Use of Mendelian randomization to assess the causal status of modifiable exposures for rheumatic diseases

Zhao, Sizheng Steven; Burgess, Stephen

doi:10.1016/j.berh.2024.101967

Cited by 2 publications

References 53 publications

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Integrating genetic data in target trial emulations improves their design and informs the value of polygenic scores for prognostic and predictive enrichment

German,

Yang,

Urbut

et al. 2024

Preprint

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Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of medical interventions but ethical, practical, and financial limitations often necessitate decisions based on observational data. The increasing volume of such data has prompted regulatory bodies to rely more on real-world evidence, primarily obtained through trial emulations. This study explores how genetic data can improve the design of both emulated and traditional trials. We successfully emulated four major cardiometabolic RCTs within FinnGen (N=425 483) and showed how reduced differences in polygenic scores (PGS) between trial arms track improved study design and consequently reduced residual confounding. Complementing these results with simulations, we show that PGS cannot be directly used to adjust for residual or unmeasured confounding. Instead, we propose an approach that uses genetic instruments for confounding detection and apply this approach to identify likely confounders in Empareg trial emulation. Finally, our results suggest that trial emulations can inform the practical application of PGS in RCTs, potentially improving statistical power. Such prognostic enrichment strategies need to be assessed in a trial-relevant population, and we show that, for 2 out of 4 emulated trials, the association between PGS and trial outcomes in the general population was different from what observed in the population included in the trial. In conclusion, our work shows that genetic information can improve the design of emulated trials. These results contribute to the establishment of a promising new era of genetically-informed clinical trials.

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Integrating genetic data in target trial emulations improves their design and informs the value of polygenic scores for prognostic and predictive enrichment

German,

Yang,

Urbut

et al. 2024

Preprint

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Potential Causal Association Between Atrial Fibrillation/Flutter and Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomisation Study

Lee,

Seo

2024

JCM

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Background: A few studies have reported controversial relationships between atrial fibrillation/flutter (AF/L) and primary open-angle glaucoma (POAG). This study aimed to investigate the potential causal relationship between AF/L and POAG. Methods: Single-nucleotide polymorphisms associated with exposure to AF/L were selected as instrumental variables with significance (p < 5.0 × 10−8) from a genome-wide association study (GWAS) by FinnGen. The GWAS summary of POAG from the UK Biobank was used as the outcome dataset. A two-sample Mendelian randomisation (MR) study was performed to assess the causal effects of AF/L on POAG. In addition, potential confounders, including hypertension, autoimmune hyperthyroidism, sleep apnoea, and alcohol use disorder, were assessed using multivariable MR analysis. Results: There was a significant causal association of AF/L with POAG (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.07–1.48, p = 0.005 using inverse-variance weighting [IVW]). Multivariable MR analysis confirmed a causal association of AF/L with POAG (OR = 1.24, 95% CI = 1.02–1.51, p = 0.034 using IVW), but hypertension, hyperthyroidism, sleep apnoea and alcohol use disorder did not show significant causal associations with POAG (all p > 0.05). Conclusions: This established causal relationship between AF/L and POAG supports the need for further investigation into the role of AF/L as a possible risk factor for POAG. Further research is required to confirm these findings.

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Use of Mendelian randomization to assess the causal status of modifiable exposures for rheumatic diseases

Cited by 2 publications

References 53 publications

Integrating genetic data in target trial emulations improves their design and informs the value of polygenic scores for prognostic and predictive enrichment

Integrating genetic data in target trial emulations improves their design and informs the value of polygenic scores for prognostic and predictive enrichment

Potential Causal Association Between Atrial Fibrillation/Flutter and Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomisation Study

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