Adaptive Sequencing Workflow for Genetic Alteration Detection
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Solution Overview
Problem
Current methods for non-invasive genetic alteration detection, such as next-generation sequencing, face challenges in achieving sufficient read coverage for accurate diagnosis, particularly in mixed biological samples like maternal plasma during prenatal testing or cancer diagnostics, where sensitivity and specificity are compromised due to insufficient sequencing depth.
Innovation Solution
A system and method that perform a first sequencing reaction to determine sample-specific properties, calculate a statistical measure, and if the read coverage is below a threshold, a second sequencing reaction is conducted with additional sample nucleic acid to achieve the required effective read coverage, ensuring accurate detection of genetic alterations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If a single sequencing reaction is performed to reduce cost and time, then productivity improves, but measurement precision deteriorates due to insufficient read coverage
Solution Approach 1:
The system dynamically adjusts the sequencing workflow based on real-time assessment of read coverage. After an initial sequencing reaction, the system evaluates whether the obtained read coverage meets the threshold for accurate genetic alteration detection. If not, the system automatically triggers a second sequencing reaction on the same sample, adapting the process depth to the specific needs of each sample rather than using a fixed single-reaction or fixed multi-reaction approach.
Solution Approach 2:
The system incorporates a feedback mechanism where the results of the first sequencing reaction are evaluated against a predetermined threshold for read coverage. Based on this feedback, the system decides whether to perform a second sequencing reaction. This closed-loop control ensures that sufficient read coverage is achieved while avoiding unnecessary additional sequencing when the first reaction already provides adequate coverage.
2Measurement precision
If read coverage is increased by performing additional sequencing reactions, then measurement precision improves, but loss of time increases due to multiple sequencing steps
Solution Approach 1:
The system uses feedback control to minimize sequencing time while ensuring adequate read coverage. The feedback mechanism evaluates the read coverage from the first sequencing reaction and only triggers a second sequencing reaction when necessary, i.e., when the first reaction fails to achieve the required threshold. This approach prevents unnecessary time consumption from performing redundant sequencing reactions on samples that already have sufficient coverage.
Solution Approach 2:
The system autonomously determines whether a second sequencing reaction is needed based on the evaluation of read coverage from the first reaction. The automated decision-making process eliminates the need for manual intervention to assess whether additional sequencing is required, allowing the system to efficiently manage its own workflow and minimize time loss while ensuring detection accuracy.
3Measurement precision
If read coverage is increased by re-sequencing the sample, then measurement precision improves, but use of energy increases due to additional sequencing reactions
Solution Approach 1:
The feedback mechanism evaluates whether the read coverage from the first sequencing reaction meets the required threshold before deciding to perform a second sequencing reaction. This energy-conscious feedback control ensures that additional sequencing reactions, which consume significant energy, are only performed when absolutely necessary to achieve adequate read coverage, thereby minimizing overall energy consumption while maintaining measurement precision.
Solution Approach 2:
The system changes the sequencing depth parameter dynamically based on the evaluation of read coverage. Rather than performing a fixed number of sequencing reactions for all samples, the system adjusts the sequencing depth parameter to match the actual needs of each sample, performing additional sequencing only when the initial read coverage is insufficient. This parameter adaptation reduces unnecessary energy consumption while ensuring adequate measurement precision.
Data Source
AI summary
Presented are automated fluid handling systems and automated sequencing methods for re-analyzing a sample to achieve a more informative test result. In one embodiment, a method of processing a sample nucleic acid to identify a target mutation comprises performing a first sequencing reaction to determine sample specific properties. The method further comprises determining a statistical measure to determine if a first read coverage for the target mutation from the first sequencing reaction is above or below a threshold. If the determined first read coverage does not exceed the threshold, the method further comprises determining if a sufficient amount of sample nucleic acid is available to perform a second sequencing reaction to increase the read coverage above the threshold. If a sufficient amount of sample nucleic acid is available, the method proceeds to perform re-sequencing of the sample nucleic acid to achieve a second read coverage exceeding the threshold.