Dynamic Iterative Depth Optimization for Fetal Chromosomal Screening
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Solution Overview
Problem
Current noninvasive prenatal screening methods face challenges in accurately determining fetal chromosomal abnormalities, particularly at low fetal fractions, due to unreliable polymorphic loci methods and cumbersome methylation difference analyses, leading to increased invasive diagnostic testing risks and anxiety.
Innovation Solution
A method involving measuring chromosome dosage and fetal fraction in maternal cell-free DNA using sequencing read counts and hybridized probes, with dynamic iterative depth optimization, to determine statistical significance and likelihood of fetal chromosomal abnormalities, allowing for re-measurement to enhance accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If polymorphic loci methods are used to determine fetal fraction, then fetal fraction can be determined, but the method becomes unreliable when fetal fraction drops below 3%
Solution Approach 1:
The patent introduces an intermediary approach by using a panel of multiple SNPs (single nucleotide polymorphisms) rather than relying on a single polymorphic locus. This panel-based method acts as a mediator that aggregates information from multiple genetic markers, providing more robust fetal fraction determination even when fetal DNA constitutes less than 3% of total cell-free DNA in the maternal bloodstream.
Solution Approach 2:
The patent changes the parameter of measurement by transitioning from qualitative presence/absence detection at single loci to quantitative allele frequency analysis across multiple SNPs. By measuring the proportion of fetal-derived alleles versus maternal alleles at multiple positions simultaneously, the method maintains reliability at low fetal fractions through statistical aggregation of multiple parameters.
2Measurement precision
If methylation differences are used to estimate fetal fraction, then fetal fraction can be estimated, but the method is cumbersome
Solution Approach 1:
The patent substitutes the complex biochemical methylation analysis system with a simpler genetic polymorphism-based detection system. Instead of requiring enzymatic reactions, methylation-specific PCR, or bisulfite conversion, the method uses standard SNP genotyping approaches that are already well-established in clinical genetics, thereby reducing procedural complexity while maintaining estimation accuracy.
Solution Approach 2:
The patent uses copies of genetic information at multiple SNP loci across the genome to estimate fetal fraction, rather than relying on a single methylation signature. By analyzing allele frequency patterns at numerous copied genetic markers, the method achieves robust estimation through redundancy, eliminating the need for complex single-point methylation analysis.
3Adaptability or versatility
If low fetal fraction samples are analyzed, then screening can be performed, but accuracy of chromosomal abnormality detection decreases
Solution Approach 1:
The patent applies partial action by analyzing only the fetal-derived portion of cell-free DNA through SNP allele frequency patterns, rather than attempting to analyze the entire mixture. By focusing computational and analytical resources on extracting and analyzing the fetal signal component, the method maintains detection accuracy even when fetal DNA represents a small fraction (including below 3%) of total input material.
Solution Approach 2:
The patent segments the total cell-free DNA signal into maternal and fetal components by analyzing allele frequencies at polymorphic loci. Through this segmentation approach, the method can isolate and analyze the fetal-derived allele frequency patterns separately from the maternal background, enabling accurate chromosomal abnormality detection even when the fetal segment constitutes a small proportion of the total sample.
Data Source
AI summary
Fetal maternal samples taken from pregnant women include both maternal cell-free DNA and fetal cell-free DNA. Described herein are methods for determining a chromosomal abnormality of a test chromosome or a portion thereof in a fetus by analyzing a test maternal sample of a woman carrying said fetus, wherein the test maternal sample comprises fetal cell-free DNA and maternal cell-free DNA. The chromosomal abnormality can be, for example, aneuploidy or the presence of a microdeletion. In some embodiments, the chromosomal abnormality is determined by measuring a dosage of the test chromosome or portion thereof in the test maternal sample, measuring a fetal fraction of cell-free DNA in the test maternal sample, and determining an initial value of likelihood that the test chromosome or the portion thereof in the fetal cell-free DNA is abnormal based on the measured dosage, an expected dosage of the test chromosome or portion thereof, and the measured fetal fraction.