Genetic Data Cleaning via Parental Genotype Interpolation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current pre-implantation genetic diagnosis (PGD) techniques for IVF are unreliable, expensive, and unable to accurately screen for aneuploidy and disease-linked loci, leading to high error rates and limited ability to detect chromosomal abnormalities, particularly in embryos, which can result in failed implantations and miscarriages.
Innovation Solution
A system that uses secondary genetic data from related individuals, such as parents and siblings, to reconstruct and clean noisy genetic data from embryos, enabling accurate detection of aneuploidy, uniparental disomy, and disease-linked loci by incorporating knowledge of meiosis and genetic variations, thereby improving the fidelity of allele calls and chromosome copy number determination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If direct measurements of DNA are performed on a single cell, then genetic data can be obtained, but the measurements are highly error-prone and noisy
Solution Approach 1:
The patent introduces an intermediary computational model that incorporates knowledge of meiosis and parental genotypes to mediate between the noisy single-cell measurements and the true genetic state. This model acts as a statistical intermediary that filters noise by comparing observed allele ratios against expected Mendelian inheritance patterns, thereby resolving the contradiction between obtaining genetic data from single cells and maintaining measurement reliability
Solution Approach 2:
The patent implements feedback through iterative statistical inference that compares measured allele ratios against expected values derived from parental genotypes and meiosis models. The system uses this feedback to identify and correct measurement errors, adjusting the interpretation of noisy data based on the consistency with known genetic inheritance patterns, thus improving reliability without requiring additional direct measurements
2Reliability
If current PGD techniques are used for screening, then aneuploidy and disease-linked loci can be detected, but the error rate is on the order of 10% and the process is expensive
Solution Approach 1:
The patent performs preliminary action by incorporating parental genotype information and meiosis knowledge into the analysis framework before interpreting embryonic genetic data. This preliminary setup creates a reference model of expected inheritance patterns that enables more accurate detection of aneuploidy and disease-linked loci, reducing error rates by comparing actual measurements against pre-established genetic expectations rather than relying on standalone single-cell measurements
Solution Approach 2:
The patent changes the parameters of the genetic analysis by moving from direct single-cell genotype calling to a statistical model that estimates allele ratios and compares them against expected Mendelian ratios. This parameter transformation from absolute genotype determination to relative ratio analysis, combined with parental information, improves screening precision and reduces error rates while maintaining cost-effectiveness
3Loss of information
If single-cell DNA analysis is performed, then genetic information can be obtained, but the data is incomplete and noisy due to the single copy of DNA available
Solution Approach 1:
The patent uses copying by creating a virtual replicate of the genetic information through statistical modeling. Instead of relying on multiple physical copies of the single-cell DNA, the system generates multiple probabilistic estimates of the true genotype based on the single measurement, parental genotypes, and meiosis models. This computational copying allows the system to recover complete genetic information and correct noise without requiring additional physical DNA samples
Data Source
AI summary
Disclosed herein is a system and method for increasing the fidelity of measured genetic data, for making allele calls, and for determining the state of aneuploidy, in one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available. Genetic material from the target individual is acquired, amplified and the genetic data is measured using known methods. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related individuals. In accordance with one embodiment of the invention, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the more complete genetic data from a larger sample of diploid cells from one or both parents, with or without haploid genetic data from one or both parents. In another embodiment of the invention, the chromosome copy number can be determined from the measured genetic data of a single or small number of cells, with or without genetic information from one or both parents. In another embodiment of the invention, these determinations are made for the purpose of embryo selection in the context of in-vitro fertilization. In another embodiment of the invention, the genetic data can be reconstructed for the purposes of making phenotypic predictions.