Plasma DNA Fragment Sizing for Universal Fetal Fraction Estimation
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Solution Overview
Problem
Existing methods for determining the fractional concentration of fetal DNA in maternal plasma are limited by the need for complex genetic markers and inter-individual variation in DNA methylation patterns, making them unreliable for all fetus-mother pairs.
Innovation Solution
A method that estimates the fractional concentration of clinically-relevant DNA in plasma samples by measuring the size distribution of DNA fragments and using calibration data points to correlate size profiles with known concentrations, enabling accurate estimation through statistical analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetic markers are used to measure fractional fetal DNA concentration, then the measurement can be performed, but the method becomes unreliable for all fetus-mother pairs due to inter-individual variation in DNA methylation patterns
Solution Approach 1:
The invention changes the measurement parameter from DNA methylation patterns (which vary inter-individually) to DNA fragment size distribution (which is consistent across individuals). Fetal DNA fragments are consistently smaller than maternal DNA fragments, providing a universal marker that works for all fetus-mother pairs without being affected by genetic or epigenetic variations.
2Measurement precision
If DNA methylation markers are used for measurement, then fetal DNA concentration can be detected, but the method complexity increases due to requirements for restriction enzyme digestion or bisulfite conversion
Solution Approach 1:
The invention extracts and utilizes the inherent size difference between fetal and maternal DNA fragments as the measurement basis, eliminating the need for complex methylation detection procedures such as restriction enzyme digestion, bisulfite conversion, or methylated DNA immunoprecipitation. This simplifies the measurement method while maintaining detection precision.
3Measurement precision
If fetal-specific paternal sequences are used for measurement, then fractional fetal DNA concentration can be calculated, but the method is limited to specific fetus-mother combinations
Solution Approach 1:
The invention creates a universal measurement method based on DNA fragment size distribution that applies to all fetus-mother pairs regardless of genetic compatibility. The size difference between fetal and maternal DNA is a universal biological characteristic that can be used for measurement in any pregnancy case, making the method multi-applicable and versatile.
Data Source
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AI summary
A fractional concentration of clinically-relevant DNA in a mixture of DNA from a biological sample is determined based on amounts of DNA fragments at multiple sizes. For example, the fractional concentration of fetal DNA in maternal plasma or tumor DNA in a patient's plasma can be determined. The size of DNA fragments in a sample is shown to be correlated with a proportion of fetal DNA and a proportion of tumor DNA, respectively. Calibration data points (e.g., as a calibration function) indicate a correspondence between values of a size parameter and the fractional concentration of the clinically-relevant DNA. For a given sample, a first value of a size parameter can be determined from the sizes of DNA fragments in a sample. A comparison of the first value to the calibration data points can provide the estimate of the fractional concentration of the clinically-relevant DNA.