Since activating the Ray Sphere in End of the Road instantly sets your karma to Infamous, would true 100% really require two full playthroughs? Just max out every Hero upgrade and side mission first, then activate the Sphere in that mission, and do it again on the other side. Would still be a long-ass run, and I'll never do it, but it seems like it wouldn't necessarily have to be two full playthroughs.

Every time you complete a good side mission in the game, an evil side mission gets eradicated, so I don't think it's possible to get all the bad missions completed.

However, given how weird the in-game percentage is tracked (I did some research, and there's still debate on what gets you 100%), I'm wondering if we should just not use the percentage counter to define the run and just make it all collectibles/stunts/upgrades/side missions. You do all collectibles and stunts on one playthrough, then get upgrades on both playthroughs and call it a run.

Let me know what you think.

Right, I forgot about that. Like I said, I have no real standing here as this isn't a run I'm at all interested in doing, but an "all stuff" run makes as much sense to me to getting the in-game counter to 100% (particularly as you can't check that counter without going to the save files screen -- a bit out of the way).

I would say that 100% would be getting all upgrades, stunts, and collectibles and side missions. Like, a non-cancer way of going about it could be 

Run 1: Good karma upgrades, good side missions, all dead drops and shards.
Run 2: Evil karma upgrades, evil side missions.

End timer after final piece (last evil side mission, for example) is done.

You experience / collect everything for the sake of the speedrun, even if the counter doesn't get to 100%. I mean its still an awful amount of stuff, but I think its a bit more reasonable.

That's exactly what I was thinking, DPad. That way there'd be no more ambiguity and slightly (slightly) more chance that someone will actually want to do the run.

Well it would also have to include the non-karma related side missions (Satellite Uplinks, Photographer, Hidden Package, etc.) wouldn't it?

Here's what I'm thinking. True 100% requires two playthroughs of the game. During one of the playthroughs, you should complete the following:

All side missions, both for the chosen karma and the neutral side missions
All Blast Shards
All Dead Drops
All Stunts
All Upgrades (this one may be debatable but I don't know)

During the second playthrough of the game you should complete the following:

All karma-related side missions (because I see no point in doing neutral side missions twice)
All Upgrades (again, up for debate, but if you get them on one playthrough they're different on the other)

In this sense, you've completed everything the game has to offer without pointless repetition.

Would the two full-mission skips we have be disallowed? I would imagine so. Where would that leave smaller skips like in Blood Trail, Zeke's Request, and Alden Strikes?

I'm thinking that during one playthrough, you have to complete the two missions you normally skip, but that's not necessarily required in the other playthrough. The main idea is that you complete everything at least once, so if you do the two missions you normally skip once that should be enough.

Small skips are perfectly okay as long as you're still completing the mission.