Without knowing your definition of midtown or weekday vs. weekend evening you have three options:
Cheapest - Arriving LGA 10p-midnight and desire cheap. Board Q70 bus to E,F or 7 subway at Roosevelt Ave and take it to your stop in Manhattan.
Next Cheapest - Arriving LGA 10p-midnight and going to Penn Station area. Board Q70 bus to Woodside LIRR station and can take the LIRR to midtown. Others, will argue this really doesn't save much time for the extra cost you incur but one stop from Woodside to NY Penn Station. The E line also goes to 34th St/Penn so the timing between the two matters. The details (Q70 after dropping off at Roosevelt makes sort of a U-Turn to get about 1 mile east to Woodside station, and when you get there you will wait for next LIRR to Manhattan (can be 1 minute, can be 15 minutes before its arrival), so would the subway arrive sooner vs. timing of LIRR? If your goal is just midtown 42nd Street - take the subway.
Expensive/Not so fast - Take rideshare from LGA (but I'm not sure if still require a shuttle to the ride-share area) or traffic encountered at that time.