A method of analyzing a biological sample of an organism, the biological sample including a mixture of at least 1,000 cell-free DNA molecules from a plurality of tissue types, including a first tissue type, the method comprising: analyzing, by a computer system, a plurality of cell-free DNA molecules from the biological sample, the plurality of cell-free DNA molecules being at least 1,000 cell-free DNA molecules, wherein analyzing a cell-free DNA molecule includes: identifying a location of the cell-free DNA molecule in a reference genome corresponding to the organism; identifying a first set of the plurality of cell-free DNA molecules that are each located at any one of N genomic sites of a first chromosomal region of the reference genome corresponding to the organism, N being an integer greater than or equal to 10; measuring N first methylation levels at the N genomic sites using the first set of the plurality of cell-free DNA molecules; determining, by the computer system, a first fractional contribution of the first tissue type in the mixture using the N first methylation levels and known methylation levels at the N genomic sites; identifying a second set of the plurality of cell-free DNA molecules that are each located at any one of K genomic sites of a second chromosomal region of the reference genome corresponding to the organism, K being an integer greater than or equal to 10, wherein the second chromosomal region is different from the first chromosomal region; measuring K second methylation levels at the K genomic sites using the second set of the plurality of cell-free DNA molecules; determining, by the computer system, a second fractional contribution of the first tissue type in the mixture using the K second methylation levels and known methylation levels at the K genomic sites; computing a first separation value between the first fractional contribution and the second fractional contribution; and comparing the first separation value to a threshold value to determine a classification of whether the first tissue type has a sequence imbalance for the first chromosomal region. analyzing, by a computer system, a plurality of cell-free DNA molecules from the biological sample, the plurality of cell-free DNA molecules being at least 1,000 cell-free DNA molecules, wherein analyzing a cell-free DNA molecule includes: identifying a location of the cell-free DNA molecule in a reference genome corresponding to the organism; identifying a first set of the plurality of cell-free DNA molecules that are each located at any one of N genomic sites of a first chromosomal region of the reference genome corresponding to the organism, N being an integer greater than or equal to 10; measuring N first methylation levels at the N genomic sites using the first set of the plurality of cell-free DNA molecules; determining, by the computer system, a first fractional contribution of the first tissue type in the mixture using the N first methylation levels and known methylation levels at the N genomic sites; identifying a second set of the plurality of cell-free DNA molecules that are each located at any one of K genomic sites of a second chromosomal region of the reference genome corresponding to the organism, K being an integer greater than or equal to 10, wherein the second chromosomal region is different from the first chromosomal region; measuring K second methylation levels at the K genomic sites using the second set of the plurality of cell-free DNA molecules; determining, by the computer system, a second fractional contribution of the first tissue type in the mixture using the K second methylation levels and known methylation levels at the K genomic sites; computing a first separation value between the first fractional contribution and the second fractional contribution; and comparing the first separation value to a threshold value to determine a classification of whether the first tissue type has a sequence imbalance for the first chromosomal region.