Why Collect Full Runs?
Again, my observation from the show was that the JLA and Batman books went quickly, as did the silver age Doctor Strange books that I bought. I say that to say, if you are collecting a full run for anything more than your personal collection (for investment purposes) you will want to focus on A-List characters. Spider-Man and Batman are good examples. If you are solely collecting a run because you love the character, look for deals and have fun!
If you are looking to collect and invest, you will want to stick with popular characters (over decades, not just the latest trend) because inevitably a portion of those books will house first appearances of villains or B list heroes that could increase in value in the future.
A great example is Amazing Spider-Man #129, the first appearance of the Punisher. If you were collecting a Spider-Man run back in the 1970s, you could have picked up this book on the cheap. Last month, a 9.8 sold on Heritage for $40,800. Take a deeper dive into the book's sales history by clicking the title.
Obviously, the Punisher has taken on a life of his own and exploded in value, but those A-list characters in general are jumping off points for new heroes and villains that could pan out for you in the future.
Why Collect Keys?
If you focus on tried and true key books that have maintained and increased in value over the past few decades, you know exactly what you are getting. The chances of coming across those key books in a cheap bin are shrinking by the day. People can determine a comic's value within minutes nowadays, so valuable books tend to get snapped up. Still, it means you will be able to easily find the key you are looking for.
The speculation comes into play when you are paying for a key book that already holds value, but may still have room to grow in the future. Be sure to reference GoCollect's Price Guide to keep up with the latest FMVs. You will want to avoid the hot book of the week if you want to grow the value over time. When it comes to collecting keys, I would look for those out-of-vogue for the time being but should come back around in the future. Again focusing on A-list characters that have stood the test of time.
Both strategies have their own merits, just do your research, and at the end of the day, do what you love!