Separate Hybridization Arrays for Copy Number Imbalance Detection
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for detecting genetic abnormalities in embryos, such as arrayCGH, face challenges including poor matching of test and reference samples, leading to assay failures, noise, and increased costs, especially in preimplantation genetic screening (PGS) where the sex of the sample is unknown and mosaicism is a concern.
Innovation Solution
A method using single channel array comparative genomic hybridization (arrayCGH) where a test DNA sample is hybridized to one array, and multiple reference DNA samples, each with known copy number changes, are hybridized to separate arrays, allowing for the comparison of signal intensities to determine copy number imbalances without the need for contrasting dyes and enabling selection of an optimal reference DNA pairing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional arrayCGH is used with co-hybridization of test and reference samples on the same array, then copy number detection can be performed, but poor matching of test and reference samples leads to assay failure, noise, and increased costs
Solution Approach 1:
The patent divides the hybridization process into separate channels: test samples are hybridized to one array while reference samples are hybridized to separate arrays. This segmentation eliminates the poor matching problem inherent in co-hybridization systems, as each sample type is processed independently under optimized conditions, thereby improving assay reliability without requiring complex co-hybridization control mechanisms
Solution Approach 2:
The patent introduces a reference sample library as an intermediary component. Instead of directly co-hybridizing test and reference samples (which causes matching problems), the system uses a pre-characterized library of reference samples with known copy number changes. This intermediary allows indirect comparison through signal intensity analysis, eliminating the harmful effects of direct sample interaction while maintaining the ability to detect copy number imbalances
2Measurement precision
If multiple reference DNA samples are hybridized to separate arrays, then optimal reference pairing can be selected and assay quality improved, but the number of arrays and hybridization steps increases
Solution Approach 1:
The patent performs preliminary hybridization of multiple reference DNA samples to separate arrays before the actual test sample analysis. This preliminary action creates a library of reference data with known copy number changes, which can then be used to optimally pair with test samples. By preparing reference arrays in advance, the system enables precise copy number detection through comparison while the high-throughput nature of array hybridization maintains overall productivity
Solution Approach 2:
The patent changes the hybridization parameter from simultaneous co-hybridization to separate hybridization events. By hybridizing test and reference samples to different arrays under identical or optimized conditions, the system achieves better signal intensity matching and reduces noise. This parameter change allows for more precise measurement of copy number imbalances while the modular array approach maintains throughput 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
This approach reduces the risk of assay failure, increases assay quality and accuracy, and allows for the determination of copy number imbalances in genomic DNA, improving the reliability of PGS by using separate hybridization arrays for test and reference samples, thus overcoming the limitations of conventional arrayCGH.
Implementation Method 1
hybridizing the labeled test DNA to a first hybridization array, labeling first reference genomic DNA from a reference sample, or an amplification product thereof, to form labeled first reference DNA, hybridizing the labeled first reference DNA to a second hybridization array
Data Source
AI summary
A method for determining the presence of a copy number imbalance in genomic DNA of a test sample is provided. The method can separately measure hybridization of a single test sample to a first hybridization array and hybridization of a plurality of reference samples to a plurality of other, respective test arrays. A determination of copy number can be based on the best fit reference array, relative to the test array. The best fit can be determined based on the closest or most similar signal-to-noise ratio of the measured signals.