Ever since custom difficulties were introduced, I have always wished for more in-depth customization. What I mean by that is that the player would be able to tweak the individual points in each difficulty slider. For example, number of plague hearts being its own slider instead of being threaded into the map difficulty slider or if you want to headshot-able by hostile humans. It would also be nice to change how fast hostile enclaves and infestations spawn and being able to pick if you want plague hearts hidden or revealed.
EDIT: It would also be nice to pick which plague freaks you want and which you don't.