Cell-Free Nucleic Acid Phasing for Reliable MRD Detection
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Solution Overview
Problem
Current methods for detecting minimal residual disease (MRD) in cancer patients using cell-free nucleic acids are limited by low input DNA amounts and high background error rates, leading to false-negative results, particularly in diffuse large B-cell lymphoma, colon cancer, and breast cancer.
Innovation Solution
A method involving sequencing data processing to identify phased variants in cell-free nucleic acids, with a focus on phased variants separated by at least one nucleotide, and analyzing these variants to determine the condition of a subject, potentially aided by insertions or deletions (indels), achieving enhanced sensitivity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If current methods for detecting minimal residual disease using cell-free nucleic acids are applied, then ease of obtaining biological specimens is improved, but detection reliability deteriorates due to false-negative results
Solution Approach 1:
The method segments the detection task by analyzing multiple phased variants at different genomic positions simultaneously. Instead of relying on a single variant or region, the system phases multiple variants relative to a reference sequence and evaluates their combined presence, thereby reducing false negatives while maintaining the ease of using cell-free nucleic acid specimens
Solution Approach 2:
The invention changes the detection parameters by introducing phased variant analysis with minimum frequency thresholds (e.g., at least 10% frequency). This parameter adjustment allows the system to distinguish true positive signals from background noise more effectively, improving detection reliability without compromising the non-invasive sampling approach
2Measurement precision
If sequencing sensitivity is increased to detect lower frequencies of cancer-derived nucleic acids, then detection precision is improved, but background error rates worsen
Solution Approach 1:
The method applies local quality by analyzing phased variants at specific genomic positions with distinct frequency thresholds. Each phased variant is evaluated independently at its local genomic context, allowing the system to distinguish true cancer signals from background errors based on their specific frequency patterns and positional characteristics
Solution Approach 2:
The system incorporates feedback mechanisms through iterative phasing and validation. By repeatedly phasing variants relative to the reference sequence and checking for consistency across multiple reads, the system can distinguish true low-frequency cancer signals from sequencing errors, thereby improving detection precision while controlling background error rates
3Reliability
If multiple phased variants are analyzed simultaneously to improve detection sensitivity, then detection sensitivity is improved, but device complexity increases
Solution Approach 1:
The invention merges multiple phased variant analyses into a unified detection framework. By combining the phasing of multiple variants at different positions and evaluating them collectively against the reference sequence, the system achieves high detection sensitivity while managing complexity through integrated computational approaches rather than separate analysis steps
Data Source
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AI summary
Processes and materials to detect cancer, transplant rejection, or fetal genetic abnormalities from a biopsy are described. In some cases, nucleic acid molecules, such as cell-free nucleic acids, can be sequenced, and the sequencing result can be utilized to detect sequences indicative of a neoplasm, transplant rejection, or fetal genetic abnormality. Detection of somatic variants occurring in phase and/or insertions and deletions (indels) can indicate the presence of cancer, transplant rejection, or fetal genetic abnormalities in a diagnostic scan, and a clinical intervention can be performed.