Some embodiments of the invention include a system comprising a positioning device configured to a hold a sample and adjust a position of a sample in response to receiving a drift compensation signal; a first light source disposed to transilluminate the sample; a second light source disposed to epi-illuminate the sample; an optical system configured to receive light from the sample and generate a three-dimensional point spread function from the light from the sample; an image sensor disposed relative to the optical system that produces an image from the light collected from the sample via the optical system; and logic electrically coupled with the image detector and the positioning device, the logic configured to determine one or more drift compensation values from images imaged by the image detector, and configured to send one or more drift compensation signals to the positioning device.