Combined size- and count-based analysis of maternal plasma for detection of fetal subchromosomal aberrations

A computer product comprising a computer readable medium storing a plurality of instructions that when executed control a computer system to perform a method of identifying a subchromosomal copy number aberration in a fetal genome of a fetus, the method comprising:

• for each of a plurality of DNA molecules in a biological sample from a female subject pregnant with the fetus, the biological sample including cell-free DNA molecules from the female subject and the fetus:
• identifying a location of the DNA molecule in a reference genome, thereby obtaining locations of the plurality of DNA molecules;
• for each of a plurality of non-overlapping bins in the reference genome:
• measuring a respective amount of the plurality of DNA molecules located in a respective non-overlapping bin using the locations of the plurality of DNA molecules,
• computing a respective bin count parameter from the respective amount, and
• comparing the respective bin count parameter to one or more bin count thresholds to determine a bin count classification of the respective non-overlapping bin;
• performing a segmentation process that merges consecutive non-overlapping bins into a merged segment based on the consecutive non-overlapping bins having a same bin count classification;
• comparing a length of the merged segment to a length threshold;
• computing a count parameter for the merged segment from bin count parameters of the non-overlapping bins of the merged segment or from amounts of the plurality of DNA molecules located in the non-overlapping bins of the merged segment;
• comparing the count parameter to one or more deviation thresholds to determine a count classification;
• classifying the fetus at risk of having a copy number aberration in a subchromosomal region corresponding to the merged segment based on the comparison of the length of the merged segment to the length threshold and the count classification;
• and
• testing the fetus to confirm the subchromosomal copy number aberration.

A method of identifying a subchromosomal copy number aberration in a fetal genome of a fetus by analyzing a biological sample from a female subject pregnant with the fetus, the biological sample including cell-free DNA molecules from the female subject and the fetus, the method comprising:

• for each of a plurality of DNA molecules in the biological sample:
• identifying a location of the DNA molecule in a reference genome by hybridizing the DNA molecule to a panel of probes with known chromosomal origin, thereby obtaining locations of the plurality of DNA molecules;
• for each of a plurality of non-overlapping bins in the reference genome:
• measuring a respective amount of the plurality of DNA molecules located in a respective non-overlapping bin using the locations of the plurality of DNA molecules,
• computing a respective bin count parameter from the respective amount, and
• comparing the respective bin count parameter to one or more bin count thresholds to determine a bin count classification of the respective non-overlapping bin;
• performing, using a computer system, a segmentation process that merges consecutive non-overlapping bins into a merged segment based on the consecutive non-overlapping bins having a same bin count classification;
• comparing a length of the merged segment to a length threshold;
• computing a count parameter for the merged segment from bin count parameters of the non-overlapping bins of the merged segment or from amounts of the plurality of DNA molecules located in the non-overlapping bins of the merged segment;
• comparing the count parameter to one or more deviation thresholds to determine a count classification;
• classifying the fetus at risk of having the aberration in a subchromosomal region corresponding to the merged segment based on the comparison of the length of the merged segment to the length threshold and the count classification;
• and
• testing the fetus to confirm the subchromosomal copy number aberration.