated version of the R code to ensure methodological clarity and
reproducibility.
Please review this paper.
user
Title: Unraveling the link between Inflammatory Bowel Disease and Perianal Abscess: Insights
from Bidirectional and Multivariable Mendelian Randomization Study
Version: 3 Date: 11 May 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: Overall, my previous comments were addressed comprehensively,
with critical technical concerns receiving methodologically sound justifications and appropriate
revisions. However, further improvements are warranted, including more cautious interpretation
of exploratory findings and enhanced reproducibility to ensure broader accessibility. I give my
detailed comments below.
REQUESTED REVISIONS:
Although the instruments used in the reverse MR analysis demonstrated adequate strength
(F-statistic > 20), the small number of SNPs still imposes a significant constraint on the
statistical power of these analyses. The authors should clearly acknowledge in the limitations
section that non-significant findings in the reverse MR may reflect limited power rather than
definitive evidence against a causal effect. Additionally, future studies could consider alternative
approaches such as Bayesian Mendelian randomization to enhance inference reliability in
settings with sparse instruments.
The analysis of ulcerative ileocolitis and other site-specific IBD subtypes was presented as
hypothesis-generating; however, the observed marginal statistical significance (e.g., p=0.0417)
requires a more cautious interpretative tone. It is recommended that these subgroup analyses be
explicitly labeled as exploratory not only in the discussion but also in the conclusion sections,
in order to prevent overstatement of their implications and to maintain alignment with best
practices for reporting secondary analyses.
While the manuscript presents robust causal findings, the translation of these results into
clinical practice could be more clearly articulated. The discussion would benefit from specific
suggestions on how genetic risk profiling or early detection of perianal abscess might inform IBD
screening protocols or therapeutic decisions. Additionally, clarifying whether perianal abscess
could feasibly serve as a trigger for early IBD evaluation—given current diagnostic tools—
would improve the clinical relevance and applicability of the study’s conclusions.
Despite prior revisions, the manuscript still contains numerous instances of overly long
sentences and dense, jargon-heavy phrasing that may impair readability for a broader audience.
For example, terms like “pleiotropy-robust analytical approaches” or “orthogonalization of
genetic instrument effects” could be rephrased using clearer, more accessible language. Further
revision by a native English-speaking scientific editor is strongly recommended.
Finally, although the provided R code includes the essential components of the Mendelian
Randomization (MR) analysis pipeline described in the manuscript, issues such as variable
overwriting, omission of reverse MR analyses, and the absence of MR-Steiger filtering limit
its completeness and reproducibility. These shortcomings raise concerns about the transparency
and robustness of the reported statistical analysis. I strongly recommend that the authors
provide a complete, well-annotated version of the R code to ensure methodological clarity and
reproducibility.
assistant