In preparation for updating my iMac (mid 2010) to Sierra I aim to give the Hard Drive a clean-up. It has become cluttered and slow with out-of-date apps and files no longer needed.
Comments/links welcome on best methods and on using apps such as OnyX, AppZapper etc. I have backed up on an external HD and Time Machine.
I consider this a manual process i.e. only you can decide what data files are no longer needed - an app can't.
Most apps that you don't want any more are sufficiently dealt with by dragging to the trash (unless the app has it's own uninstaller which is the best way). That may leave the odd app related file somewhere on your hard disc but these shouldn't cause problem.
I remember reading online a review of app deleting software (can't find it with a quick look) but whilst they all performed fairly well, they all missed the odd file or two that was well hidden, hence my suggestion of just dragging to the trash.
After cloning my computer, I restored my iMac (mid 2010) to factory settings and restarted from scratch, installing the Apps. from the App store as required.
A good discipline before an OS update is to run Disk Utility and Verify the disk. If it shows errors, then run Repair. On Sierra, the two are merged and First Aid does Verify/Repair in one.
Don't get too distracted by Permissions, they're not a big problem any more.
I'm thinking about presenting something on Disk Utility at Bournemouth in March, it's an important little utility (but I don't suggest you wait).