One-Genome dd-cfDNA Quantification Without Donor Genotype
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Solution Overview
Problem
Current methods for monitoring allograft health in transplant recipients, such as biopsy, are invasive and costly, and existing Genome Transplant Dynamics (GTD) methods require donor genotype information which is often unavailable, limiting their effectiveness.
Innovation Solution
A 'one-genome' method using shotgun sequencing that estimates donor-derived cell-free DNA (dd-cfDNA) levels without donor genotype information, employing a hidden Markov model to handle closely related recipients and donors, and differentiating between graft-versus-host disease and relapse by comparing dd-cfDNA to recipient DNA in white blood cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If biopsy is used for allograft rejection surveillance, then measurement precision is improved, but object-generated harmful factors increase due to invasiveness and complications
Solution Approach 1:
The patent replaces the mechanical invasive biopsy procedure with a molecular-based liquid biopsy method that sequences cell-free DNA in blood plasma. This substitution eliminates the need for physical tissue sampling while maintaining rejection detection capability through genomic analysis of circulating DNA fragments.
Solution Approach 2:
The patent uses cell-free DNA in blood plasma as an intermediary marker to indirectly assess allograft health status. Instead of directly examining graft tissue through biopsy, the method measures donor-derived cfDNA levels in the recipient's bloodstream, which serve as a non-invasive proxy for graft injury and rejection.
2Measurement precision
If two-genome GTD method is used requiring both donor and recipient genotyping, then measurement precision is improved, but device complexity increases due to unavailability of donor genotype
Solution Approach 1:
The patent extracts and removes the requirement for donor genotype information from the GTD methodology. By developing statistical models that rely solely on recipient genotype data and population allele frequencies, the method eliminates the need to obtain, store, and process donor genomic information while maintaining quantification accuracy.
Solution Approach 2:
The patent creates a simplified version of the two-genome method by using recipient genotype data as a proxy for both donor and recipient genotypes. The approach copies the essential functional elements of full GTD (SNP-based discrimination) while using only one genome (recipient) to achieve the same objective through statistical inference.
3Ease of operation
If one-genome method is used without donor genotype, then ease of operation is improved, but measurement precision deteriorates due to inability to discriminate donor and recipient DNA
Solution Approach 1:
The patent makes the recipient genotype serve multiple functions simultaneously: it identifies recipient-specific SNPs, provides population allele frequency context, and enables statistical discrimination of donor-derived DNA. This multi-functional use of single-genotype data replaces the need for separate donor genotype information.
Solution Approach 2:
The patent changes the analytical parameters from direct SNP matching (requiring both genotypes) to statistical probability models that incorporate population allele frequencies. By transforming the discrimination approach from deterministic to probabilistic, the method achieves donor-recipient DNA separation using only recipient genotype data.
Data Source
AI summary
Prediction of allograft rejection is provided based on the quantification of transplant-derived circulating cell-free DNA (dd-cfDNA levels) in the absence of a donor genotype. The technology provided herein alleviates some of the barriers to the implementation of Genome Transplant Dynamics (GTD), which will further widen its clinical application.