I'm building this addition as a slab on grade, so I won't have to worry about crawl space issues. It is also a two-story, with the 2nd story under roof, so there is basically no attic. The ductwork will have to run inside a closet/chase area that is central in the addition. The branch lines will have to run in the space between the floor joists.
It is the above considerations as to why I am worrying over this ductwork issue now (we are going to pour footings for the addition in a couple of days from now. I've gotten the unit sized from a couple of different sources, and it comes out the same no matter which way it goes.
Thanks for the advice, guys.