A handheld diagnostic system may include a disposable sample holder and an analysis module having a chip-scale microscope. The sample holder may have a transparent portion that may be inserted into the analysis module. The transparent portion may have test chambers for containing respective portions of a biological sample. The transparent portion may also include built-in reference features such as reference surfaces, reference markings, and/or reference structures. The chip-scale microscope may include an image sensor for capturing images of the sample and the reference features as the sample holder is inserted into the analysis module. Images of the reference features may be compared with images of the sample and may be used to determine the color, opacity, reflectivity, cell size, and/or cell concentration associated with the sample. The analysis module may transmit sample imaging data to a portable electronic device.