This became a major issue in the development of the R-2800 - well documented in "No Short Days: The Struggle to Develop the R-2800
"Double Wasp" Crankshaft" by Kimble D. McCutcheon.
The second-order effect of ignition timing (due to the geometry of master rod and articulating rods, some cylinders fire a bit early, some a bit late...) causes large torsional vibratory loads within the crankshaft. Several engines came apart during development!