RISK CALCULATION FOR EVALUATION OF FETAL ANEUPLOIDY
First Claim
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1. A method to calculate a risk that a first fetal chromosome in a maternal sample comprising maternal and fetal nucleic acids is aneuploid, comprising:
- designing sequence-specific oligonucleotide probes directed to a plurality of non-polymorphic loci on each of at least a first and second chromosome;
designing sequence-specific oligonucleotide probes directed to a plurality of polymorphic loci on at least a third chromosome;
amplifying the plurality of non-polymorphic and polymorphic loci using the sequence-specific oligonucleotide probes;
determining a number of each non-polymorphic locus on the at least first and second chromosomes;
determining a number of alleles at each polymorphic locus on the at least third chromosome;
estimating a chromosome frequency for the at least first and second chromosomes based on the number of non-polymorphic loci on the at least the first and second chromosomes;
calculating a fetal nucleic acid proportion in the maternal sample based on the number of alleles at the polymorphic loci;
determining whether the fetal nucleic acid proportion in the maternal sample is adequate to reliably perform analysis;
calculating a value of likelihood that the first fetal chromosome is disomic using the fetal nucleic acid proportion to adjust the estimated chromosome frequency of the first and second chromosomes;
calculating a value of likelihood that the first fetal chromosome is aneuploid using the fetal nucleic acid proportion to adjust the estimated chromosome frequency of the first and second chromosomes; and
calculating the risk of a fetal aneuploidy of the first fetal chromosome by comparing the values of likelihood to a first mathematic model assuming a disomic first fetal chromosome and a second mathematic model assuming an aneuploid first fetal chromosome.
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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.
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Citations
20 Claims
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1. A method to calculate a risk that a first fetal chromosome in a maternal sample comprising maternal and fetal nucleic acids is aneuploid, comprising:
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designing sequence-specific oligonucleotide probes directed to a plurality of non-polymorphic loci on each of at least a first and second chromosome; designing sequence-specific oligonucleotide probes directed to a plurality of polymorphic loci on at least a third chromosome; amplifying the plurality of non-polymorphic and polymorphic loci using the sequence-specific oligonucleotide probes; determining a number of each non-polymorphic locus on the at least first and second chromosomes; determining a number of alleles at each polymorphic locus on the at least third chromosome; estimating a chromosome frequency for the at least first and second chromosomes based on the number of non-polymorphic loci on the at least the first and second chromosomes; calculating a fetal nucleic acid proportion in the maternal sample based on the number of alleles at the polymorphic loci; determining whether the fetal nucleic acid proportion in the maternal sample is adequate to reliably perform analysis; calculating a value of likelihood that the first fetal chromosome is disomic using the fetal nucleic acid proportion to adjust the estimated chromosome frequency of the first and second chromosomes; calculating a value of likelihood that the first fetal chromosome is aneuploid using the fetal nucleic acid proportion to adjust the estimated chromosome frequency of the first and second chromosomes; and calculating the risk of a fetal aneuploidy of the first fetal chromosome by comparing the values of likelihood to a first mathematic model assuming a disomic first fetal chromosome and a second mathematic model assuming an aneuploid first fetal chromosome. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A method to calculate a risk that a first fetal chromosome in a maternal sample comprising maternal and fetal nucleic acids is aneuploid, comprising:
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designing sequence-specific oligonucleotide probes directed to a plurality of non-polymorphic loci on each of at least a first and second chromosome; designing sequence-specific oligonucleotide probes directed to a plurality of polymorphic loci on at least a third chromosome; amplifying the plurality of non-polymorphic and polymorphic loci using the sequence-specific oligonucleotide probes; determining a number of each non-polymorphic locus on the at least first and second chromosomes; determining a number of alleles at each polymorphic locus on the at least third chromosome; estimating a chromosome frequency for the at least first and second chromosomes based on the number of the non-polymorphic loci on the at least the first and second chromosomes; calculating a fetal nucleic acid proportion in the maternal sample based on the number of alleles at the polymorphic loci; determining whether the fetal nucleic acid proportion in the maternal sample is adequate to reliably perform analysis; calculating a value of likelihood that the first fetal chromosome is disomic; calculating a value of likelihood that the first fetal chromosome is aneuploid using the fetal nucleic acid proportion in the maternal sample to adjust the estimated chromosome frequency of the first and second chromosomes; calculating the risk of a fetal aneuploidy of the first fetal chromosome by comparing the values of likelihood to a first mathematic model assuming a disomic first fetal chromosome and a second mathematic model assuming an aneuploid first fetal chromosome; and adjusting the calculated risk using extrinsic information on prior risk. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18)
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19. A method to calculate a risk that a first fetal chromosome in a maternal sample comprising maternal and fetal nucleic acids is triploid, comprising:
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designing sequence-specific oligonucleotide probes directed to a plurality of non-polymorphic loci on each of at least a first and second chromosome; identifying a set of non-polymorphic loci best able to discriminate trisomy samples from normal samples; designing sequence-specific oligonucleotide probes directed to a plurality of polymorphic loci on at least a third chromosome; amplifying a plurality of non-polymorphic loci using the identified non-polymorphic loci best able to discriminate trisomy samples from normal samples and amplifying a plurality of polymorphic loci using the sequence-specific oligonucleotide probes; determining a number of each non-polymorphic locus on the at least first and second chromosomes; determining a number of alleles at each polymorphic locus on the at least third chromosome; estimating a chromosome frequency for the at least first and second chromosomes based on the number of non-polymorphic loci on the at least the first and second chromosomes; calculating a fetal nucleic acid proportion in the maternal sample based on the number of alleles at the polymorphic loci; determining whether the fetal nucleic acid proportion in the maternal sample is adequate to reliably perform analysis; calculating a value of likelihood that the first fetal chromosome is disomic using the fetal nucleic acid proportion to adjust the estimated chromosome frequency of the first and second chromosomes; calculating a value of likelihood that the first fetal chromosome is triploid using the fetal nucleic acid proportion to adjust the estimated chromosome frequency of the first and second chromosomes; and calculating the risk of a fetal trisomy of the first fetal chromosome by comparing the values of likelihood to a first mathematic model assuming a disomic first fetal chromosome and a second mathematic model assuming an triploid first fetal chromosome. - View Dependent Claims (20)
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Specification