MR Dictionary

Two-step or Mediation MR

An MR framework that aims to quantify whether an exposure-outcome association (that is either established or has supportive evidence from MR analyses) is mediated by another factor.

In many published examples, initial MR will assess evidence for a causal effect of the exposure on an outcome and then go on to undertake two-step MR. First, genetic instrumental variables (IVs) associated with the exposure are used to determine the causal effect of the exposure on the potential mediator (step one). Secondly, genetic IVs associated with the potential mediator and independent of those used for step one are used to determine the effect of the potential mediator on the outcome of interest (step two). Alternatively, multivariable MR can be used for the second step to estimate the direct effect of both the exposure and mediator on the outcome. Methods such as the product-of-coefficients can then be used to explore the extent of this mediation. The MR assumptions must be met for the two steps of the MR analyses of the (i) exposure on mediator and (ii) mediator on outcome. This methodology can be extended to networks of relationships (i.e., network MR).

Two-step Mendelian randomization for exploring mediation. (A) In the first step of two-step MR, a genetic variant (Z1) is used as an instrument for the exposure of interest (X) to estimate the causal impact of the exposure on a hypothesized mediator (M) of the association between the exposure (X) and outcome (Y). (B) In the second step, an independent (of Z1) genetic variant (Z2) is used as an instrument for the mediator (M) to establish the causal impact of the mediator (M) on the outcome (Y). If there is evidence for a causal effect of X on M and M on Y (as well as X on Y), the estimates from these two steps can be combined to provide evidence for or against the mediating role of a variable on the exposure-outcome effect using e.g., multivariable MR.
Figure 2.7 - Two-step Mendelian randomization for exploring mediation. (A) In the first step of two-step MR, a genetic variant (Z1) is used as an instrument for the exposure of interest (X) to estimate the causal impact of the exposure on a hypothesized mediator (M) of the association between the exposure (X) and outcome (Y). (B) In the second step, an independent (of Z1) genetic variant (Z2) is used as an instrument for the mediator (M) to establish the causal impact of the mediator (M) on the outcome (Y). If there is evidence for a causal effect of X on M and M on Y (as well as X on Y), the estimates from these two steps can be combined to provide evidence for or against the mediating role of a variable on the exposure-outcome effect using e.g., multivariable MR.

References

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