Cell-free DNA Copy Number Variation Detection via Saturation Correction
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Solution Overview
Problem
Current methods for detecting copy number variation in tumors are invasive, time-consuming, and often not representative of the entire tumor population, with conventional techniques like biopsies and sequencing data being biased by factors such as amplification efficiency and guanine-cytosine content.
Innovation Solution
A method involving the analysis of cell-free bodily fluids, which includes obtaining sequencing reads, performing saturation equilibrium correction and probe efficiency correction, and determining copy number states by removing high-variance genetic loci and applying transformations based on GC content and probability of DNA representation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional biopsy methods are used to detect copy number variation, then cellular samples can be obtained for analysis, but the process is painful, time-intensive, and may not represent the entire tumor population
Solution Approach 1:
The patent extracts and analyzes cell-free DNA molecules from bodily fluids (blood, urine, saliva) instead of requiring cellular biopsy samples. This extraction approach allows direct access to tumor-derived genetic material circulating in the body, eliminating the need for invasive tissue sampling while maintaining detection capability for copy number variations
Solution Approach 2:
The patent uses cell-free DNA molecules as an intermediary between the tumor and the detection system. These DNA fragments serve as mediators that carry tumor genetic information through bodily fluids, allowing indirect but accurate assessment of tumor copy number variations without direct tumor tissue contact
2Quantity of substance
If conventional sequencing methods are used, then genetic data can be obtained, but amplification efficiency and GC content cause bias in depth of coverage
Solution Approach 1:
The patent implements a feedback mechanism by using observed depth of coverage across the genome to iteratively refine and update copy number estimates. The system continuously adjusts its model based on the relationship between observed coverage and estimated copy number, correcting for biases in amplification efficiency and GC content through this iterative feedback process
Solution Approach 2:
The patent transforms the analysis by changing from absolute depth of coverage measurements to relative depth of coverage ratios. By comparing coverage at different loci and normalizing for GC content and amplification efficiency, the system converts biased absolute measurements into corrected relative measurements that accurately reflect copy number variations
3Measurement precision
If more sequencing reads are obtained to improve coverage, then more data is available for analysis, but the cost and complexity of the process increases
Solution Approach 1:
The patent applies partial action by focusing sequencing efforts on specific genomic regions of interest rather than whole-genome sequencing. By targeting only the loci relevant to tumor copy number analysis, the system achieves sufficient detection precision with reduced sequencing depth and lower computational complexity compared to comprehensive genomic analysis
Data Source
AI summary
Methods are provided herein to improve automatic detection of copy number variation in nucleic acid samples. These methods provide improved approaches for determining baseline copy number of genetic loci within a sample, reduce variation due to features of genetic loci, sample preparation, and probe exhaustion.