Non-invasive Prenatal Ploidy Calling via Joint Distribution Modeling
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Solution Overview
Problem
Current prenatal diagnosis methods either have low accuracy or involve invasive procedures that carry risks, such as miscarriage, and existing non-invasive methods lack precision in detecting chromosomal abnormalities in fetuses.
Innovation Solution
A method for determining the ploidy status of a fetus by isolating and analyzing DNA from maternal and fetal sources, using polymorphic loci analysis, joint distribution modeling, and allele counting to accurately identify chromosomal abnormalities without invasive procedures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If invasive procedures such as amniocentesis or chorion villus biopsy are used for prenatal diagnosis, then measurement precision of chromosomal abnormalities is improved, but object-affected harmful factors increase due to miscarriage risk
Solution Approach 1:
The patent extracts fetal DNA from maternal blood plasma, separating the diagnostic target (fetal DNA) from the harmful invasive procedure. By analyzing cell-free fetal DNA that naturally circulates in maternal blood, the method achieves accurate chromosomal abnormality detection without physical intervention into the fetus or uterus, thereby eliminating miscarriage risk while maintaining high measurement precision
Solution Approach 2:
The patent uses maternal blood plasma as an intermediary medium to access fetal genetic material. Instead of directly sampling fetal tissue through invasive procedures, the method analyzes fetal DNA that has been released into the maternal circulation, using the maternal bloodstream as a safe intermediary that provides indirect access to fetal chromosomal information without harm to the fetus
2Object-affected harmful factors
If non-invasive methods such as maternal serum hormone level testing or ultrasound measurements are used, then object-affected harmful factors are reduced, but measurement precision of chromosomal abnormalities deteriorates
Solution Approach 1:
The patent replaces mechanical and chemical screening methods (ultrasound measurements and hormone level testing) with direct genetic analysis. Instead of inferring chromosomal status indirectly through physical measurements or biochemical markers, the method uses DNA sequencing and polymorphic locus analysis to directly detect chromosomal abnormalities, achieving high measurement precision while maintaining non-invasiveness
Solution Approach 2:
The patent changes the diagnostic parameter from indirect proxies (hormone levels, ultrasound measurements) to direct genetic markers (polymorphic loci, allele counts). By analyzing specific DNA sequences and allele frequencies at polymorphic sites, the method transforms the diagnostic approach from indirect inference to direct detection, significantly improving measurement precision while keeping the procedure non-invasive
3Measurement precision
If DNA analysis at multiple polymorphic loci with joint distribution modeling is performed, then measurement precision of ploidy status is improved, but device complexity increases
Solution Approach 1:
The patent segments the complex joint distribution model into manageable computational components: first identifying informative polymorphic loci, then counting alleles at each locus separately, and finally integrating results through a structured statistical framework. This segmentation of the analytical process reduces computational complexity while maintaining high measurement precision in ploidy status determination
Data Source
AI summary
The present disclosure provides methods for determining the ploidy status of a chromosome in a gestating fetus from genotypic data measured from a mixed sample of DNA comprising DNA from both the mother of the fetus and from the fetus, and optionally from genotypic data from the mother and father. The ploidy state is determined by using a joint distribution model to create a plurality of expected allele distributions for different possible fetal ploidy states given the parental genotypic data, and comparing the expected allelic distributions to the pattern of measured allelic distributions measured in the mixed sample, and choosing the ploidy state whose expected allelic distribution pattern most closely matches the observed allelic distribution pattern. The mixed sample of DNA may be preferentially enriched at a plurality of polymorphic loci in a way that minimizes the allelic bias, for example using massively multiplexed targeted PCR.