Determining progress of chromosomal aberrations over time

A computer program product comprising a non-transitory computer readable medium storing a plurality of instructions for controlling a computer system coupled to a sequencer to perform an operation for determining a progress of chromosomal aberrations in an organism using biological samples including cell-free nucleic acid molecules originating from normal cells and potentially from cells associated with a disease, the operation comprising:

• a) identifying non-overlapping chromosomal regions of a reference genome of the organism, each chromosomal region including at least 5 kilobases and a plurality of loci;
• b) at each of a plurality of times:
• i) sequencing, using the sequencer, a plurality of cell-free nucleic acid molecules in a biological sample of the organism to obtain sequenced tags;
• ii) identifying, using the sequenced tags, locations of the plurality of cell-free nucleic acid molecules in the reference genome;
• and
• iii) for each of the non-overlapping chromosomal regions:
• identifying a respective group of cell-free nucleic acid molecules within the plurality of cell-free nucleic acid molecules as being from the chromosomal region based on the identified locations, the respective group of cell-free nucleic acid molecules including at least one nucleic acid molecule located at each of the plurality of loci of the chromosomal region;
• determining a respective value of the respective group of nucleic acid molecules, the respective value defining a property of the cell-free nucleic acid molecules of the respective group;
• and
• comparing the respective value to a reference value to determine a classification of whether the chromosomal region exhibits a deletion or an amplification, wherein at least two of the non-overlapping chromosomal regions are classified as exhibiting the deletion or the amplification at two times of the plurality of times;
• and
• c) determining whether an amount of the chromosomal aberrations in the organism has increased, wherein determining whether the amount has increased comprises determining, for each of the at least two non-overlapping chromosomal regions, a change in a numerical value for the classification between the two times of the plurality of times at which the non-overlapping chromosomal region was determined to exhibit the deletion or the amplification, the numerical value for the classification comprising a difference between the respective value and the reference value for each of the at least two non-overlapping chromosomal regions at each of the two times.

A computer system for determining a progress of chromosomal aberrations in an organism using biological samples including cell-free nucleic acid molecules originating from normal cells and potentially from cells associated with a disease, the computer system coupled to a sequencer and comprising computer processors configured for:

• a) identifying non-overlapping chromosomal regions of a reference genome of the organism, each chromosomal region including at least 5 kilobases and a plurality of loci;
• b) at each of a plurality of times:
• i) sequencing, using the sequencer, a plurality of cell-free nucleic acid molecules in a biological sample of the organism to obtain sequenced tags;
• ii) identifying, using the sequenced tags, locations of the plurality of cell-free nucleic acid molecules in the reference genome;
• and
• iii) for each of the non-overlapping chromosomal regions:
• identifying a respective group of cell-free nucleic acid molecules within the plurality of cell-free nucleic acid molecules as being from the chromosomal region based on the identified locations, the respective group of cell-free nucleic acid molecules including at least one nucleic acid molecule located at each of the plurality of loci of the chromosomal region;
• determining a respective value of the respective group of nucleic acid molecules, the respective value defining a property of the cell-free nucleic acid molecules of the respective group;
• and
• comparing the respective value to a reference value to determine a classification of whether the chromosomal region exhibits a deletion or an amplification, wherein at least two of the non-overlapping chromosomal regions are classified as exhibiting the deletion or the amplification at two times of the plurality of times;
• and
• c) determining whether an amount of the chromosomal aberrations in the organism has increased, wherein determining whether the amount has increased comprises determining, for each of the at least two non-overlapping chromosomal regions, a change in a numerical value for the classification between the two times of the plurality of times at which the non-overlapping chromosomal region was determined to exhibit the deletion or the amplification, the numerical value for the classification comprising a difference between the respective value and the reference value for each of the at least two non-overlapping chromosomal regions at each of the two times.