Systems and methods for optimizing detection of optical signals indicating the presence of an analyte of interest in a blood sample are described. In one aspect, a blood culture test vial having a sensor is inoculated with the blood sample, light at an excitation frequency of the sensor is transmitted to the test vial, an intensity of a plurality of fluorescence signals emitted from the test vial is measured, and the plurality of measured fluorescence signals are normalized using by a reference signal that is not dependent on a measured intensity of a fluorescence signal emitted from the test vial. In another aspect, a measurement system measures fluorescence signals from one or more reference vials performing in extreme pH conditions. Fluorescence signals emitted from test vials inoculated with samples under test are measured and compared to the signals measured from the one or more reference vials to address or mitigate variability in hardware components of the measurement system.