Reclaiming mendelian randomization from the deluge of papers and misleading findings

causal inference
editorial
genetic epidemiology
mendelian randomization
publication bias
quality control
  • Core Concern: The paper addresses the decline in quality of Mendelian Randomization (MR) research due to an overwhelming number of low-value Two-Sample MR (2SMR) papers and the premature, unvalidated application of highly complex MR methods.
  • Recommendations for Editors: Editors are advised to set a higher bar, specifically to reject papers that report only standard 2SMR findings without additional supporting evidence, methodological novelty, or validation.
  • Reviewer Focus: Reviewers must enforce rigorous quality control, demanding comprehensive sensitivity analyses (e.g., MR-Egger, Steiger filtering) and ensuring that findings, especially those from complex non-linear MR, are biologically plausible and properly validated.
Published

23 January 2026

PubMed: 39244551 DOI: 10.1186/s12944-024-02284-w Overview generated by: Gemini 2.5 Flash, 28/11/2025

Key Findings and Statement of Concern

This comment piece addresses the burgeoning crisis of low-quality papers in Mendelian Randomization (MR) that is jeopardizing the method’s reputation as a robust causal inference tool. The authors identify two primary concerning trends driven by the availability of large genetic datasets:

  1. Deluge of Two-Sample MR (2SMR) Studies: An explosion of studies that simply apply standard 2SMR to publicly available Genome-Wide Association Study (GWAS) summary data, yielding results that often lack novelty or sufficient rigor.
  2. Premature Application of Complex Methods: The rapid development and use of novel, highly complex MR methods (e.g., non-linear MR, multi-variable MR) without adequate testing, leading to misleading or spurious findings, some of which have resulted in retractions or corrections (e.g., relating to vitamin D).

Recommendations for Journal Editors and Peer Reviewers

To “reclaim” the methodology, the authors propose strict guidelines for editorial and peer review processes aimed at improving the quality and impact of published MR research.

Handling Two-Sample MR (2SMR) Studies

The authors advise a heightened threshold for acceptance of standard 2SMR studies:

  • Recommendation for Editors: Editors are advised to simply reject papers that only report standard 2SMR findings with no additional supporting evidence (e.g., individual-level data validation, unique data resources, or advanced methodological innovation).
  • Recommendation for Reviewers: Reviewers should use a template for rejection that flags studies lacking sufficient rigor, such as those that fail to:
    • Conduct comprehensive sensitivity analyses (MR-Egger, Weighted Median, Steiger filtering).
    • Demonstrate clear novelty or clinical/biological plausibility.
    • Adequately harmonize data or check for sample overlap.

Handling Novel and Complex MR Methods

For studies using new or highly complex MR methods, the review process must ensure robustness:

  • Rigorous Testing: Reviewers should demand evidence that the complex MR methods (e.g., non-linear MR) have been properly tested and validated by the authors, particularly for the specific exposure and outcome under investigation.
  • Biological Plausibility: Findings must be scrutinized for biological plausibility. Results that challenge established biology must be exceptionally well-supported by evidence.
  • Comparison to Simpler Methods: Results from complex methods should be compared against robust, well-established methods (e.g., standard Inverse Variance Weighted MR) to ensure consistency, if appropriate.

Conclusion

The article concludes that the current publishing landscape threatens to damage the credibility of MR. The burden is placed on the scientific community—especially editors and peer reviewers—to enforce stricter standards of rigor and novelty to ensure that MR continues to be a trustworthy and valuable tool for causal inference in epidemiology.