As far as the natural/neutral positioning of your hands is concerned... The Wii Pro Stick is by far the most comfortable controller to hold, it also has the least amount of "thumb-travel" to switch from the Control Sticks to the D-Pad or Buttons.
Even with fairly large (long) hands, the bulkier/larger bodied controllers aren't any more comfortable.
At least the XBox Elite solves one problem that nearly all game-pads have -- half of your fingers are underneath the controller body, and are not needed to hold/support the controller --- a well designed controller will comfortably est on the bottom and sides of your palms, which leaves your fingers nothing to do at all.
What the XBox Elite doesn't solve is a console control-scheme problem --- the complete inability to use a button/key press as a modifier key... along with console games that assign disparate actions to the same button in a different context, instead of considering the flexibility of a modifier key.