Cell-Free DNA Methylation Analysis for Fetal Haplotype Detection
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Solution Overview
Problem
Existing methods for determining fetal haplotype inheritance are limited by the use of specific SNPs, which restrict data accuracy and clinical utility, especially when DNA samples from additional family members are unavailable, and direct haplotype analysis methods are costly.
Innovation Solution
A method using methylation patterns of cell-free DNA mixtures to determine fractional contributions of fetal and maternal tissues, allowing identification of inherited haplotypes through methylation levels and separation values, enabling accurate fetal genome analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If specific SNPs are used for RHDO analysis, then the analysis can be performed with available data, but the loci that can be used are limited, reducing data accuracy and clinical utility
Solution Approach 1:
The patent changes the parameter used for haplotype analysis from specific SNP genotypes to DNA methylation levels. By measuring methylation levels at multiple CpG sites across different haplotypes, the method overcomes the limitation of using only specific SNPs, thereby increasing both the number of usable loci and the accuracy of fetal haplotype determination without requiring additional family member samples
2Loss of information
If direct haplotype analysis methods are used, then comprehensive haplotype information can be obtained, but the costs of the analysis increase
Solution Approach 1:
The patent replaces complex direct haplotype analysis methods with a simpler methylation-based approach. Instead of using costly direct sequencing or family-based analysis, the method uses methylation level measurements at multiple CpG sites to infer haplotype inheritance, thereby obtaining comprehensive haplotype information at lower cost
3Measurement precision
If DNA samples from additional family members are required, then more complete haplotype information can be obtained, but the method becomes less clinically useful when samples are unavailable
Solution Approach 1:
The patent enables the fetal haplotype analysis to be self-sufficient by using only maternal plasma DNA samples. The method leverages the natural methylation differences between maternal and fetal DNA to determine fetal haplotype inheritance without requiring additional family member samples, thereby maintaining high accuracy while improving ease of operation and clinical applicability
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
Enhances data accuracy and clinical utility by accurately identifying fetal haplotypes and detecting sequence imbalances, aneuploidy, and disease states in fetal and maternal tissues.
Implementation Method 1
A method using methylation patterns of cell-free DNA mixtures to determine fractional contributions of fetal and maternal tissues, allowing identification of inherited haplotypes through methylation levels
Data Source
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AI summary
Systems, apparatuses, and method are provided for determining the contributions of different tissues to a biological sample that includes a mixture of cell-free DNA molecules from various tissues types, e.g., as occurs in plasma or serum and other body fluids. Embodiments can analyze the methylation patterns of the DNA mixture (e.g., methylation levels at particular loci) for a particular haplotype and determine fractional contributions of various tissue types to the DNA mixture, e.g., of fetal tissue types or tissue types of specific organs that might have a tumor. Such fractional contributions determined for a haplotype can be used in a variety of ways.