Infusion systems, infusion devices, and related operating methods are provided. An exemplary method of operating an infusion device capable of delivering fluid to a user involves obtaining one or more uncalibrated measurements indicative of the physiological condition, obtaining one or more reference measurements of the physiological condition, determining a raw calibration factor based on a relationship between the one or more uncalibrated measurements and the one or more reference measurements corresponding to the respective uncalibrated measurements of the one or more uncalibrated measurements, and determining an adjusted calibration factor based at least in part on an expected calibration factor and the raw calibration factor, wherein operation of the infusion device to deliver the fluid is influenced by the adjusted calibration factor.