Two-Tier Molecular Screening for Rare Condition Detection
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Solution Overview
Problem
Diagnostic technologies struggle to accurately identify individuals with rare health conditions in large populations due to poor performance and invasiveness of centralized testing, while POC tests lack the necessary accuracy.
Innovation Solution
A multiple-tiered analysis method involving a first screen to eliminate non-at-risk individuals, followed by an intra-individual analysis to account for unique baseline biological signatures, and a second analysis to detect the presence of health conditions using background-corrected methylation information from target and reference nucleic acids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If complex centralized testing is deployed for rare population testing, then testing coverage is improved, but performance deteriorates with high false positives and low positive predictive value
Solution Approach 1:
The testing process is divided into multiple tiers: a first simplified screen for large populations followed by a second more complex analysis only for at-risk individuals. This segmentation allows complex centralized testing to be applied selectively rather than universally, improving positive predictive value while managing complexity.
Solution Approach 2:
A preliminary screening step is performed using simplified molecular testing to identify at-risk individuals before applying complex centralized testing. This preliminary action filters the population, ensuring that complex testing is only applied to those who need it, thereby improving reliability without unnecessarily increasing overall testing complexity.
2Measurement precision
If simplified molecular testing is applied to large populations, then testing accessibility is improved, but diagnostic accuracy deteriorates for rare health conditions
Solution Approach 1:
The testing strategy is segmented into two tiers: a high-throughput simplified screen for broad population coverage, followed by a high-precision complex analysis for at-risk individuals. This segmentation allows the system to maintain both high productivity in the first tier and high measurement precision in the second tier.
Solution Approach 2:
Different testing approaches are applied to different subsets of the population based on risk stratification. Simplified testing with lower precision is applied locally to the general population, while complex testing with high precision is applied locally to the at-risk subset, optimizing both productivity and diagnostic accuracy for each group.
3Reliability
If complex centralized testing is applied to large populations, then detection sensitivity is improved, but false positive rate increases
Solution Approach 1:
A preliminary risk assessment screen is performed to identify at-risk individuals before applying complex centralized testing. This preliminary action ensures that complex testing with high sensitivity is applied only to those with elevated risk, thereby maintaining high specificity while reducing false positives that would occur if complex testing were applied universally.
Solution Approach 2:
The simplified molecular test acts as an intermediary between the general population and complex centralized testing. It filters and stratifies individuals by risk level, serving as a mediator that directs appropriate testing intensity to appropriate populations, thereby improving overall specificity and reducing false positives.
Data Source
AI summary
Disclosed herein are methods, non-transitory computer readable media, systems, and kits for performing a multiple tiered analysis for identifying individuals with a health condition for monitoring, treating, and/or enrolling the individuals in a clinical trial. Specifically, the multiple tiered analysis involves a first screen, which eliminates a large proportion of individuals who are identified as not at risk for a health condition, and a subsequent second analysis which detects presence of a health condition in the remaining individuals. The second analysis includes an intra-individual analysis, which involves combining sequence information from target nucleic acids and reference nucleic acids obtained from the individual. The target nucleic acids include signatures that may be informative for determining presence or absence of the health condition and the reference nucleic acids include baseline biological signatures of the individual. Altogether, the multiple tiered analysis achieves improved performance and accurate identification of individuals with the health condition.