Under the InSIDE assumption, the intercept term θ^0UE can be interpreted as an estimate of the average direct effect of the genetic variants.8 If the average direct effect is zero (referred to as “balanced pleiotropy”), and the InSIDE assumption is satisfied, the intercept term should tend to zero as the sample size increases, and the MR‐Egger estimate ( θ^UE) and the IVW estimate ( θ^UI) are both consistent estimates of the causal effect. If the intercept term differs from zero, then either the InSIDE assumption is violated or the average direct effect differs from zero (referred to as “directional pleiotropy”); this is a test of the validity of the instrumental variable assumptions (the MR‐Egger intercept test).
