Provided herein are methods that are useful in determining the cellular origin of cell-free nucleic acid (cfNA) fragments from cfNA samples, such as liquid biopsy samples. The methods disclosed herein typically improve the specificity and/or sensitivity of assays for detecting diseased cell nucleic acids (e.g., cancer cell DNA) in cfNA samples by identifying variant alleles produced by non-target cells, such as hematopoietic stem cells, in certain embodiments. Yet other aspects include related systems and computer readable media, among numerous other applications.