For an example of just how much of a rabbit hole this is, Lucas Pope's forum post[0] about the dithering in Obra Dinn shows how much time can be spent on getting it right.
To be fair, most of the complication there is because it's dynamically generated in 3D, where moving the camera makes the dithering unstable. In 2D hand-drawn art, it's a skill, but it's not quite the same challenge as described in that post.