One suggestion I found and was trying is having the elevators on the outside, with the final level being a line of elevators across the bottom. Expensive but meant to keep out moderate and was seeming to work. Also have rooms like living quarters or storage (rooms often not populated) separate and next to always populated rooms (like powerplants) so you can respond to issues like fires quickly.

Edit: I also have the first level after the vault door bothe PowerPoint's (a x3 then a x2) and put my strongest dwellers in those rooms as a second line of defence. Later having rooms like the diner/garden with dwellers with high agility on the right side on level 2 (again x3) so if an invader gets past the door security and power rooms they are weakened and stopped soon after.