Cell-Free Nucleic Acid Sequencing for Phased Variant 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 insufficient detection of residual disease and 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 cell-free nucleic acid molecules with phased variants relative to a reference genomic sequence, allowing for enhanced detection of cancer-derived nucleic acids by analyzing phased variants and insertions or deletions (indels), with a limit of detection as low as 1 out of 50,000 observations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current methods are used for detecting minimal residual disease, then the detection process is simple, but the sensitivity is insufficient leading to false-negative results
Solution Approach 1:
The patent segments the detection task by analyzing multiple phased variants separately rather than treating all variants equally. The method identifies and analyzes phased variants at different positions relative to reference sequences, allowing selective detection of cancer-derived nucleic acids with higher precision and reduced false negatives.
Solution Approach 2:
The patent changes the detection parameters by using phased variants separated by at least one nucleotide as a distinguishing feature. This parameter change enables the system to achieve a limit of detection of 1 out of 50,000 observations, significantly improving sensitivity while maintaining reliability.
2Measurement precision
If sequencing depth is increased to improve detection sensitivity, then the limit of detection improves, but the background error rate increases
Solution Approach 1:
The patent extracts and focuses analysis on a specific subset of variants - those that are phased and separated by at least one nucleotide. By taking out only these informative variants for analysis, the method achieves high detection precision (1 out of 50,000) while minimizing background errors from random sequencing variations.
Solution Approach 2:
The patent applies local quality filtering by examining the specific properties of phased variants at different positions. Not all variants are treated equally; only those meeting the phased variant criteria with specific separation distances are analyzed, improving the signal-to-noise ratio and reducing background error rates.
Data Source
AI summary
Processes and materials to detect cancer, transplant rejection, or fetal genetic abnormalities from a biopsy are described. In some cases, 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.