cfDNA Target Capture Strategy for Deep Variant and Broad Epigenetic Reads
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Solution Overview
Problem
Existing methods for isolating cell-free DNA in liquid biopsies are inadequate due to low concentration and heterogeneity, leading to challenges in achieving accurate and sensitive analysis.
Innovation Solution
A method for isolating cell-free DNA that captures sequence-variable and epigenetic target regions with different yields, allowing for deep sequencing in the sequence-variable set and shallow, broad coverage in the epigenetic set, using target-specific probes to enhance capture efficiency and accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If equal capture yield is used for both sequence-variable and epigenetic target regions, then data generation is balanced, but sequencing depth becomes insufficient for accurate genotypic determination in sequence-variable regions
Solution Approach 1:
The patent applies local quality by differentiating the sequencing depth between different target region types. Sequence-variable target regions receive deeper sequencing (higher read depth) to enable accurate genotypic determination, while epigenetic target regions receive shallower sequencing sufficient for detecting epigenetic modifications. This localized differentiation of sequencing intensity optimizes both accuracy and resource utilization.
2Measurement precision
If deep sequencing is applied to both target region sets, then sequence determination accuracy improves, but data redundancy increases and analysis efficiency decreases
Solution Approach 1:
The patent implements local quality by applying deep sequencing selectively only to sequence-variable target regions where accurate genotypic determination is critical, while using shallower sequencing for epigenetic target regions where sequence accuracy is less critical. This localized approach eliminates redundant deep sequencing of epigenetic regions, thereby improving overall data analysis efficiency.
3Productivity
If shallow sequencing is used for both target region sets, then data generation cost is reduced, but accuracy of genotypic determination in sequence-variable regions deteriorates
Solution Approach 1:
The patent resolves this contradiction by applying local quality through differential sequencing depth. Sequence-variable target regions receive deep sequencing to ensure accurate genotype detection, while epigenetic target regions receive shallow sequencing that is sufficient for their analysis needs. This localized strategy maintains cost efficiency while ensuring high accuracy where required.
4Adaptability or versatility
If broad coverage is applied to both target region sets, then epigenetic analysis completeness improves, but sequence determination accuracy in sequence-variable regions decreases due to diluted read depth
Solution Approach 1:
The patent applies local quality by differentiating coverage strategies: sequence-variable target regions receive focused deep sequencing to maintain high read depth and accuracy, while epigenetic target regions receive broad shallow coverage to capture comprehensive epigenetic modifications. This localized differentiation allows both high accuracy and broad coverage to coexist in their respective domains.
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 enables more accurate and efficient isolation of cell-free DNA, facilitating deeper sequencing of sequence-variable regions and broader epigenetic analysis, improving cancer detection and recurrence monitoring.
Implementation Method 1
contacting the cfDNA with a set of target-specific probes... wherein the set of target-specific probes comprises target-binding probes specific for a sequence-variable target region set and target-binding probes specific for an epigenetic target region set
Data Source
AI summary
Disclosed herein are compositions and methods for isolating DNA, such as cell-free DNA (cfDNA). In some embodiments, the cell-free DNA is from a subject having or suspected of having cancer and/or the cell-free DNA comprises DNA produced by a tumor. In some embodiments, the DNA isolated by the method is captured using a sequence-variable target region set and an epigenetic target region set, wherein the sequence-variable target region set is captured with a greater capture yield than the epigenetic target region set. In some embodiments, captured cfDNA of the sequence-variable target region set is sequenced to a greater depth of sequencing than captured cfDNA of the epigenetic target region set.