CNV Detection Using Chromosome Dose Ratios in cfDNA Sequencing
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Solution Overview
Problem
Existing methods for detecting copy number variations (CNVs) in nucleic acid sequences, particularly in noninvasive prenatal diagnostics and cancer diagnosis, suffer from insufficient sensitivity and sequencing bias, necessitating more reliable and noninvasive techniques.
Innovation Solution
A method using next-generation sequencing to determine CNVs by calculating chromosome doses through ratios of mapped sequence tags for specific chromosomes, accounting for variability, and comparing these ratios to threshold values to identify conditions like fetal aneuploidies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional invasive procedures (amniocentesis) are used to obtain cells for karyotype analysis, then diagnostic reliability is improved, but patient safety deteriorates due to invasive risks
Solution Approach 1:
The patent extracts and analyzes cell-free fetal DNA that naturally circulates in maternal blood, eliminating the need for invasive procedures. By detecting fetal genetic material already present in the maternal circulation, the method achieves diagnostic reliability without exposing the fetus to procedural risks associated with amniocentesis or chorionic villus sampling
Solution Approach 2:
The patent uses cell-free DNA in maternal blood as an intermediary to convey fetal genetic information. Instead of directly sampling fetal cells through invasive means, the method analyzes fetal DNA fragments that have been released into the maternal circulation, serving as a safe intermediary carrier of the diagnostic information needed
2Ease of operation
If next-generation sequencing is used to analyze cfDNA, then noninvasive detection capability is improved, but measurement precision deteriorates due to limited cfDNA levels and sequencing bias
Solution Approach 1:
The patent segments the genome into numerous small regions and analyzes the distribution of sequencing reads across these segments. By dividing the genome into many small intervals and counting reads in each, the method can detect copy number variations even with limited cfDNA, as the segmented approach allows statistical analysis of regional variations rather than requiring uniform coverage across the entire genome
Solution Approach 2:
The patent changes the analytical parameter from requiring a minimum threshold of reads per interval to analyzing the relative distribution pattern of reads across many intervals. This parameter change allows the method to achieve measurement precision with limited cfDNA by focusing on the proportional distribution of reads across genomic segments rather than absolute read counts in each segment
3Adaptability or versatility
If genome-wide sequencing is performed to detect CNVs, then detection coverage is improved, but complexity of analysis increases due to need to account for multiple sources of variability
Solution Approach 1:
The patent segments both the genome and the analysis process into manageable intervals. By dividing the genome into many small intervals and analyzing read distribution across these segments, the method achieves comprehensive detection coverage while reducing analysis complexity through standardized counting and comparison procedures for each segment
Solution Approach 2:
The patent performs sequencing with intentionally excessive depth to ensure sufficient coverage across all genomic intervals, then uses statistical methods to account for variability. By generating more reads than the minimum required and analyzing the distribution pattern across many intervals, the method achieves comprehensive coverage while managing complexity through standardized statistical frameworks
Data Source
AI summary
A method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions.