Gestational Age Estimation via cfDNA Methylation and Fragmentation

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Solution Overview

Problem

Current methods for noninvasive prenatal diagnosis lack accuracy in estimating gestational age and detecting pregnancy-associated disorders using cell-free fetal DNA in maternal plasma, as they fail to reliably differentiate between fetal and maternal DNA and do not account for temporal changes in DNA fragmentation patterns and methylation levels.

Innovation Solution

The analysis of cell-free DNA in maternal plasma focuses on temporal changes in DNA fragmentation patterns and methylation levels, using techniques such as massively parallel sequencing and methylation profiling to estimate gestational age and detect fetal-specific alleles, thereby identifying potential pathological conditions like preeclampsia or fetal chromosomal aneuploidies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If cell-free fetal DNA analysis is used for noninvasive prenatal diagnosis, then the ability to detect fetal-derived genes and chromosomal aneuploidies is improved, but the accuracy in estimating gestational age and detecting pregnancy-associated disorders deteriorates due to inability to differentiate fetal and maternal DNA and lack of temporal change analysis

Engineering Contradiction:

Improvedetection of fetal chromosomal aneuploidiesVSAvoidestimation of gestational age

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent segments the mixed cell-free DNA population into fetal-derived and maternal-derived components by analyzing temporal changes in DNA fragmentation patterns and methylation levels. This segmentation allows independent analysis of fetal DNA characteristics, resolving the contradiction between detecting fetal aneuploidies and accurately estimating gestational age.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent utilizes parameter changes in DNA fragmentation patterns and methylation levels over time during pregnancy. By monitoring these dynamic parameters, the system can distinguish fetal from maternal DNA and simultaneously perform both aneuploidy detection and gestational age estimation with high precision.

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If traditional cell-free DNA screening methods are used, then the noninvasive detection of fetal sex and Rhesus D status is achieved, but the accuracy for detecting pregnancy-associated disorders like preeclampsia and intrauterine growth restriction deteriorates

Engineering Contradiction:

Improvenoninvasive prenatal diagnosisVSAvoiddetection of pregnancy-associated disorders

Core Design Contradiction:

Ease of operationVSMeasurement precision

Solution Approach 1:

The patent implements continuous monitoring of DNA fragmentation patterns and methylation levels throughout pregnancy. This continuous analysis enables the detection of temporal changes that are characteristic of pregnancy-associated disorders, maintaining ease of noninvasive operation while significantly improving diagnostic precision for conditions like preeclampsia and intrauterine growth restriction.

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The system incorporates feedback mechanisms by comparing observed DNA characteristics against expected temporal patterns. When deviations are detected, the system can identify potential pregnancy-associated disorders, thereby improving measurement precision while maintaining the ease of noninvasive operation through automated analysis.

Inventive Principle:

Principle #23Feedback

3Quantity of substance

If DNA methylation level analysis is performed on mixed maternal plasma DNA, then the overall methylation profile can be obtained, but the ability to specifically assess fetal DNA methylation status deteriorates due to contamination by maternal DNA

Engineering Contradiction:

Improveoverall methylation level measurementVSAvoidfetal DNA methylation status

Core Design Contradiction:

Quantity of substanceVSMeasurement precision

Solution Approach 1:

The patent applies dynamic analysis by examining temporal changes in DNA methylation levels and fragmentation patterns throughout pregnancy. This dynamic approach allows the system to track fetal DNA methylation status independently from maternal DNA, as fetal and maternal DNA exhibit different temporal methylation trajectories, thereby improving measurement precision for fetal assessment.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent applies local quality analysis by examining specific regions and characteristics of DNA fragments that are distinctive to fetal origin. By focusing on local methylation patterns and fragmentation characteristics that differ between fetal and maternal DNA, the system can accurately assess fetal DNA methylation status even in the presence of maternal DNA contamination.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP4209598A1Gestational age assessment by methylation and size profiling of maternal plasma DNA

Publication Date: 2023.07.12 THE CHINESE UNIVERSITY OF HONG KONG

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AI summary

Temporal variations in one or more characteristics measured from a cell-free DNA sample are used to estimate a gestational age of a fetus. Example characteristics include the methylation level measured from the cell-free DNA sample, size of DNA fragments measured from the cell-free DNA sample (e.g., proportion of fetal-derived DNA fragments longer than a specified size), and ending patterns of the DNA fragments align to a reference genome.