cfDNA Methylome Atlas Deconvolution for Tissue-Origin Detection
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Solution Overview
Problem
Existing methods for determining the tissue origin of cell-free DNA (cfDNA) are limited in accurately identifying the source of cfDNA molecules, especially when they constitute a small fraction of the total DNA, which is crucial for diagnosing conditions like neurodegenerative, inflammatory, or ischemic diseases, and monitoring tissue-specific cell death in cancer and drug toxicity.
Innovation Solution
A method involving the creation of a methylome atlas using the 100 most uniquely methylated and unmethylated sites for each cell type or tissue, combined with DNA methylation measurement and comparison, allows for accurate assignment of cfDNA origin by comparing these sites to a comprehensive methylome atlas.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing methods for determining tissue origin of cfDNA are used, then the process is simpler, but the accuracy of identifying cfDNA source is insufficient
Solution Approach 1:
The patent applies preliminary action by constructing a comprehensive methylome atlas in advance that contains methylation profiles from multiple tissue types. This pre-built reference database enables accurate cfDNA origin identification without requiring complex real-time analysis, as the comparison framework is established beforehand.
Solution Approach 2:
The patent utilizes parameter changes by focusing on specific methylation markers (CpG sites) that exhibit tissue-specific methylation patterns. By measuring methylation levels at these selected parameters rather than analyzing the entire genome, the method achieves high accuracy while maintaining practical feasibility.
2Measurement precision
If comprehensive methylome atlas with many methylated sites is used, then the identification accuracy improves, but the measurement and analysis time increases
Solution Approach 1:
The patent extracts and focuses on the most informative methylation markers - specifically the 100 most differentially methylated CpG sites across tissue types. By selecting only these key markers rather than analyzing all possible methylation sites, the method achieves high identification precision while significantly reducing measurement and analysis time.
Solution Approach 2:
The patent applies local quality by identifying and measuring methylation at specific CpG sites that have high discriminatory power for tissue origin identification. Rather than uniform analysis across the genome, the method concentrates measurement resources on locally optimized markers that provide maximum information for the specific task of cfDNA deconvolution.
3Reliability
If cfDNA constitutes a small fraction of total DNA, then the diagnostic information for tissue-specific cell death is more specific, but the detection sensitivity becomes insufficient
Solution Approach 1:
The patent overcomes the detection difficulty by measuring methylation status at specific CpG sites that serve as sensitive markers for tissue origin. Even when cfDNA constitutes a small fraction of total DNA, the tissue-specific methylation patterns at these markers remain detectable, enabling reliable identification of the originating tissue type.
Solution Approach 2:
The patent uses tissue-specific methylation patterns as an intermediary signal that amplifies the detectability of low-abundance cfDNA. By comparing methylation levels at multiple CpG sites against the reference atlas, the method can reliably identify tissue origin even when the cfDNA signal is weak, effectively using methylation markers as mediators to enhance detection sensitivity.
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
Enables precise identification of the tissue or cell type of origin for cfDNA, even when it constitutes a small percentage of the total DNA, facilitating early diagnosis of conditions and monitoring tissue-specific cell death.
Implementation Method 1
measuring DNA methylation of the cfDNA
Data Source
AI summary
Methods of determining the origin of cell free DNA (cfDNA) and for detecting death of a cell type or tissue in a subject by determining the origin of cfDNA in the subject are provided. Computer program products, computerized methods and computerized systems for doing same, as well as methods for constructing a methylome atlas, are also provided.