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1 Mendelian randomization
Mendelian randomisation is a research method that provides evidence about putative causal relations between modifiable risk factors and disease, using genetic variants as natural experiments
Mendelian randomisation is less likely to be affected by confounding or reverse causation than conventional observational studies
Three key assumptions that must hold for a Mendelian randomisation study to be valid
| Tools to assess plausibility | |||
|---|---|---|---|
| Assumption | Description | Single sample | Two sample |
| Relevance assumption | The genetic variants associate with the risk factor of interest | The partial F statistic and partial r squared, or risk difference | Variants are associated with the risk factor in a large ge- nome-wide study |
| Independence assumption | There are no unmeasured confounders of the associations between genetic variants and outcome | Covariate balance tests and bias component plots. Adjusting for principal components of population stratification | Evidence from large genome-wide association studies on the association of the genetic variants used as instruments with other baseline covariates |
| Exclusion restriction | The genetic variants affect the outcome only through their effect on the risk factor of interest | Biological knowledge, tests of association of the genetic variants and potential alternative mediating pathways | Evidence from large genome-wide association studies that the genetic variants associate with alternative pathways. MR Egger test for pleiotropy, Cook’s distance evaluation of outliers |
Figure 1.1: A simplified causal diagram depicting confounding of the association of alcohol consumption and blood pressure by existing disease or social deprivation. The instrumental variable assumptions are that the genetic variants are associated with the risk factor, that they have no other influence on the outcome, except through alcohol,and that there are no confounders of the genetic variants-outcome association, [Kısacası bu kabul edilebilir varsayımı bozmaz
Figure 1.2: Confounding by ancestry could occur if variants associated with alcohol consumption had different frequencies in different ethnic groups in the population sampled and if cultural differences affected blood pressure between ethnic groups. This would violate the second instrumental variable assumption-the independence assumption.
Figure 1.3: An example of horizontal pleiotropy, in which the genetic variants associated with alcohol consumption also affect tobacco consumption (violating the third assumption—the exclusion restriction assumption)
Figure 1.4: An example of vertical pleiotropy, in which the effect of ALDH2 on coronary heart disease is mediated by blood pressure. This example does not violate the Mendelian randomisation assumptions and does not cause bias
Mendelian randomisation estimates require that genetic variants do not have such horizontally pleiotropic effects. This means the results could be biased if a genetic variant or an allele score has pleiotropic effects on the outcome that are not mediated through the risk factor of interest.Genetic variants can also affect the outcome through a pathway affected by the risk factor of interest (vertical pleiotropic effects. This does not invalidate the instrumental variable assumptions and does not result in bias.
Figure 1.5: Parameters in a simple model with interaction
Various methods have been developed that allow for genetic pleiotropy.These provide useful sensitivity analyses to explore whether a finding depends on the assumption that all the variants have no pleiotropic effects.
One such approach, known as the median estimator, can provide reliable evidence as long as at least half the genetic variants have no pleiotropic effects
A second method, known as MR Egger regression, allows all variants to have pleiotropic effects, provided they are not proportional to the variants’ effects on the risk factor of interest
MR Egger regression yields less precise estimates than other methods, owing to a power penalty. Most of these methods assume that the risk factor has the same effect on everyone.