MRD Lesion Detection With Personalized Ultra-Deep Sequencing
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Solution Overview
Problem
Existing methods for detecting minimal residual disease (MRD) using circulating tumor DNA (ctDNA) face challenges such as inaccurate removal of repetitive sequences, high cycle number amplification errors, and inability to monitor high-evidence-level genes and sites, leading to insufficient sensitivity and specificity in predicting recurrence.
Innovation Solution
A method utilizing second-generation sequencing technology, combining whole exome sequencing with targeted drug gene panels, involves constructing tumor and blood cell DNA libraries, hybridization capture with mixed probes, and personalized combination panels to achieve differentiated sequencing depth, screening and filtering mutation signals, and using unique molecular identifiers for accurate detection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If multiple amplification reactions are performed to detect single nucleotide variants, then detection capability is improved, but amplification errors increase due to high cycle number
Solution Approach 1:
The patent extracts and removes repetitive sequences from the sequencing data before variant calling. By using tools like GATK's RemoveDuplicates and custom algorithms to identify and filter out reads containing repetitive elements, the method eliminates a major source of amplification errors while preserving true variants, thus resolving the contradiction between detection accuracy and error rate
Solution Approach 2:
The patent applies different quality filtering criteria to different regions of the sequencing data. High-stringency filtering is applied to regions with repetitive sequences known to generate artifacts, while standard filtering is applied to unique regions. This localized quality control maintains detection accuracy in problematic regions while preserving sensitivity in reliable regions
2Measurement precision
If conventional WES panels are used to determine tissue sites, then cost is reduced, but sensitivity for monitoring high-evidence-level genes is insufficient
Solution Approach 1:
The patent segments the detection system into two parts: a comprehensive WES panel for initial broad screening and a customized high-evidence gene panel for focused monitoring. The WES panel captures all possible variants, while the customized panel (derived from WES data but focused on high-evidence genes) provides sensitive monitoring of clinically relevant mutations, resolving the contradiction between sensitivity and panel complexity
Solution Approach 2:
The patent performs preliminary whole exome sequencing to identify all patient-specific mutations and their frequencies before constructing the customized monitoring panel. This preliminary action allows the system to focus subsequent monitoring on high-evidence-level genes with known clinical significance, improving sensitivity while controlling panel complexity through informed selection
3Measurement precision
If personalized panel tracking is performed, then patient-specific mutation monitoring is improved, but ability to detect second primary mutations is lost
Solution Approach 1:
The patent designs the sequencing and analysis system to serve multiple functions simultaneously: it detects patient-specific recurrence mutations, identifies second primary tumors, and monitors tumor evolution. By using a unified approach that analyzes all mutations in the context of the patient's cancer history and compares them against normal controls, the system maintains versatility while focusing on patient-specific concerns, resolving the contradiction between specialized monitoring and comprehensive detection
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enhances detection sensitivity and accuracy by identifying patient-specific mutation spectra, detecting second primary mutations, and monitoring tumor evolution, while reducing false positives and negatives, and achieving ultra-high depth sequencing at controlled costs.
Implementation Method 1
mix the two libraries with equal mass ratio, and use WDC probe for hybridization capture to obtain captured DNA library
Data Source
AI summary
The current application reveals a method, apparatus, device, and storage medium for detecting micro residual lesions, falling within the domain of medical detection technology. This method is based on differentiated deep whole-exome/targeted drug sequencing and tissue-blood cell-plasma co-capture technology, and 100,000× ultra-high depth personalized/high evidence hotspot combination panel sequencing to evaluate tiny residual lesions and tumor evolution/second primary in plasma samples. It resolves the challenges of existing techniques, such as elevated tissue detection thresholds, restricted tracking locations, inadequate detection sensitivity and precision, or elevated costs when ctDNA concentrations in the bloodstream are minimal. Furthermore, it surmounts the challenge of simultaneously achieving personalized tracking detection and monitoring tumor evolution or second/primary detection. It markedly boosts the precision of forecasting the likelihood of recurrence following patient therapy within a restricted budget.