I've stolen some ideas from other testers and came up with some of my own.
A lot of customization probably should be made after you've used it for awhile. Adjust to the "standard" layout you use (I use dvorak) and, over time, decide what things you feel you need to change to make easier.
One of the changes I stole was the number pad layout. Someone made it so that you still have all 10 digits in their normal spots across the top - convenient for those of us who are not really good with a number pad so we can, if just typing in an isolated number, actually see it. This also meant moving the zero on the number pad from the lower left to the upper right. Turns out that works for me better anyway. You end up with two 6's, but that's no big deal.
For my own changes, I moved around a lot of math stuff. For example, +-*/ are all on the left hand home row, green layer right below the number pad. Makes sense for me at least, which is all that matters.
I've been used to using command-V for paste for so long, I never have gotten into using the special paste combo WT added to that standard, but sometimes I find myself in need of pasting something I copied using the mouse rather than the keyboard. This involves, usually, two hands. Press DF (to go into edit mode) with the left hand and then V on the right hand (this would be the period on qwerty) or press the qwerty N key (TB's special approach). Either way, it takes two hands. Or, since I have hot corners set up, I can hold down the left side of the space blade and stretch over to get my V key. But the stretch is an issue. If I used qwerty, it would be no problem one-handed.
But since I do use dvorak, I've been thinking of another solution. The qwerty N key, if you hold the space bar down, gives [. Well, first, I almost never use that character. Second, if I do, I can get it by holding down space/shift/N and get the same thing. So, I think I may change the space/N to be paste. Easily done with one hand. Since the same would apply to qwerty M (giving me ]), I may change that to something more useful as well (most likely an undo).