Tumor Fraction Estimation Using Solid and Liquid Variant Profiles
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for estimating tumor fraction in cancer patients are inadequate, particularly when sequencing coverage is low, and there is a need for improved techniques to determine tumor fraction using both liquid and solid tumor samples for more accurate and less invasive cancer detection.
Innovation Solution
A method using both cell-free DNA from liquid biological samples and solid tumor tissue samples, employing Bayesian approaches and estimated smoothed noise rates to calculate tumor fraction, accounting for sequencing errors and other factors, with the use of whole-genome sequencing or targeted sequencing to determine variant allele counts and fractions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional tumor fraction estimation methods are used, then the process is simpler, but reliability is poor especially at low sequencing coverage
Solution Approach 1:
The method segments the tumor fraction estimation process into distinct components: (1) obtaining sequencing data from both liquid biopsy and solid tumor samples, (2) identifying variants present in both samples, (3) calculating variant allele fractions separately for each sample type, and (4) using the solid tumor VAF as a reference to correct the liquid biopsy VAF. This segmentation allows each component to be optimized independently, improving overall reliability while managing complexity through structured methodology.
Solution Approach 2:
The solid tumor sequencing data serves as an intermediary reference that mediates the tumor fraction estimation from liquid biopsy data. By using variants identified in the solid tumor sample as a known reference point, the method corrects for sequencing errors and biases in the liquid biopsy sample, thereby improving the reliability of tumor fraction estimates without requiring direct measurement of pure tumor DNA from the liquid sample.
2Measurement precision
If liquid biopsy alone is used, then the method is less invasive, but measurement precision is insufficient at low sequencing coverage
Solution Approach 1:
The method merges data from two different sample types: liquid biopsy (blood plasma) and solid tumor tissue. By combining the variant information from both sources, the approach achieves higher measurement precision than liquid biopsy alone would provide, while maintaining the less invasive advantage of liquid biopsy for the primary tumor fraction assessment. The solid tumor sample serves to validate and correct the liquid biopsy measurements.
3Measurement precision
If sequencing coverage is increased, then measurement precision improves, but use of energy and cost increase
Solution Approach 1:
The method applies partial sequencing coverage to the solid tumor sample rather than requiring high-depth sequencing of both samples. By using the solid tumor data primarily for variant identification and reference VAF calculation rather than for comprehensive tumor fraction measurement, the approach achieves sufficient measurement precision without the excessive energy consumption that would result from high-coverage sequencing of both sample types.
Data Source
AI summary
Systems and methods for cancer subject tumor fraction estimation comprise obtaining a first plurality of nucleic acid fragment sequences from the subject's liquid biological sample. The first plurality of sequences represent cell-free nucleic acids in the liquid sample. A second plurality of nucleic acid fragment sequences is obtained from the subject's tumor sample. The second plurality of sequences represent nucleic acid molecules in the tumor. Smoothed noise rates, each determined using nucleic acid fragment sequences from non-cancer samples mapping to a corresponding allele position in a plurality of allele positions, are obtained. Variant allele counts and coverages are determined for the allele positions using the first plurality of sequences. Solid variant allele fractions are determined for the plurality of allele positions using the second plurality of sequences. The subject tumor fraction is calculated using the smoothed noise rates, variant allele counts, coverages, and solid variant allele fractions.