NIPS False-Positive Reduction via Chromosomal Binning Ideogram
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Solution Overview
Problem
Current non-invasive prenatal screening (NIPS) methods for fetal aneuploidy using cell-free fetal DNA (cff DNA) often produce false-positive results, leading to unnecessary invasive procedures and potential miscarriage, prompting some women to terminate their pregnancies without further testing.
Innovation Solution
The method involves dividing chromosomes into bins of chromosomal locations, calculating bin-specific test parameters, and generating an ideogram to detect 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
1Ease of operation
If current NIPS methods are used to screen for fetal aneuploidy, then screening can be performed non-invasively, but false-positive results occur leading to unnecessary invasive procedures and potential miscarriage
Solution Approach 1:
The patent segments the chromosome into multiple bins along its length and analyzes bin-specific test parameters to detect patterns. By dividing the chromosome into discrete segments and examining each separately, the method can distinguish between true aneuploidy (consistent elevation across substantial portions) and false positives (elevations limited to specific bins), thereby reducing false-positive rates while maintaining non-invasive screening capability
Solution Approach 2:
The patent applies local quality analysis by examining bin-specific test parameters at different locations along the chromosome. Instead of treating the chromosome as a uniform unit, the method analyzes local variations in test parameter elevation across different bins, allowing differentiation between true aneuploidic regions and localized false-positive signals, thus improving reliability without compromising the non-invasive approach
2Measurement precision
If NIPS methods produce high-risk results, then further diagnostic testing can be recommended, but this leads to invasive procedures carrying risk of procedure-related miscarriage
Solution Approach 1:
The patent employs a computational ideogram as a disposable analytical tool that visualizes bin-specific test parameters to guide clinical decision-making. This ideogram serves as a temporary, non-invasive assessment mechanism that can be generated from maternal blood samples, providing sufficient diagnostic information to reduce the need for high-risk invasive procedures while maintaining measurement precision
Solution Approach 2:
The bin-specific test parameter analysis acts as an intermediary between the non-invasive NIPS screening and invasive diagnostic procedures. By introducing this intermediate layer of analysis that examines patterns across chromosomal bins, the method provides additional diagnostic precision that can justify avoiding invasive procedures in many cases, thereby reducing procedure-related miscarriage risk while maintaining accuracy
3Ease of operation
If NIPS results lead to termination of pregnancy without additional testing, then women avoid invasive procedures, but this results in loss of life and prevents confirmation of diagnosis
Solution Approach 1:
The patent performs preliminary analysis by generating an ideogram that visualizes bin-specific test parameters before making diagnostic recommendations. This preliminary visualization allows clinicians and patients to better understand the nature and extent of potential aneuploidy signals, enabling more informed decisions about whether to proceed with invasive testing or termination, thereby maintaining diagnostic reliability while preserving patient autonomy and avoiding unnecessary procedures
Data Source
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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.