Title: Serum Creatinine as a Risk Factor for Endometriosis: Insights from Cross-Sectional
Study, Mendelian Randomization Analysis, and Diagnostic Model Study
Version: 2 Date: 07 Mar 2025
Reviewer's report:
The manuscript presents a well-structured and comprehensive study on the association between
serum creatinine  levels and endometriosis, employing cross-sectional analysis, Mendelian
randomization, and diagnostic model development. The research is valuable in suggesting
a potential non-invasive biomarker for endometriosis. However, several aspects require
improvement to enhance clarity.
- Logistic regression models need better justification regarding the choice of confounders
adjusted for in the different models. How were the covariates selected?
- The description of MR analysis should clearly state whether the genetic instruments used have
been validated in previous studies. Are the SNPs exclusively related to creatinine, or do they
have pleiotropic effects?
- Sensitivity analyses (MR-Egger, MR-PRESSO) are mentioned, but their results should be more
explicitly discussed in the results section.
- The model development process should provide more detail regarding variable selection,
collinearity checks, and overfitting mitigation strategies.
- Were alternative models (e.g., machine learning approaches) considered, or was logistic
regression chosen exclusively?
- The odds ratios in the cross-sectional analysis seem unusually high (e.g., OR = 107.38).
This should be critically discussed in terms of biological plausibility and potential confounding
effects.
- Mendelian randomization results suggest a weak causal effect (IVW result of 1.001, 95% CI:
1.0001-1.002, P = 0.0350). The practical significance of such a small effect should be discussed.
- While the discussion contextualizes the findings well, some claims should be tempered,
particularly regarding causality. The MR findings suggest a weak causal relationship, which
should be acknowledged as a limitation.
- The potential confounding effects of renal function impairment on serum creatinine levels
should be discussed.
- The authors should discuss potential mechanisms linking creatinine to endometriosis in greater
depth, citing relevant metabolic and inflammatory pathways.
- Limitations should explicitly mention the single-center nature of the study, lack of external
validation, and potential confounding biases.
- The authors should expand the discussion by integrating findings from metabolomic studies
that have identified potential biomarkers for endometriosis. Several metabolites, such as
phospholipids, prostaglandins, amino acids, and inflammatory cytokines, have been suggested
as potential non-invasive biomarkers (https://doi.org/10.1007/978-3-030-57866-4_2   https://
doi.org/10.1016/j.jeud.2024.100077 doi: 10.1080/09513590.2023.2227276 ) . The authors
should connect their findings on serum creatinine with these broader biomarker discoveries
to strengthen the argument for a multi-biomarker approach in endometriosis diagnosis. Future
studies should explore how metabolomic and multi-omics data can be integrated with serum
creatinine assessments to enhance diagnostic accuracy and provide personalized treatment
strategies for patients.