Methods and devices are provided for optically interrogating subsurface tissues of a body. Optical interrogation includes illumination of a target tissue through an external body surface and detection of light emitted in response to the illumination. Parameters of such optical interrogation are controlled according to operational modes that are selected to maximize detector sensitivity to a target property of the target subsurface tissues. Operational modes are selected based on detected properties of the target tissue and of intervening tissues (e.g., thickness of intervening tissues between the target tissue and an external body surface) between the target tissue and an interrogating optical device. Operational modes can be determined based on simulated optical interrogation of subsurface tissue across a range of optical detector configurations and tissue conditions. Operational modes can include calibration curves specifying optical interrogation parameters based on intervening tissue properties.
