Genotyping Particle Suspension Hybridization Algorithm

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Solution Overview

Problem

Existing DNA-array technologies face challenges in simultaneously detecting genetic variations with high sensitivity, specificity, and reproducibility, limiting their application in clinical diagnosis due to the need for amplification and purification reactions and the lack of high specificity and sensitivity in differential hybridization methods.

Innovation Solution

A method involving particle suspensions with oligonucleotide probe pairs attached to solid supports, where the intensity of hybridization signals is analyzed using a sequential algorithm to determine genotypes, allowing for the detection of genetic variations such as SNPs, insertions, and deletions with high specificity and reproducibility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If differential hybridization methods are used for genotyping, then the detection of genetic variations can be performed, but the sensitivity and specificity are insufficient for clinical diagnosis

Engineering Contradiction:

Improvedetection sensitivity and specificityVSAvoidreproducibility for clinical diagnosis

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The invention divides the genotyping process into separate functional modules: particle suspension for sample presentation, oligonucleotide probes for specific binding, and sequential algorithm for data interpretation. This segmentation allows each component to be optimized independently, improving overall detection precision and reliability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The sequential algorithm processes hybridization signals through multiple computational steps including background subtraction, signal normalization, and genotype classification. This feedback-based computational approach enhances the reliability of genotyping results by continuously refining the interpretation of hybridization data.

Inventive Principle:

Principle #23Feedback

2Measurement precision

If amplification and purification reactions are required for genotyping, then genetic variations can be detected, but the process complexity increases and limits clinical application

Engineering Contradiction:

Improvegenetic variation detectionVSAvoidamplification and purification process

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The method performs preliminary capture of target DNA sequences on particle surfaces before hybridization with oligonucleotide probes. This preliminary concentration and purification step occurs automatically during the assay setup, eliminating the need for separate amplification and purification reactions while maintaining detection precision.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The particle suspension system automatically concentrates and purifies target sequences through specific binding to particle surfaces. The system serves itself by using the particles' inherent binding capacity to perform purification functions without requiring external amplification or purification equipment.

Inventive Principle:

Principle #25Self-service

3Productivity

If high density DNA-chips are used with in situ synthesized oligonucleotides, then the detection capacity increases, but the manufacturing complexity and cost increase

Engineering Contradiction:

Improvedetection capacity for multiple genetic variationsVSAvoidphotolithography and in situ synthesis

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The invention uses particle suspensions that can be easily replicated and distributed. Each particle carries copies of the necessary binding sites, allowing high-throughput detection without the complex manufacturing processes required for solid-supported arrays. This copying approach maintains detection capacity while simplifying manufacturing.

Inventive Principle:

Principle #26Copying

Solution Approach 2:

Instead of immobilizing probes on a solid support as in traditional DNA-chips, the invention inverts the approach by suspending particles with probes in solution. This inversion eliminates the need for complex photolithography and in situ synthesis, allowing probes to be attached to particles using simpler chemistry while maintaining high detection capacity.

Inventive Principle:

Principle #13The other way round (Inversion)

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 sensitive, specific, and reproducible genotyping of genetic variations, making it suitable for clinical genetic diagnosis by accurately determining genotypes associated with conditions like IBD, erythrocyte antigens, and adverse reactions to pharmaceuticals.

Implementation Method 1

one probe in each pair being capable of hybridising to genetic variation A and the other probe in each pair being capable of hybridising to genetic variation B

Methodology Applied

Scientific EffectHybridization: Chemical Bonding

Data Source

PatentUS8153363B2Methods and products for in vitro genotyping

Publication Date: 2012.04.10 PROGENIKA BIOPHARMA SA

AI summary

An in vitro method for genotyping genetic variations in an individual, and products for use in the method.