Risk calculation for evaluation of fetal aneuploidy

Inventors

Oliphant, Arnold • Sparks, Andrew • Wang, Eric • Struble, Craig

Assignees

Roche Molecular Systems Inc

Abstract

The present invention provides processes for determining accurate risk probabilities for fetal aneuploidies. Specifically, the invention provides non-invasive evaluation of genomic variations through chromosome-selective sequencing and non-host fraction data analysis of maternal samples.

Core Innovation

The disclosure describes a non-invasive, computer-implemented method to calculate a risk that a first fetal chromosome in a maternal sample from a pregnant female comprising maternal and fetal nucleic acids is aneuploid. The method uses sequence-specific oligonucleotide probes directed to non-polymorphic loci on at least a first and second chromosome and sequence-specific oligonucleotide probes directed to polymorphic loci on at least a third chromosome. The method amplifies the plurality of non-polymorphic and polymorphic loci and determines a number of each amplified non-polymorphic locus and a number of alleles at each amplified polymorphic locus.

From these counts, the method estimates a chromosome frequency for the at least first and second chromosomes based on the number of amplified non-polymorphic loci and calculates a fetal nucleic acid proportion in the maternal sample based on the number of alleles at the amplified polymorphic loci. The method then calculates values of likelihood for disomic and aneuploid states by adjusting the estimated chromosome frequency using the fetal nucleic acid proportion. The risk of fetal aneuploidy is calculated by comparing values of likelihood to mathematic models assuming a disomic first fetal chromosome and an aneuploid first fetal chromosome.

In additional embodiments, a set of non-polymorphic loci best able to discriminate trisomy samples from normal samples is identified and used for amplifying non-polymorphic loci for a triploid risk calculation. For triploidy, the method calculates a value of likelihood that the first fetal chromosome is disomic and a value of likelihood that the first fetal chromosome is triploid, then calculates the risk of fetal trisomy by comparing likelihood values to mathematic models assuming a disomic first fetal chromosome and an triploid first fetal chromosome. The risk calculation can be adjusted using extrinsic information on prior risk, including maternal age and/or gestational age.

Claims Coverage

The partial claims include three independent method claims. Each independent claim centers on computing likelihoods and a risk value by comparing a disomic mathematical model against an aneuploid or triploid mathematical model, with chromosome frequency estimated from non-polymorphic loci and fetal nucleic acid proportion derived from polymorphic loci allele counts, and one claim further using an identified set of discriminative non-polymorphic loci.

Across the independent claims, inventive coverage is directed to profiling non-polymorphic and polymorphic loci using sequence-specific oligonucleotide probes, converting non-polymorphic locus counts into an estimated chromosome frequency, converting polymorphic locus allele counts into a fetal nucleic acid proportion, computing likelihood values for disomic versus aneuploid or triploid states using fetal nucleic acid proportion to adjust chromosome frequency, and calculating risk by comparing likelihood values to disomic and aneuploid or triploid mathematic models; in one embodiment the risk is further adjusted using extrinsic prior risk information.

Stated Advantages

Documented Applications