Sectioned Cell-Free DNA Read Analysis for Fetal Sex Chromosome Aneuploidy
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Solution Overview
Problem
Current methods for non-invasive detection of sex chromosome aneuploidies and fetal gender face challenges due to sequencing bias, sequence similarity between chromosomes X and Y, and the unknown sex of the fetus, leading to mapping difficulties and reduced signal-to-noise ratios, especially in the presence of maternal and fetal mosaicism.
Innovation Solution
The methods involve obtaining counts of sequence reads mapped to a reference genome, determining GC bias, and calculating genomic section levels to identify the presence or absence of sex chromosome aneuploidy and determine fetal gender, using systems and computer programs to analyze circulating cell-free nucleic acid from pregnant females.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If sequence reads are mapped to reference genome sections to detect sex chromosome aneuploidies, then detection accuracy is improved, but mapping difficulties arise due to sequence similarity between chromosomes X and Y
Solution Approach 1:
The reference genome is divided into multiple sections or bins, with each section independently analyzed for read count deviations. This segmentation allows the method to focus on specific chromosomal regions, reducing the impact of sequence similarity between X and Y chromosomes on overall mapping difficulty while maintaining detection accuracy for aneuploidies.
2Measurement precision
If GC bias correction is applied to sequence read counts, then measurement precision is improved, but computational complexity increases
Solution Approach 1:
GC bias correction is performed as a preliminary step before aneuploidy detection. By pre-calculating GC content for each genomic section and establishing correction factors in advance, the method reduces computational complexity during the actual detection phase while maintaining improved measurement precision through bias-corrected read count analysis.
3Object-affected harmful factors
If non-invasive prenatal diagnosis is performed using maternal plasma, then invasiveness is reduced, but signal-to-noise ratio decreases due to maternal DNA background
Solution Approach 1:
The method analyzes specific local regions (genomic sections) of the reference genome rather than attempting to analyze the entire genome uniformly. By focusing on specific chromosomal sections and comparing read count deviations locally, the method can detect fetal aneuploidies in maternal plasma even when fetal DNA constitutes a small fraction, effectively managing the signal-to-noise challenge while maintaining non-invasive benefits.
Data Source
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AI summary
The present invention relates to a system comprising one or more processors and memory, which memory comprises instructions executable by the one or more processors and which memory comprises counts of nucleotide sequence reads mapped to genomic sections of a reference genome, which sequence reads are reads of circulating cell-free nucleic acid from a pregnant female bearing a fetus; and which instructions executable by the one or more processors are configured to: (a) determine an experimental bias for each of the sections of the reference genome for multiple samples from a fitted relation for each sample between (i) the counts of the sequence reads mapped to each of the sections of the reference genome, and (ii) a mapping feature for each of the sections; (b) calculate a genomic section level for each of the sections of the reference genome from a fitted relation between the experimental bias and the counts of the sequence reads mapped to each of the sections of the reference genome, thereby providing calculated genomic section levels; and (c) determine sex chromosome karyotype for the fetus according to the calculated genomic section levels.