Abstract: Methods and systems described herein include using various characteristics of cell-free DNA molecules to determine a property of a biological sample or a subject. Such characteristics can include size (e.g., where characteristic is of long cell-free DNA molecules), methylation, and end motifs. The method includes determining disease classification and/or predicting tissue of origin. In some instances, the characteristics includes determining an amount of long cell-free DNA molecules, and the disease classification can be based on the determined amount. The characteristics can also include identifying methylation pattern of a cell-free DNA molecule, then comparing the methylation pattern to a reference pattern to predict the tissue origin. In some instances, the methylation-pattern analysis includes using a trained machine-learning model.