I got habituated into WASD, despite seeing the obvious potential benefits from ESDF. On paper, i have to say i prefer the ESDF approach, BUT, as was mentioned above, certain games "hard bind" WASD, and if you try to convert it to ESDF, you'll encounter non-conforming situations where your rebinds are ignored, and in those moments, you're stuck with WASD anyway... which defeats the whole purpose of a total conversion to an alternate control scheme.
I've also attempted a "dual alternating position" scheme, when playing my sage in swtor: normal "QWE" for strafes/forward, but left hand moves to 90-=[backspace] and op[]\, for "being the healer." Sometimes a healer should be assisting focus fires, and other times, the healer should be ignoring offensive abilities and doing pro-healer-magic on the entire team at once, while they concentrate on attacking furiously. I found it pretty effective actually, but that position swap delay did tie me up sometimes. There were occasions where i'd find my hand "hovering" rapidly back and forth, across the gap between "heal mode" and "regular mode." I still felt faster than using modifiers, for what it's worth. So, for me, it came down to having two single-key-bind "areas" or "regions," being slightly faster and easier to mentally process, than using modifier keys on a single region of binds.
ESDF ideally, but WASD is often more practical, because i get tired of having to redesign the entire control scheme for every game i want to play. Due to the amount of hassle eliminated from the equation by simply adopting whatever is the default control scheme, i feel it is "better," to just roll with whatever the defaults are, and try to find a comfortable position for that. Don't worry, you'll get bored of whatever game it is, before it becomes important to have a perfect control scheme. It's simply not that difficult to learn to move your hand just enough to press the keys past #6. What's hard, is staying moving in an acceptable direction at all times, without blocking your available fingers from needed key presses, by having your fingers busy pressing movement buttons.