The validity of multivariable MR‐Egger and its ability to estimate consistent causal effects is dependent upon the InSIDE assumption being satisfied. While it is not possible to determine whether the InSIDE assumption has been violated, we believe it is more likely to hold for multivariable MR‐Egger then univariable MR‐Egger. When the βX 1 parameters are associated with at least one of the sets of βXk parameters for k=2,3,…,K, the InSIDE assumption for univariable MR‐Egger is automatically violated and causal estimates from the method will be inconsistent. The direct effects of the genetic variants on the outcome will consist of fewer components for multivariable MR‐Egger compared to its univariable counterpart, making it more plausible that the InSIDE assumption will hold for multivariable MR‐Egger.
