Chromosome Normalization in Maternal Plasma for Fetal Aneuploidy Detection
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Solution Overview
Problem
Current methods for non-invasive prenatal diagnosis of fetal chromosomal aneuploidies, such as Down syndrome, have high false positive rates and require invasive procedures that pose risks to both mother and fetus, while existing non-invasive methods lack sensitivity and specificity in detecting multiple aneuploidies.
Innovation Solution
A method using next-generation sequencing to determine fetal chromosomal aneuploidies by calculating normalizing values for specific chromosomes and comparing them to threshold values, ensuring accurate detection and verification of aneuploidies in maternal samples.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If invasive methods (CVS, amniocentesis, cordocentesis) are used to obtain definite genetic information about the fetus, then measurement precision is improved, but object-affected harmful factors increase due to risks to mother and fetus
Solution Approach 1:
The patent extracts fetal nucleic acids from maternal plasma, separating the diagnostic target (fetal DNA) from the problematic invasive procedure. By analyzing cell-free DNA naturally present in maternal circulation, the method obtains definitive genetic information without physical intrusion into the fetus or uterus, thereby eliminating procedural risks while maintaining diagnostic precision
Solution Approach 2:
The patent uses maternal plasma as an intermediary medium to access fetal genetic information. Instead of directly sampling fetal tissue through invasive procedures, the method analyzes fetal nucleic acids that have been transferred to the maternal circulation, using plasma as a safe intermediary that carries diagnostic information without requiring direct fetal access
2Object-affected harmful factors
If non-invasive methods are used to avoid risks to mother and fetus, then object-affected harmful factors are reduced, but measurement precision deteriorates due to high false positive rates and inconclusive results
Solution Approach 1:
The patent implements a feedback mechanism by comparing the observed ratio of nucleic acid sequences against expected ratios for normal chromosomal composition. The system continuously refines its analysis by comparing multiple sequence ratios and using statistical algorithms to determine whether deviations indicate aneuploidy, thereby achieving high measurement precision through iterative verification rather than single-measurement screening
Solution Approach 2:
The patent replaces traditional mechanical/invasive sampling methods with molecular sequencing technology. Instead of physically extracting fetal cells or tissue, the method uses next-generation sequencing to analyze nucleic acid sequences in maternal plasma, substituting a non-invasive biochemical analysis system that provides definitive diagnostic information without procedural risks
3Productivity
If massively parallel DNA sequencing is used to obtain millions of sequence tags, then productivity is improved, but device complexity increases due to the need for optimized algorithms and deep sequencing
Solution Approach 1:
The patent segments the complex sequencing analysis into distinct computational steps: (1) obtaining sequence tags from massively parallel sequencing, (2) mapping tags to reference genome locations, (3) counting tags at each location, (4) calculating ratios of observed to expected tag counts, and (5) comparing ratios to determine aneuploidy. This segmentation transforms an overwhelming complex algorithm into a series of manageable computational tasks that can be efficiently executed
4Device complexity
If single normalization value is used to determine aneuploidy, then device complexity is reduced, but measurement precision deteriorates due to inability to verify correct determination
Solution Approach 1:
The patent applies local quality by using different normalization chromosomes for different regions of the genome. Instead of a single universal normalization factor, the method selects specific normalizing chromosomes (such as chromosome 9 for chromosome 21 analysis) based on their suitability for particular chromosomal comparisons. This localized approach to normalization improves measurement precision by accounting for regional variations in genomic composition and sequencing bias
Data Source
AI summary
The present invention provides a method capable of detecting single or multiple fetal chromosomal aneuploidies in a maternal sample comprising fetal and maternal nucleic acids, and verifying that the correct determination has been made. The method is applicable to determining copy number variations (CNV) of any sequence of interest in samples comprising mixtures of genomic nucleic acids derived from two different genomes, and which are known or are suspected to differ in the amount of one or more sequence of interest. The method is applicable at least to the practice of noninvasive prenatal diagnostics, and to the diagnosis and monitoring of conditions associated with a difference in sequence representation in healthy versus diseased individuals.