Rare Clonotype Selection for MRD Monitoring
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Solution Overview
Problem
Current methods for assessing minimal residual disease (MRD) in cancer patients are often unreliable due to the use of clonotypes that are common or lack diversity, leading to false positive indications of relapse, as they may be shared by non-cancerous cells.
Innovation Solution
A method involving the selection of rare patient-specific clonotypes correlated with lymphoid neoplasms by sequencing T-cell and B-cell receptor genes, comparing them to a database to determine rarity and uniqueness, thereby minimizing false positive outcomes and accurately monitoring MRD.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If common clonotypes are used for MRD assessment, then the detection sensitivity is improved, but the specificity deteriorates due to false positive outcomes from shared clonotypes
Solution Approach 1:
The patent changes the parameter of clonotype selection from common to rare clonotypes. By using rare clonotypes (those absent from or below a frequency threshold in a clonotype database), the system maintains detection sensitivity while eliminating false positives caused by shared clonotypes, thereby resolving the contradiction between sensitivity and specificity.
Solution Approach 2:
The patent creates a virtual copy of the patient's clonotype profile by sequencing and comparing against a database of clonotypes from healthy individuals. This copying process allows identification of rare clonotypes that are specific to the patient, enabling accurate MRD detection without false positives from commonly shared clonotypes.
2Device complexity
If clonotypes with low diversity are used, then the assay simplicity is maintained, but the accuracy deteriorates due to inability to distinguish patient-specific from common clonotypes
Solution Approach 1:
The patent introduces a clonotype database as an intermediary tool. By comparing patient clonotypes against this database of healthy individual clonotypes, the system can accurately identify patient-specific rare clonotypes without increasing assay complexity. The database serves as a reference that enables accurate distinction between common and rare clonotypes.
Solution Approach 2:
The patent adds a dimensional aspect by introducing frequency information from the clonotype database. Instead of just analyzing clonotype sequences in isolation, the system analyzes them in the dimension of their frequency occurrence across a population, enabling accurate identification of patient-specific clonotypes while maintaining assay simplicity.
Data Source
AI summary
The invention is directed to a method of selecting disease-correlated clonotypes that have a reduced likelihood of producing a false positive signal of relapse when, used to monitor minimal residual disease. In accordance with the invention, candidate correlating clonotype are obtained from a patient, the rarity of each is determined either by comparison with a clonotype database or a clonotype model, and one or more of the rarest of such clonotypes are used to monitor the minimal residual disease.