Non-Invasive Prenatal Ploidy Calling via Joint Distribution Modeling
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Solution Overview
Problem
Current prenatal diagnosis methods either lack accuracy or involve invasive procedures that carry risks, such as miscarriage, and existing non-invasive methods have low accuracy for 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 in maternal plasma, using polymorphic loci analysis, joint distribution modeling, and allele counting to accurately predict 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 and analyzes cell-free fetal DNA that has naturally entered maternal circulation, separating the diagnostic target (fetal DNA) from the invasive procedure requirement. This allows prenatal diagnosis without physically invading the fetus or uterus, thereby eliminating miscarriage risk while maintaining detection capability through molecular analysis of chromosomal abnormalities
Solution Approach 2:
The patent uses cell-free DNA in maternal blood as an intermediary substance that carries fetal genetic information. Instead of directly accessing fetal tissue through invasive procedures, the method analyzes this intermediate molecular carrier to detect chromosomal abnormalities, achieving diagnostic precision without physical invasion
2Object-affected harmful factors
If non-invasive methods such as maternal blood hormone levels 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/physical measurement systems (ultrasound, hormone level assessment) with molecular biological analysis. By substituting the diagnostic approach from macroscopic physical measurements to microscopic DNA sequence analysis, the method achieves high precision in detecting chromosomal abnormalities while maintaining the non-invasive advantage of blood sampling
3Object-affected harmful factors
If cell-free fetal DNA analysis is performed on maternal blood, then invasiveness is reduced, but detection accuracy for chromosomal abnormalities may be insufficient due to low fetal DNA fraction
Solution Approach 1:
The patent segments the analysis by focusing on specific chromosomal regions and using multiple independent genetic markers rather than attempting to analyze the entire genome or relying on a single marker. This segmentation approach allows accurate detection of chromosomal abnormalities even when fetal DNA constitutes a small fraction of total DNA in maternal blood
Solution Approach 2:
The patent employs excessive action by analyzing multiple polymorphic loci and using statistical methods that aggregate information from many genetic markers. This over-sampling of genetic information ensures sufficient detection accuracy despite the limited fetal DNA fraction, as the cumulative signal from multiple markers overcomes the noise from maternal DNA dominance
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.