Aneuploidy Detection Using Diploid Bias Models

Solution Overview

Problem

Current methods for detecting aneuploidy in chromosome or chromosome segments are costly and require a high number of DNA sequencing reads, limiting their accessibility and accuracy in diagnostics such as prenatal and cancer testing.

Innovation Solution

The method involves setting a bias model using genetic data from diploid samples to adjust and normalize data from test samples, reducing the need for extensive sequencing by identifying diploid samples within a parallel analysis and using them as controls to determine aneuploidy with fewer reads.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If high levels of DNA sequencing are used to detect copy number variation, then measurement precision is improved, but cost and the number of reads required increase

Engineering Contradiction:

Improveaneuploidy detection accuracyVSAvoidnumber of sequencing reads

Core Design Contradiction:

Measurement precisionVSQuantity of substance

Solution Approach 1:

The method performs preliminary identification of diploid samples from the same batch before final aneuploidy detection. By pre-selecting samples with normal diploid genomes through initial analysis, the system establishes reliable control groups that enable accurate detection in subsequent steps with reduced sequencing depth, thus resolving the contradiction between detection accuracy and sequencing read requirements

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

Diploid samples serve as intermediary control groups between the sequencing process and final aneuploidy diagnosis. These control samples provide reference data for comparing test samples, enabling accurate aneuploidy detection with fewer reads by using the diploid samples as mediators to establish baseline expectations for normal genomic patterns

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If high levels of DNA sequencing are used to detect copy number variation, then measurement precision is improved, but cost increases

Engineering Contradiction:

Improveaneuploidy detection accuracyVSAvoidsequencing cost

Core Design Contradiction:

Measurement precisionVSLoss of energy

Solution Approach 1:

The method performs preliminary identification of diploid samples from the same batch before final aneuploidy detection. By pre-selecting samples with normal diploid genomes through initial analysis, the system establishes reliable control groups that enable accurate detection in subsequent steps with reduced sequencing depth, thus resolving the contradiction between detection accuracy and sequencing read requirements

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The system uses samples from the same batch to serve as their own controls. By identifying diploid samples within the batch and using them for comparison, the method eliminates the need for separate external control samples, reducing overall sequencing requirements and cost while maintaining detection accuracy

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS12260934B2Systems and methods for detection of aneuploidy

Publication Date: 2025.03.25 NATERA INC

AI summary

Provided herein are improved methods for detecting aneuploidy in a sample. The methods in certain embodiments are used for the analysis of circulating DNA in serum samples, such as circulating fetal DNA or circulating tumor DNA. In certain embodiments, chromosome or chromosome segments of interest are used to set a bias model and/or a control value for a z-score determination, in illustrative examples without the use of a control chromosome.