Cell-Free DNA Fragmentation Analysis for Early Tumor Detection
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Solution Overview
Problem
Current methods for detecting tumors using cell-free DNA in plasma lack sensitivity and specificity, particularly at early stages, leading to high false positive and false negative results due to low tumor DNA amounts and low prevalence of the condition.
Innovation Solution
A method involving two assays: a first assay measuring copy number of cell-free nucleic acid from a pathogen and a second assay with massively parallel sequencing to generate sequence reads, determining alignment to a reference genome, and analyzing size and proportion of nucleic acid molecules to improve sensitivity and specificity for tumor detection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a single assay measuring copy number of cell-free nucleic acid is used for tumor detection, then the detection process is simple and fast, but the sensitivity and specificity are low leading to high false positive and false negative rates
Solution Approach 1:
The detection method is divided into two distinct assays: a first assay for measuring copy number of cell-free nucleic acid, and a second assay for massively parallel sequencing to generate sequence reads. This segmentation allows each assay to contribute different types of information, with the first assay providing quantitative data and the second assay providing sequence-specific data, thereby improving overall sensitivity and specificity while maintaining manageable complexity through modular design
Solution Approach 2:
The patent combines results from two different assays (copy number measurement and massively parallel sequencing) to make the final tumor detection determination. By merging the data from both assays and requiring concordance between them, the method achieves higher reliability in detecting tumors while reducing false positives and false negatives compared to using either assay alone
2Measurement precision
If massively parallel sequencing is performed to improve detection accuracy, then the positive predictive value increases, but the time and cost of the detection process increase
Solution Approach 1:
The first assay measuring copy number of cell-free nucleic acid is performed as a preliminary screening step before the more time-consuming massively parallel sequencing. This preliminary action filters samples that are likely to be positive, allowing the second assay to be focused on a smaller subset of samples, thereby reducing the overall time loss while maintaining high measurement precision for the final detection
Data Source
AI summary
Methods are provided to improve the positive predictive value for cancer detection using cell-free nucleic acid samples. Various embodiments are directed to applications (e.g., diagnostic applications) of the analysis of the fragmentation patterns and size of cell-free DNA, e.g., plasma DNA and serum DNA, including nucleic acids from pathogens, including viruses. Embodiments of one application can determine if a subject has a particular condition. For example, a method of present disclosure can determine if a subject has cancer or a tumor, or other pathology. Embodiments of another application can be used to assess the stage of a condition, or the progression of a condition over time. For example, a method of the present disclosure may be used to determine a stage of cancer in a subject, or the progression of cancer in a subject over time (e.g., using samples obtained from a subject at different times).