A computer-implemented method of determining an amplification or a deletion in a first chromosomal region in a biological sample, the method comprising: identifying a first chromosomal region of a reference genome; determining the first chromosomal region to have a first GC content in the reference genome; assembling an artificial reference chromosome from a plurality of disjoint regions of the reference genome such that the artificial reference chromosome is determined to have the first GC content within a specified percentage, wherein the plurality of disjoint regions have a normal copy number or are from one or more chromosomes that have a normal copy number, and each disjoint region of the plurality of disjoint regions has a minimum length of 50 kb; aligning each of a plurality of sequence tags with the first chromosomal region and with the artificial reference chromosome, wherein the sequence tags have been obtained by sequencing nucleic acids in a biological sample comprising cell-free nucleic acids from a first tissue and a second tissue; determining a first amount of sequence tags that align with the first chromosomal region with 0, 1, or 2 mismatches; determining a reference amount of sequence tags that align with the artificial reference chromosome with 0, 1, or 2 mismatches; determining a parameter by calculating a ratio or a difference from the first amount and the reference amount; and comparing the parameter to a cutoff value, the cutoff value signifying whether the parameter is statistically different than a reference value, the reference value determined from a healthy person or determined theoretically, thereby determining a classification of the first chromosomal region as having or not having an amplification or as having or not having a deletion. identifying a first chromosomal region of a reference genome; determining the first chromosomal region to have a first GC content in the reference genome; assembling an artificial reference chromosome from a plurality of disjoint regions of the reference genome such that the artificial reference chromosome is determined to have the first GC content within a specified percentage, wherein the plurality of disjoint regions have a normal copy number or are from one or more chromosomes that have a normal copy number, and each disjoint region of the plurality of disjoint regions has a minimum length of 50 kb; the plurality of disjoint regions have a normal copy number or are from one or more chromosomes that have a normal copy number, and each disjoint region of the plurality of disjoint regions has a minimum length of 50 kb; aligning each of a plurality of sequence tags with the first chromosomal region and with the artificial reference chromosome, wherein the sequence tags have been obtained by sequencing nucleic acids in a biological sample comprising cell-free nucleic acids from a first tissue and a second tissue; determining a first amount of sequence tags that align with the first chromosomal region with 0, 1, or 2 mismatches; determining a reference amount of sequence tags that align with the artificial reference chromosome with 0, 1, or 2 mismatches; determining a parameter by calculating a ratio or a difference from the first amount and the reference amount; and comparing the parameter to a cutoff value, the cutoff value signifying whether the parameter is statistically different than a reference value, the reference value determined from a healthy person or determined theoretically, thereby determining a classification of the first chromosomal region as having or not having an amplification or as having or not having a deletion.