Mixed-Sample Genetic Assay Combining Source Contribution and CNV Detection
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Solution Overview
Problem
Current diagnostic techniques face challenges in accurately determining copy number variation (CNV) in mixed biological samples, particularly in identifying low levels of nucleic acid from one source amidst a higher background from another source.
Innovation Solution
A single assay system utilizing non-polymorphic and polymorphic detection methods to determine source contribution and copy number variations (CNVs) from a single source within a mixed sample, employing amplification and detection of selected loci to calculate source contribution and identify CNVs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If a single assay system is used to detect CNV in mixed samples, then the complexity of multiple assays is reduced, but the precision of detecting low-level nucleic acid from one source in the background of another source deteriorates
Solution Approach 1:
The assay system segments the detection process into two distinct detection modes: non-polymorphic detection for determining source contribution (e.g., fetal fraction) and polymorphic detection for identifying CNVs. This segmentation allows each detection mode to be optimized for its specific purpose while operating within a unified assay platform, thereby maintaining measurement precision without requiring separate complex assay systems.
Solution Approach 2:
The single assay system is designed with multi-functionality to perform both non-polymorphic and polymorphic detections using the same sample and reagents. The system can detect both the overall source contribution and specific CNV events simultaneously, eliminating the need for multiple separate assays while maintaining detection precision through integrated signal processing and analysis algorithms.
2Loss of information
If non-polymorphic and polymorphic detection are combined in a single assay, then comprehensive genetic information is obtained, but the difficulty of detecting and measuring increases
Solution Approach 1:
The detection process is segmented into distinct analytical steps: first, non-polymorphic markers are analyzed to determine source contribution ratios; second, polymorphic markers are analyzed to identify CNVs. This segmentation of the analytical process reduces the complexity of individual measurements while maintaining comprehensive genetic information through the combination of both detection types.
Solution Approach 2:
The assay uses intermediate calculations and reference comparisons to bridge the complexity of simultaneous non-polymorphic and polymorphic detections. By first establishing source contribution through non-polymorphic detection and then using this information as a basis for polymorphic CNV analysis, the system mediates the complexity through a stepwise analytical approach.
3Measurement precision
If source contribution determination is performed before CNV identification, then accurate CNV detection is enabled, but the time required for diagnosis increases
Solution Approach 1:
The assay performs preliminary determination of source contribution through non-polymorphic detection before proceeding to CNV identification through polymorphic detection. This preliminary action establishes the baseline information needed for accurate CNV interpretation, ensuring measurement precision while organizing the diagnostic process in an efficient sequential manner that minimizes total diagnosis time.
Solution Approach 2:
The assay maintains continuous useful action by processing both non-polymorphic and polymorphic detections in an integrated workflow using the same sample preparation and initial processing steps. The transition from source contribution determination to CNV identification is seamless, with results from the first detection type immediately informing the second, thereby minimizing idle time and maintaining diagnostic efficiency.
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 accurate determination of CNVs and source contribution in mixed samples, providing valuable genetic information for clinical decisions, such as disease diagnosis, prognosis, and treatment options.
Implementation Method 1
introducing a first set of fixed sequence oligonucleotides to a mixed sample under conditions that allow the fixed oligonucleotides to specifically hybridize to complementary regions on one or more loci in or associated with a genomic region
Implementation Method 2
ligating the hybridized oligonucleotides to create contiguous ligation products complementary to the selected loci
Implementation Method 3
amplifying the contiguous ligation products to create amplification products
Data Source
AI summary
The present invention provides assay systems and methods for detection of copy number variation at one or more loci and polymorphism detection at one or more loci in a mixed sample from an individual.