Using the global randomization test as a Mendelian randomization falsification test for the exclusion restriction assumption

Mendelian randomization may give biased causal estimates if the instrument affects the outcome not solely via the exposure of interest (violating the exclusion restriction assumption). We demonstrate use of a global randomization test as a falsification test for the exclusion restriction assumption....

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Bibliographic Details
Published in:European journal of epidemiology 2024-08, Vol.39 (8), p.843-855
Main Authors: Millard, Louise A. C., Davey Smith, George, Tilling, Kate
Format: Article
Language:English
Subjects:
Bias
Cardiology
Cardiovascular disease
Cardiovascular diseases
Coronary artery disease
Epidemiology
Genetic diversity
Genetic variance
Heart diseases
Infectious Diseases
Medicine
Medicine & Public Health
Methods
Oncology
Permutations
Pleiotropy
Public Health
Randomization
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Summary:Mendelian randomization may give biased causal estimates if the instrument affects the outcome not solely via the exposure of interest (violating the exclusion restriction assumption). We demonstrate use of a global randomization test as a falsification test for the exclusion restriction assumption. Using simulations, we explored the statistical power of the randomization test to detect an association between a genetic instrument and a covariate set due to (a) selection bias or (b) horizontal pleiotropy, compared to three approaches examining associations with individual covariates: (i) Bonferroni correction for the number of covariates, (ii) correction for the effective number of independent covariates, and (iii) an r 2 permutation-based approach. We conducted proof-of-principle analyses in UK Biobank, using CRP as the exposure and coronary heart disease (CHD) as the outcome. In simulations, power of the randomization test was higher than the other approaches for detecting selection bias when the correlation between the covariates was low (r 2  
ISSN:0393-2990
1573-7284
1573-7284
DOI:10.1007/s10654-024-01097-6