A computer-implemented method of analyzing a biological sample, including a mixture of cell-free DNA molecules from a plurality of tissues types that includes a first tissue type, to determine a classification of a proportional contribution of the first tissue type in the mixture, the method comprising: identifying a first set of genomic positions at which ends of short cell-free DNA molecules occur at a first rate above a first threshold for samples containing the first tissue type, wherein the short cell-free DNA molecules have a first size; analyzing a first plurality of cell-free DNA molecules from the biological sample of a subject, wherein analyzing a cell-free DNA molecule includes: determining a genomic position in a reference genome corresponding to at least one end of the cell-free DNA molecule; based on the analyzing of the first plurality of cell-free DNA molecules, determining that a first number of the first plurality of cell-free DNA molecules end within one of a plurality of windows, each window including at least one of the first set of genomic positions; computing a relative abundance of the first plurality of cell-free DNA molecules ending within one of the plurality of windows by normalizing the first number of the first plurality of cell-free DNA molecules using a second number of cell-free DNA molecules, wherein the second number of cell-free DNA molecules includes cell-free DNA molecules ending at a second set of genomic positions outside of the plurality of windows including the first set of genomic positions; and determining the classification of the proportional contribution of the first tissue type by comparing the relative abundance to one or more calibration values determined from one or more calibration samples whose proportional contributions of the first tissue type are known. identifying a first set of genomic positions at which ends of short cell-free DNA molecules occur at a first rate above a first threshold for samples containing the first tissue type, wherein the short cell-free DNA molecules have a first size; analyzing a first plurality of cell-free DNA molecules from the biological sample of a subject, wherein analyzing a cell-free DNA molecule includes: determining a genomic position in a reference genome corresponding to at least one end of the cell-free DNA molecule; based on the analyzing of the first plurality of cell-free DNA molecules, determining that a first number of the first plurality of cell-free DNA molecules end within one of a plurality of windows, each window including at least one of the first set of genomic positions; computing a relative abundance of the first plurality of cell-free DNA molecules ending within one of the plurality of windows by normalizing the first number of the first plurality of cell-free DNA molecules using a second number of cell-free DNA molecules, wherein the second number of cell-free DNA molecules includes cell-free DNA molecules ending at a second set of genomic positions outside of the plurality of windows including the first set of genomic positions; and determining the classification of the proportional contribution of the first tissue type by comparing the relative abundance to one or more calibration values determined from one or more calibration samples whose proportional contributions of the first tissue type are known. <EOS>