A computer-implemented method for determining a copy number variation of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes, the method comprising: (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 comprising 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 at least some of the cell-free nucleic acid fragments present in the test sample; (d) calculating coverages of the sequence tags for the bins of the reference genome by, for each bin: (i) determining a number of sequence tags aligning to the bin, and (ii) normalizing the number of sequence tags aligning to the bin by accounting for bin-to-bin variations due to factors other than copy number variation; (e) determining a t-statistic for the sequence of interest using coverages of bins in the sequence of interest and coverages of bins in a reference region for the sequence of interest; and (f) determining a copy number variation in the sequence of interest using the t-statistic and information about the sizes of the cell-free nucleic acid fragments, wherein the method includes performing (d) and (e) twice, once for fragments in a first size domain using sequence tags for the cell-free nucleic acid fragments having sizes in the first size domain and again for fragments in a second size domain using sequence tags for the cell-free nucleic acid fragments having sizes in the second size domain, wherein the second size domain is different from the first size domain, thereby obtaining a first t-statistic for the sequence of interest using the sequence tags in the first size domain and a second t-statistic for the sequence of interest using the sequence tags in the second size domain, wherein (f) comprises: calculating a likelihood ratio from the first t-statistic and the second t-statistic, and determining the copy number variation in the sequence of interest using the likelihood ratio, and wherein the likelihood ratio is calculated from the first t-statistic and the second t-statistic and is calculated as a first likelihood that the test sample is an aneuploid sample over a second likelihood that the test sample is a euploid sample. (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 comprising 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 at least some of the cell-free nucleic acid fragments present in the test sample; (d) calculating coverages of the sequence tags for the bins of the reference genome by, for each bin: (i) determining a number of sequence tags aligning to the bin, and (ii) normalizing the number of sequence tags aligning to the bin by accounting for bin-to-bin variations due to factors other than copy number variation; (i) determining a number of sequence tags aligning to the bin, and (ii) normalizing the number of sequence tags aligning to the bin by accounting for bin-to-bin variations due to factors other than copy number variation; (e) determining a t-statistic for the sequence of interest using coverages of bins in the sequence of interest and coverages of bins in a reference region for the sequence of interest; and (f) determining a copy number variation in the sequence of interest using the t-statistic and information about the sizes of the cell-free nucleic acid fragments,