Putting the design in the middle under the head with very flat material and using the Set Focus will allow you to get pretty good camera alignment, but the official specs are 1/4" and less off from the preview.
So jigs work great, but you have hit on one of the continuing challenges of using the Glowforge, re-aligning an image after the print has taken place to add more or correct something. You can also use a very light score on the masking and immediately stop the print. Then shift the design over with the arrow keys. Not exact. You can add artwork that is a cross to align to that is outside of the area you want to redo. As long as you select the whole design including the cross and the main image, you will be able to sift. Just score that cross hair until it aligns.
Depends on what you are using to generate the file. Some folks prefer PDFs because their design software generates good files and there are some options like not having to convert text to paths for saving PDFs.
I have found that I have to work to ensure that all the different variables are correct if I am saving as a PDF to ensure correct size.
I mainly use Inkscape so I just save as SVGs.