Non-Invasive Prenatal Screening with Bin-Level False-Positive Filtering
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Solution Overview
Problem
Current non-invasive prenatal screening (NIPS) methods using cell-free fetal DNA (cff DNA) produce false-positive results, leading to unnecessary invasive procedures and potential miscarriage risks, prompting some women to terminate pregnancies without further testing.
Innovation Solution
The method involves dividing chromosomes into bins, obtaining bin-specific test parameters, plotting these parameters against chromosomal locations to create an ideogram, and detecting false-positives by identifying consistent bin-specific test parameters across less than a substantial portion of the chromosome, improving positive predictive value (PPV) through techniques like sequencing and Z-score analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current NIPS methods are used to detect fetal aneuploidy, then screening can be performed non-invasively, but false-positive results occur leading to unnecessary invasive procedures and potential miscarriage risks
Solution Approach 1:
The patent divides the chromosome into multiple bins (e.g., 100 bins) along its length, allowing analysis of DNA fragment abundance at specific chromosomal regions. This segmentation enables detection of whether aneuploidy is present throughout the chromosome or only in specific regions, thereby reducing false-positives from maternal chromosomal variations while maintaining sensitivity for true fetal aneuploidies.
Solution Approach 2:
The patent analyzes bin-specific test parameters at different chromosomal locations to determine the pattern of DNA fragment abundance. By examining local variations across bins, the method can distinguish between uniform chromosomal overrepresentation (indicative of fetal aneuploidy) and localized variations (indicative of maternal chromosomal variations), thereby improving diagnostic accuracy.
2Reliability
If bin-specific test parameters are analyzed across the entire chromosome, then comprehensive aneuploidy detection is achieved, but computational complexity and analysis time increase
Solution Approach 1:
By dividing the chromosome into discrete bins, the patent transforms the complex problem of analyzing entire chromosomal sequences into multiple smaller, manageable units. Each bin can be processed independently, and results can be aggregated to determine overall chromosomal representation, thereby reducing computational complexity while maintaining comprehensive detection capability.
Solution Approach 2:
The patent analyzes only the necessary bins that show abnormal test parameters rather than processing every possible chromosomal region in detail. This selective analysis approach reduces computational burden while maintaining high detection accuracy for true aneuploidies.
Data Source
AI summary
The present disclosure provides methods for non-invasive prenatal screening (NIPS) of fetal aneuploidies. The present methods are based on analyzing cell-free fetal DNA (cff DNA) found in a pregnant woman's circulation through the next generation sequencing (NGS) technology. Particularly, the present methods analyze the relative abundance of different fetal genomic fragments present in the maternal sample, where the fragments can be aligned to particular chromosomal locations of the fetal genome. The relative abundance information is indicative as to whether a particular chromosome is overrepresented or underrepresented in a fetal genome as compared to normal individuals, and thus can be used to detect fetal aneuploidy. Additionally, methods for increasing the positive predictive values (PPV) of NIPS by excluding false-positive detections are also provided.