Fetal Chromosomal Aneuploidy Detection via GC-Content Normalization

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Solution Overview

Problem

Current non-invasive methods for detecting fetal chromosomal aneuploidy using massively parallel sequencing of DNA in maternal plasma have low sensitivity and specificity due to ambiguous thresholds for distinguishing between euploid and aneuploid fetuses.

Innovation Solution

A method involving obtaining sequence information from nucleic acid fragments in a biological sample, mapping these fragments to a reference genome, calculating GC content and read fractions, selecting adaptive reference samples, and calculating z scores to determine chromosomal aneuploidy by comparing verification and test samples.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If massively parallel sequencing of fetal DNA is carried out, then non-invasive diagnosis of fetal chromosomal aneuploidy is feasible, but sensitivity and specificity for chromosomal aneuploidy detection are low due to ambiguous threshold

Engineering Contradiction:

Improvesensitivity and specificity for chromosomal aneuploidy detectionVSAvoidthreshold discrimination between euploid and aneuploid fetuses

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent transforms the detection approach by changing from direct read count analysis to GC-content normalized read fraction analysis. This parameter transformation allows for more accurate discrimination between euploid and aneuploid fetuses by accounting for GC-content biases in sequencing data, thereby improving both sensitivity and specificity while establishing clear diagnostic thresholds

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces GC-content as an intermediary parameter that mediates the relationship between raw read counts and actual chromosomal copy number. By normalizing read fractions against GC-content expectations, the method creates a more reliable intermediate metric that resolves the ambiguous threshold problem in direct sequencing-based detection

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If invasive diagnostic methods are used, then accurate fetal chromosomal aneuploidy detection can be achieved, but abortion, diseases, or malformations may occur by impacting the fetus

Engineering Contradiction:

Improvefetal chromosomal aneuploidy detection accuracyVSAvoidabortion, diseases, or malformations from fetal impact

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent extracts fetal DNA information from maternal plasma, separating the diagnostic target (fetal DNA) from the diagnostic route (maternal blood draw). This extraction approach enables accurate fetal chromosomal analysis without direct fetal intervention, eliminating the harmful effects of invasive procedures while maintaining diagnostic precision

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The method analyzes copies of fetal DNA that naturally circulate in maternal plasma rather than directly accessing fetal tissue. This copying approach allows repeated, safe sampling from the mother's blood while obtaining sufficient genetic material for accurate chromosomal aneuploidy detection

Inventive Principle:

Principle #26Copying

Data Source

PatentUS20230368918A1Method of detecting fetal chromosomal aneuploidy

Publication Date: 2023.11.16 THERAGEN GENOMECARE CO LTD

AI summary

Provided are a method of detecting chromosomal aneuploidy of a targeted fetal chromosome, and a computer-readable medium having recorded thereon a program to be applied to performing the method. According to the present disclosure, fetal chromosomal aneuploidy may be non-invasively and prenatally diagnosed with excellent sensitivity and specificity.