The recommendation of orientating the genetic variants in multivariable MR‐Egger to the risk factor‐increasing or risk factor‐decreasing allele for the risk factor of interest may be considered arbitrary. While we accept this limitation, we would argue that it brings consistency to the results. This recommendation may result in the analysis being performed up to K times to obtain the causal estimates for all K risk factors. The orientation of the genetic variants will also affect the interpretation of the direct effect, thereby altering the InSIDE assumption. This may result in the MR‐Egger intercept estimate varying between different orientations. This was seen in the applied example where the intercept term was non‐significant when the alleles were orientated with respect to LDL‐C, and significant when orientated with respect to HDL‐C and trigclyercides.
