We nearly always stay midstrip. We have stayed downtown (once), North (Sahara--our 1st 2 trips when we were young, broke & clueless), South (Mandalay Bay--still my FAV resort, but location turns me away). We have stayed at Excalibur, MGM, Monte Carlo, Paris, Ballys, Caesars, Flamingo, Mirage & TI. plus Golden Nugget DT. We will be at Wynn this time, ONLY because we got a deal on a room w/ rights to a March Madness viewing party (DH insisted).
The location we have stayed the most is Ballys--dead center on the strip (and typically comped or very cheap). This way I can wander north one day, south another. Personally I find Wynn-PH a far more interesting end of the strip--old school properties and high end. I like MGM, but not much else on that end.
The one time we took the monorail, we realized we could have walked MGM to Ballys as quickly, by the time we walked clear back to the monorail & waited for it to arrive. And it was free then--and we determined not worth it for us. Now it is rather pricey, IMO. Plus it is in bankruptcy...much talk of how long it will be open.
Is midstrip NECESSARY for a first trip? No, but it will make your sightseeing easier, and is advised by many who have traveled there often.
Again, looking at your choices:
Encore is by far the most luxurious
Caesars is almost as nice as long as it is Forum, Palace or Augustus Tower. (they beat Encore for best location of the 4)
Signature is a lovely property & it is nice to have a kitchenette. But it is on the south end of midstrip, and far east edge of MGM property...quite a trek to the strip)
NYNY isn't in the same category as your other choices. A very average property.
An interesting combination of properties you have narrowed to--what was your criteria?