Unsupervised learning-based reference selection for enhanced defect inspection sensitivity

An optical characterization system and a method of using the same are disclosed. The system comprises a controller configured to be communicatively coupled with one or more detectors configured to receive illumination from a sample and generate image data. One or more processors may be configured to receive images of dies on the sample, calculate dissimilarity values for all combinations of the images, perform a cluster analysis to partition the combinations of the images into two or more clusters, generate a reference image for a cluster of the two or more clusters using two or more of the combinations of the images in the cluster; and detect one or more defects on the sample by comparing a test image in the cluster to the reference image for the cluster.