Review for 10.1186/s12876-025-04137-x (2025)

Title: Unraveling the link between Inflammatory Bowel Disease and Perianal Abscess: Insights
from Bidirectional and Multivariable Mendelian Randomization Study
Version: 2 Date: 21 Apr 2025
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (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 technical rigor to allow
confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall, this is a well-conceived study that addresses an important
clinical question using robust Mendelian randomization (MR) methodology to investigate the
causal relationship between inflammatory bowel disease (IBD) and perianal abscess (PA). The
authors have utilized large-scale GWAS datasets, conducted bidirectional and multivariable
MR analyses, and applied appropriate sensitivity tests to validate their findings. However,
the manuscript falls short in several areas of best practice. Some important methodological
details are either missing or inadequately addressed. While the study's findings are potentially
impactful, improvements in transparency, reproducibility, and reporting in line with STROBE-
MR guidelines are needed to meet the standards expected of high-quality genetic epidemiology
research. I give my detailed comments below.
REQUESTED REVISIONS:
1. The title currently refers generically to a “Mendelian randomization study” without specifying
its bidirectional nature. Including this detail in the title would better reflect the scope and rigor
of the study design and align the manuscript with STROBE-MR reporting recommendations
(https://www.strobe-mr.org/).
2. The methods section is comprehensive, with rigorous delineation of GWAS sources, including
discovery, replication, and exploration cohorts. The use of large European datasets enhances
statistical power and minimizes population stratification bias. Yet, the manuscript omits detail
on participant overlap between exposure and outcome datasets in the two-sample MR, a
key requirement under STROBE-MR, which may raise concerns of weak instrument bias or
confounding if overlap was substantial.
3. Instrumental variable assumptions are appropriately discussed and tested. The selection
of SNPs adheres to standard criteria (genome-wide significance, LD independence, use of
PhenoScanner), and assumptions of relevance, independence, and exclusion restriction are
addressed. Sensitivity analyses, including MR-Egger intercept, Cochran’s Q, and MR-PRESSO,
were applied to test horizontal pleiotropy and heterogeneity. However, the potential impact of
weak instruments in reverse MR is a concern given the small number of SNPs (8–12), which
may impair the precision and reliability of the reverse causality findings.
4. Statistical methods are clearly defined and align with good MR practice. The IVW method
was the primary estimator, complemented by WM, MR-Egger, and MVMR. Multiple testing
was addressed with Bonferroni correction. However, no detail is given on handling of missing
data, nor is there a discussion of model assumptions for continuous versus binary traits, which
may reduce reproducibility and transparency.
5. Heterogeneity and pleiotropy statistics suggest some degree of inconsistency in SNP effects,
especially in replication cohorts, which should be more directly addressed in the discussion
regarding its potential to bias estimates.
6. The discussion aligns findings with prior observational evidence and extends interpretation
to clinical and biological relevance. However, the language sometimes overreaches, implying
definitive causality without reiterating the core IV assumptions and their conditional nature,
potentially misleading less technically informed readers. Although the authors note the lack
of individual-level data and the coarse classification of PA as limitations, there is insufficient
critique of potential selection bias, residual confounding, and lack of generalizability beyond
European populations.
7. According to the STROBE-MR guidelines (item 19), I recommend that the authors provide
the statistical code used for the analyses upon resubmission to enhance transparency and ensure
reproducibility of the results.
ADDITIONAL REQUESTS/SUGGESTIONS:
Although evaluating the presentation of the manuscript is beyond the intended scope of the
research quality review, I must note that the language quality of the manuscript is inconsistent
and requires significant revision. Grammatical errors, awkward phrasing, and occasional misuse
of terminology detract from the clarity and professionalism of the writing. The frequent use
of overly complex sentence structures also compromises readability. In addition, redundant
expressions and inconsistent terminology further hinder effective communication. I strongly
recommend a comprehensive language edit prior to submission."