NIPT Sample Qualification via Fetal Fraction and Read Representation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Non-Invasive Prenatal Testing (NIPT) methods face challenges in determining fetal aneuploidy status due to low fetal fraction in cell-free DNA, leading to high 'no call' rates and unnecessary repeated sampling, as current methods disregard samples with fetal fraction below the Limit of Detection (LoD) regardless of read representation of a chromosome.
Innovation Solution
A method that assesses both fetal fraction and read representation of a chromosome to determine the suitability of a sample for fetal aneuploidy status, using specific criteria to qualify samples for trisomy or monosomy analysis, thereby reducing the 'no call' rate and avoiding unnecessary sample dismissal.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If samples with fetal fraction below LoD are discarded regardless of read representation, then the false positive rate is controlled, but the no call rate increases to 5%-8%
Solution Approach 1:
The patent changes the decision parameters from a single fetal fraction threshold to a dual-parameter system combining fetal fraction with chromosome read representation. This allows samples to be evaluated based on multiple parameters simultaneously, transforming the binary discard/analyze decision into a more nuanced classification that reduces false positives while maintaining high detection rates.
Solution Approach 2:
The patent adds a new dimension to the decision-making process by incorporating chromosome read representation as a second parameter. Instead of relying solely on fetal fraction (one dimension), the system now evaluates samples in a two-dimensional parameter space, allowing for more accurate classification and reducing the no call rate while controlling false positives.
2Ease of operation
If a single fetal fraction threshold is used to determine sample suitability, then the method is simple to implement, but the detection rate decreases due to high no call rates
Solution Approach 1:
The patent transitions from a single-parameter threshold system to a dual-parameter evaluation system. The implementation remains relatively simple by establishing predefined criteria for the combination of fetal fraction and read representation, making the increased complexity manageable while significantly improving detection rates.
Solution Approach 2:
The patent segments the sample evaluation process into distinct criteria: fetal fraction assessment, read representation analysis, and combined qualification determination. This segmentation allows each parameter to be evaluated independently according to its own standards, then integrated into a final decision, maintaining clarity and ease of implementation.
3Reliability
If samples are reassessed using both fetal fraction and read representation, then the detection rate increases to 99%-100%, but the analysis complexity increases
Solution Approach 1:
The patent introduces a second parameter (read representation) to complement fetal fraction analysis. By defining specific criteria for how these parameters combine to qualify samples, the system achieves near-perfect detection rates while managing analysis complexity through structured evaluation rules.
Solution Approach 2:
The patent implements a feedback mechanism where samples initially rejected based on fetal fraction alone are reassessed using read representation data. This feedback loop allows the system to correct potential false rejections, achieving high detection rates by leveraging additional information from the sequencing data.
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present application relates to Non-Invasive Prenatal Testing (NIPT). Particularly, the present application relates to methods for determining whether or not a sample obtained from a pregnant subject is qualified for determining the fetal aneuploidy status. In addition, the present application relates to methods for determining the limit of detection (LoD) for trisomy and the limit of detection for monosomy, respectively, on a chromosome within the read-counting approach to the non-invasive prenatal testing.