Abstract: The present invention relates generally to classification of biological samples, and more specifically to cell of original classification. In particular, some embodiments of the invention relate to diffuse large B cell lymphoma cell of origin classification using machine learning models. The machine learning models can be based on decision trees such as a random forest algorithm or a gradient boosted decision tree. Features for the models can be determined through analysis of variant data from plasma or blood samples from a plurality of subjects with the disease.