Non-Invasive Fetal Ploidy Calling via Joint Allele Distribution
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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 techniques like PCR and sequencing to create a joint distribution model for allele counts, allowing for non-invasive and accurate detection of chromosomal abnormalities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If invasive procedures like amniocentesis or chorion villus biopsy are used for prenatal diagnosis, then detection accuracy of chromosomal abnormalities is improved, but the risk of miscarriage increases
Solution Approach 1:
The patent extracts fetal DNA from maternal plasma, separating the diagnostic target (fetal DNA) from the source material (maternal blood). This allows non-invasive acquisition of fetal genetic material that contains chromosomal abnormalities, achieving high detection accuracy without the physical invasion required by traditional methods like amniocentesis
Solution Approach 2:
Maternal plasma serves as an intermediary medium that contains fetal DNA shed from the placenta. By analyzing this intermediary substance rather than directly accessing fetal tissue, the method achieves accurate chromosomal abnormality detection without invasive procedures that could cause miscarriage
2Object-affected harmful factors
If non-invasive methods like maternal serum hormone level testing or ultrasound measurements are used, then miscarriage risk is reduced, but detection accuracy of chromosomal abnormalities deteriorates
Solution Approach 1:
The patent replaces mechanical/invasive sampling methods with molecular biological detection methods. Instead of physically accessing fetal tissue through invasive procedures, the method uses DNA extraction and analysis from maternal plasma, substituting mechanical invasion with biochemical analysis that achieves superior detection accuracy
Solution Approach 2:
The patent changes the measured parameter from indirect indicators (hormone levels, ultrasound measurements) to direct genetic material (fetal DNA sequences). This parameter change from proxy markers to actual chromosomal material enables accurate detection of chromosomal abnormalities while maintaining non-invasive status
3Measurement precision
If DNA is preferentially enriched at polymorphic loci using PCR, then detection sensitivity of fetal DNA is improved, but allele bias may be introduced
Solution Approach 1:
The patent applies local quality by preferentially enriching DNA at specific polymorphic loci rather than uniformly amplifying all DNA. This localized enrichment at informative sites improves detection sensitivity for fetal DNA while the method accounts for potential allele bias through statistical modeling that considers the non-uniform amplification patterns
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables accurate and non-invasive detection of fetal chromosomal abnormalities, reducing the risk of miscarriage and improving the accuracy of prenatal diagnosis, particularly for conditions like Down syndrome and other aneuploidies.
Implementation Method 1
The PCR conditions are selected to suppress maternal genomic DNA amplification and promote preferential amplification of the fetal DNA sequences.
Implementation Method 2
The reverse transcription conditions are selected to suppress maternal genomic DNA reverse transcription and promote preferential reverse transcription of the fetal DNA.
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.