Polymorphism Count Analysis for Robust Fetal Fraction Estimation
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Solution Overview
Problem
Existing methods for detecting fetal fraction in maternal blood samples are unreliable due to variability from factors like parental ethnicity, embryo sex, gestational age, and sequencing errors, making it difficult to accurately estimate the relative abundance of fetal DNA.
Innovation Solution
A computational method using polymorphism counts, such as SNPs, to estimate fetal fraction by mapping DNA segments to a reference sequence, determining allele frequencies, and applying a mixture model to classify zygosity combinations, thereby accounting for environmental factors and sequencing errors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If sex chromosome abundance measures are used to detect fetal fraction, then male embryonic DNA relative abundance can be measured, but the method is limited to male embryos and cannot be universally applied
Solution Approach 1:
The patent transitions from sex chromosome-specific detection to SNP-based detection that works for both male and female embryos. By using autosomal SNPs rather than sex chromosome markers, the method achieves universal applicability across all embryo sexes while maintaining detection accuracy through polymorphism allele frequency analysis
2Measurement precision
If mRNA sequence of differentially expressed genes is used to estimate fetal fraction, then fetal DNA abundance can be detected, but the results vary due to gestational age and tissue expression variability
Solution Approach 1:
The patent changes the detection parameter from mRNA expression levels (which vary with gestational age and tissue type) to SNP allele frequencies (which are genetically stable). This parameter change eliminates variability caused by gestational age differences while maintaining the ability to estimate fetal fraction through polymorphism analysis
3Measurement precision
If existing fetal fraction detection methods are used, then relative abundance can be measured, but results are affected by parental ethnicity and sequencing errors
Solution Approach 1:
The patent extracts and removes the confounding factors (parental ethnicity effects and sequencing errors) from the detection process by using heterozygous SNP sites where the father differs from the mother. This extraction approach isolates the fetal DNA signal from maternal background noise and systematic errors, achieving reliable measurements across diverse populations
Data Source
AI summary
Methods of reliably estimating genomic fraction (e.g., fetal fraction) from polymorphisms such as small base variations or insertions-deletions are disclosed. Sequenced data from a multigenomic source is used to determine allele counts for one or more of the polymorphisms. For one or more of the polymorphisms, zygosity is assigned, and genomic fraction is determined from the zygosity and allele counts. Certain embodiments employ SNPs as the relevant polymorphism. The disclosed methods can be applied as part of an intentional, pre-designed re-sequencing study targeted against known polymorphisms or can be used in a retrospective analysis of variations found by coincidence in overlapping sequences generated from maternal plasma (or any other setting where a mixture of DNA from several people are present).