Detecting and classifying copy number variation

A computer program product comprising a non-transitory computer readable medium on which is provided program instructions for classifying a copy number variation in a fetal genome, the program instructions comprising:

• (a) code for receiving sequence reads from fetal and maternal nucleic acids in a maternal test sample obtained from a mother carrying a fetus, wherein the sequence reads are provided in an electronic format;
• (b) code for aligning the sequence reads to one or more bins from a reference sequence using a computing apparatus and thereby providing sequence tags corresponding to the sequence reads, wherein each bin contains a subsequence within the reference sequence;
• (c) code for computationally identifying a number of those sequence tags that are from one or more bins by using the computing apparatus and determining that a first bin of interest in the fetal genome harbors a copy number variation;
• (d) code for calculating a first fetal fraction value by a first method that does not use information from sequence tags from the first bin of interest;
• (e) code for calculating a second fetal fraction value by a second method that uses information from the sequence tags from the first bin of interest, wherein the second method includes a ploidy assumption that the fetal genome has a complete aneuploidy within the subsequence of the first bin of interest;
• and
• (f) code for comparing the first fetal fraction value and the second fetal fraction value and using the comparison to classify the copy number variation of the first bin of interest in the fetal genome as harboring a complete aneuploidy or another type of copy number variation.

A system for classifying a copy number variation in a fetal genome, the system comprising:

• (a) an interface for receiving at least about 10,000 sequence reads from fetal and maternal nucleic acids in a maternal test sample obtained from a mother carrying a fetus, wherein the sequence reads are provided in an electronic format;
• (b) memory for storing, at least temporarily, a plurality of said sequence reads;
• (c) a processor designed or configured with p(i) aligning the sequence reads to one or more reference sequences and thereby providing sequence tags corresponding to the sequence reads;
• (ii) identifying a number of those sequence tags that are from one or more bins of interest and determining that a first bin of interest in the fetal genome harbors a copy number variation, wherein each bin contains a subsequence within the reference sequence;
• (iii) calculating a first fetal fraction value by a first method that does not use information from sequence tags from the first bin of interest;
• (iv) calculating a second fetal fraction value by a second method that uses information from the sequence tags from the first bin of interest, wherein the second method includes a ploidy assumption that the fetal genome has a complete aneuploidy within the subsequence of the first bin of interest;
• and
• (v) comparing the first fetal fraction value and the second fetal fraction value and using the comparison to classify the copy number variation of the first bin of interest in the fetal genome as harboring a complete aneuploidy or another type of copy number variation.