Liquid Biopsy MSI Classification Using Microsatellite Repeat Metrics
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Solution Overview
Problem
Conventional methods for detecting microsatellite instability in cancer using solid tissue biopsies are invasive, prone to sampling bias, and limited by spatial and temporal genetic heterogeneity, while liquid biopsies face challenges in accurately determining tumor fraction and signal-to-noise ratio, leading to inaccurate genomic alteration detection.
Innovation Solution
A computer-implemented method using novel metrics (percentage score, lower mean score, and likelihood score) to classify microsatellite stability from a liquid biopsy sample, combined with a classifier trained on solid tumor biopsy tissue, to improve accuracy in determining MSI status.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If solid tissue biopsies are used for detecting microsatellite instability, then measurement precision is improved, but ease of operation deteriorates due to invasive procedures
Solution Approach 1:
The patent uses liquid biopsy (blood-based cell-free DNA) as a non-invasive copy or surrogate for solid tissue biopsy. Instead of directly sampling tumor tissue through invasive procedures, the method analyzes circulating tumor DNA fragments in the blood that carry microsatellite instability signatures, providing an indirect but accurate representation of the tumor's genomic status.
2Ease of operation
If liquid biopsies are used for detecting microsatellite instability, then ease of operation is improved, but measurement precision deteriorates due to tumor fraction determination challenges
Solution Approach 1:
The patent transforms the measurement approach by shifting from direct tumor DNA analysis to analyzing the distribution patterns of microsatellite loci in cell-free DNA. Instead of attempting to determine tumor fraction directly, the method uses statistical parameters (distribution width, skewness, kurtosis) of microsatellite repeat lengths to infer microsatellite instability status, bypassing the tumor fraction determination problem.
Solution Approach 2:
The patent replaces the mechanical/biological challenge of separating and quantifying tumor DNA from normal DNA with a computational/statistical approach. By using algorithms to analyze the distribution characteristics of microsatellite repeat lengths and comparing them against reference distributions, the method substitutes physical separation challenges with mathematical modeling and pattern recognition.
3Ease of operation
If conventional liquid biopsy methods are used, then ease of operation is improved, but reliability deteriorates due to signal-to-noise ratio issues
Solution Approach 1:
The patent introduces microsatellite locus distribution patterns as an intermediary marker. Instead of directly detecting rare tumor DNA fragments amidst overwhelming normal DNA background, the method uses the collective distribution pattern of multiple microsatellite loci as a mediator signal. This intermediary approach amplifies the detectable signal by aggregating information across many loci, making the tumor signal distinguishable from normal DNA background.
Data Source
Figure 1A
Figure 1B
Figure 1C~1D
AI summary
Methods, systems, and software are provided for determining a microsatellite instability (MSI) status of a subject. Nucleotide sequences are obtained for cell-free DNA molecules from a liquid biopsy sample of the subject. The nucleotide sequences are used to determine, for each respective microsatellite locus in a plurality of predetermined microsatellite loci, one or more independent corresponding metrics, where each metric in the one or more metrics is determined at least in part by the distribution of the number of repeat units at the respective microsatellite locus. The one or more metrics are input into a classifier trained to distinguish between stable and unstable microsatellite loci, in order to classify the MSI status of the subject. In certain aspects, microsatellite stability metrics are compared against metrics from solid tumor samples and/or normal tissues. In certain aspects, the microsatellite stability metrics are determined relative to a subject-specific standard for microsatellite stability.