Unlike traditional tissue tests[1, 2], cell-based liquid biopsy assays enable selection of individual CTCs for the analysis of chromosomal instability using next-generation sequencing by quantification of large-scale state transitions (LST) [3-9]. Chromosomal instability is a genomic characteristic of cancer cells that drives tumor evolution and metastatic potential [10-19]. However, whole genome sequencing assays are laborious, requiring a complex workflow that invariably results in a considerable turnaround time that sometimes is not compatible with clinical practice [20]. A previous study has shown that we can partially predict chromosomal instability in individual cells by developing algorithms that analyze a range of features, including cell shape, size, morphology, and protein levels, from images of CTCs using an automated digital pathology pipeline [3]. Predicting chromosomal instability through morphology offers significant advantages; it can significantly reduce turnaround times compared to whole-genome assays, providing crucial information about the genomic characteristics of CTCs in a patient in a shorter timeframe [3]. Timely information on the presence of CTCs with the highest metastatic potential may be critical for making optimal clinical decisions. A key challenge in predicting chromosomal instability through morphology is the utilization of a machine-learning method that accurately classifies morphology patterns from all CTC features and provides a generalization and reproducibility, compatible with potential validation for clinical use [21-24]. Key limitations of commonly used machine learning techniques in biology applications, such as support vector machines (SVMs) with Gaussian kernels, include the following [21-24]: 1) The increase in dimensionality that arises from combinations of multiple features exponentially complicates the prediction task, as often seen with cell morphologies.