The following is my personal view on game planning. It is based on forum readings, checking my own logs, and checking what other successful owners were doing in the league (Codus, Bangers, Beans, OT in the past iteration and Baffled in this one just to name a few)


GAME PLAN

My suggestion is to first build a simple game plan that is reasonable, and then create a few rules to override it. Eventually, with time, sliders can be adjusted to change the base version of the game plan, but at least initially my suggestion is to keep it simple.

1/ Defense

For all downs/distances/areas of the field, we set the linebackers to the same value. It is worth nothing that Blitz 2 destroys inside runs, but also is more vulnerable to pass. We will override the base setting with rules, if needed be.
For all downs/distances/areas of the field, we set the keying to neutral.

Secondary instead requires some more thought. 2-Deep Man works best against pass, Man and 1-Deep Man are reasonable choices for intermediate situations. Safety blitz is the most powerful tool against inside runs, but is far more risky against pass than any other. Corner blitz I'm not sure whether it is usable or not. Possibly against outside runs, but I don't have data to back it up.
I've also steered clear of zone defense for secondary, so by default I never pick any plays that use 2, 3 or 4-Deep Zone, nor 3 or 4-Deep Man plays.

So a reasonable choice for the sliders here is: 1-Deep Man and man whenever uncertain. A mixture of 1 and 2-Deep Man for second and third long situations.

2/ Offense

For all downs/distances/areas of the field, set the personnel sliders to be the same value for all the sets. There is no significant reason why on a certain area you should prefer a set; you might find that for some distance a set might be more appropriate, but I suggest to keep things simple initially. You can slowly customise later.

Now, for the actual game plan, this comes down to your preference. The only rule here is: do not be predictable. Under any circumstances, if your total passes (short+medium) is unbalanced with respect to runs (inside+outside), then you are giving the opponent the possibility to optimise their defence. Don't do that. Anything above 70% might be considered risky.

If you click "view plays" under a certain down/distance/area you will see the plays that will be called. First, the percentages of your run/pass are taken into account, then plays are picked within the selected pass type. The specific play is picked depending on the weight (the red bar).
For offese plays, the weight is computed taking into account the formation set (but if they are all equal, they don't matter), hence all the weights should be a full red bar.
For defense plays, the set is chosen to match the number of WRs the opponent is using. Then, the weight is assigned taking into account the linebackers sliders and the secondary sliders. If you follow this guide, then only the secondary will affect the weight.

From previous iterations, I've actually changed to prefer medium over short passes, which I now use more sparingly. I did not mention long passes on purpouse. Don't use them, they are a plead to be sacked.

PLAYS

1/ Defense

My rule of thumb here is to select defensive plays which man-mark all 5 eligible receivers. To see that, if you click on a play, then "assignments", you will see what your defensive players are doing. You need to find Man WR-1 up to Man-WR-5, with no exception. The only plays that I'm fine with not having man-mark is the goal line attack plays. This also explains why I don't usee 3 or 4-Deep man plays. They don't man-mark WRs.

Over time, you can monitor the results of your plays, and eventually prune plays that average 5 or more yards conceded.

2/ Offense

Here the situation is more diverse. What you really need, for each personnel set (i.e. 113, 122, etc), a balance between pass and runs. If not, you will give the opportunity to your opponent to optimise their defense.
If you follow this guideline, you don't have any bias to personnel depending on downs/distances/areas. This is simplify balancing personnel sets. My suggestion is to roughly have the same number of run and pass plays for each personnel set.

Also, you should monitor what winning teams are using. I've learned a lot from other successful owners in the league. Then, over time, you can monitor the results and prune or test new plays. One good suggestion is, for pass plays, to try plays which contain flare runs, especially those which go behind a WR that goes deep. The RB will find himself near the sideline with room to run, since the WR will lure the CB away. Many successful pass plays are characterized by this. In any case, do monitor the success of your plays over time.

I personally dislike 230, because it can be easily locked. I also found very little use in 005, 014 or 104 sets, as a good owner will be ready for a pass there.
Runs from 113 and 203 can be very powerful, since the default Nickel defense is quite terrible against the run. 212 is a nice all rounder set. 311 and 221 have some merit. 122 could be useful, although I didn't find strong plays, but your mileage might vary.

In any case remember the golden rule: be balanced within each set. To see that, select the last 4 or 5 games, and do the sum of your pass and your run plays. If there is a strong discrepancy, then your personnel set under scrutiny is not balanced.


RULES

1/ Defense

Must have rules:
1/ if the set is 005, 100% pass key, quarter defense, for all downs/distances/areas
2/ if the set is 014, 100% pass key, dime defense, for all downs/distances/areas
3/ if the set is 104, 100% pass key, dime defense, for all downs/distances/areas

Theh, I typically have 2 rules for each opponent's personnel set. One is tailored to pass, and one to run defense. By default, these rules are not enabled.
Example 1: 311 pass defense. For all downs/distances/areas, I choose normal defense set, 1 o 2-Deep man. Why's that? because the goal line defense (default against 311) is weak against 311 passes. If I see that the opponent is heavily relying on 311 passes, I activate this rule. Keying will be 100 pass key.

Example 2: 212 run defense. In this case I choose normal defense, but i select only blitz 1 and blitz 2. This will override our sliders, and optimize the defense against run. I might change on which down/distance/area where this rule is active.

Example 3: 212 pass defense. In this case, I might go for a Dime defense, 1 or 2-Deep man, which provides the best cover against pass.

Example 4: 203 run defense. In this case, I use normal defense, because that's so more powerful against runs than the default Nickel. Sometimes I go pass keying rather than run, to offset the use of a normal defense in case the opponent actually pass. It depends on the likelihood of the opponent running for sure or not.

The rest of the rules are just a repetition.
I also have a few rules for end-game, i.e. to protect against passes if I'm winning, or be more productive against clock management if I'm losing.

2/ Offense

With respect to past iterations where I had a gazillion rules, nowadays I'm keeping it simple. Just rules for 4th down situations, and hurrying up at the end of the half. You can be creative if you want to have ad-hoc plays under certain conditions.

THE ROUTINE

So what is the routine I have for each game?

1/ Check the defense tab, and look for any down/distance/area where the opponent is not balanced. If so, change the default keying from neutral to pass or run key. Note: run keying is very risky, and should be used with care.
2/ Scout the opponent offense. For each personnel set, look if in the past 4 or 5 games the plays were not balanced. If the opponent is passing only from 113, activate the rule that optimise your defense for 113 pass. Repeat this for all the personnel sets. This explains why, for your offensive game plan, you need to be balanced.
3/ Scout the defense. I avoid scouting zone and zone-in plays for possible familiarity bug.