A comprehensive strategy is used to determine valid reference time-concentration curves (TCCs) from image data. The image data corresponds to a series of image scans acquired over time for an area of interest of a patient to which a contrast agent was previously administered. The image scans are initially registered to a common coordinate system. Then, observed potential reference TCCs in the image scans are compared to modeled reference TCCs to determine if the potential reference TCCs are plausible reference TCCs. Thereafter, any plausible reference TCCs are evaluated to determine if they contain residual, isolated motion artifacts. If a plausible reference TCC does not include any motion artifacts, the plausible reference TCC is considered a valid reference TCC. If a plausible reference TCC is determined to include motion artifacts, the plausible reference TCC is modified to a valid reference TCC by removing the motion artifacts, or otherwise the plausible reference TCC is rejected. The valid reference TCCs can be used to improve the effectiveness of dynamic, contrast-enhanced imaging studies.