A computer-implemented method for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample including cell-free nucleic acid fragments originating from two or more genomes, wherein the method includes: (a) receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample; (b) aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome including the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins; (c) determining fragment sizes of the cell-free nucleic acid fragments existing in the test sample; (d) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain; (e) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain; (f) calculating fragment size characteristics for the bins of the reference genome using the fragment sizes determined in (c), wherein the size characteristic for a bin includes a ratio of fragments of size smaller than a defined value to total fragments in the bin; and (g) determining a copy number variation in the sequence of interest using a ploidy likelihood calculated from the coverages calculated in (d) and (e) and the size characteristics calculated in (f), wherein the test sample comprises cell-free nucleic acid fragments originating from: (i) a mother and one or more fetuses of the mother, or (ii) normal cells and cancerous cells. (a) receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample; (b) aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome including the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins; (c) determining fragment sizes of the cell-free nucleic acid fragments existing in the test sample; (d) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain; (e) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain; (f) calculating fragment size characteristics for the bins of the reference genome using the fragment sizes determined in (c), wherein the size characteristic for a bin includes a ratio of fragments of size smaller than a defined value to total fragments in the bin; and (g) determining a copy number variation in the sequence of interest using a ploidy likelihood calculated from the coverages calculated in (d) and (e) and the size characteristics calculated in (f), <EOS>