Combined Size and Count Analysis for Fetal CNA Detection
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Solution Overview
Problem
Current noninvasive prenatal testing (NIPT) using cell-free DNA in maternal plasma struggles to accurately distinguish between fetal and maternal subchromosomal copy number aberrations (CNAs), leading to false-positive results and inability to determine if a fetus has inherited a CNA from its mother.
Innovation Solution
A combined size-based and count-based analysis approach is used to detect fetal subchromosomal copy number aberrations (CNAs) in maternal plasma. The count-based analysis identifies CNAs by counting DNA fragments, while the size-based analysis distinguishes between fetal and maternal DNA by analyzing the size distribution of DNA molecules, thereby determining the origin of the aberrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If count-based analysis is used to detect subchromosomal CNAs in maternal plasma, then detection sensitivity is improved, but specificity deteriorates because the method cannot distinguish between fetal and maternal DNA sources
Solution Approach 1:
The patent segments the DNA analysis into two independent components: count-based analysis for detecting CNAs and size-based analysis for determining DNA origin. By dividing the detection problem into separate analytical steps, the system can first identify potential aberrations through counting, then resolve the source ambiguity through size distribution analysis, thereby improving specificity without sacrificing sensitivity.
Solution Approach 2:
The patent introduces size-based analysis as an intermediary step between the count-based detection and the final diagnosis. This intermediary analysis examines the size distribution of DNA fragments to determine whether CNAs originate from the fetus or mother, serving as a mediating factor that resolves the ambiguity in source attribution while maintaining the sensitivity of the original detection method.
2Measurement precision
If more subchromosomal regions are analyzed to improve detection coverage, then detection sensitivity is improved, but false-positive results increase
Solution Approach 1:
The patent implements a feedback mechanism where size-based analysis results are used to validate and filter count-based detection results. By examining the size distribution of DNA fragments from each subchromosomal region, the system can feedback to confirm true positives and eliminate false positives, thereby maintaining high detection coverage while reducing false-positive rates through cross-validation.
3Ease of operation
If count-based analysis alone is used, then the testing process is simple, but the ability to determine fetal inheritance status is lost
Solution Approach 1:
The patent merges two complementary analysis approaches: count-based analysis for CNA detection and size-based analysis for origin determination. By combining these methods into a unified testing framework, the system maintains the simplicity of count-based detection while adding the informative capability to determine whether CNAs are fetal or maternal in origin, thereby preventing information loss.
Data Source
AI summary
An aberration in a fetal genome can be identified by analyzing a sample of fetal and maternal DNA. Classifications of whether an aberration (amplification or deletion) exists in a subchromosomal region are determined using count-based and size-based methods. The count classification and the size classification can be used in combination to determine whether only the fetus or only the mother, or both, have the aberration in the subchromosomal region, thereby avoiding false positives when the mother has the aberration and the fetus does not.