MACHINE LEARNING PLATFORM FOR GENERATING RISK MODELS
The disclosed embodiments concern methods, apparatus, systems, and computer program products for developing polygenic risk score (PRS) models with improved performance across different ethnicities and for different target phenotypes.
1 . A method for generating a cross-traits polygenic risk score (PRS) model, comprising:
selecting a phenotype of interest having a set of summary statistics from a genome wide association study (GWAS);
selecting a plurality of candidate phenotypes, each candidate phenotype having a set of summary statistics from a corresponding GWAS for that candidate phenotype;
determining a set of genetic correlations between the phenotype of interest and each candidate phenotype of the plurality of candidate phenotypes;
filtering the plurality of candidate phenotypes based on the set of genetic correlations to assemble a cohort of filtered candidate phenotypes;
retrieving a plurality of PRS models, each PRS model corresponding to a phenotype of the cohort of filtered candidate phenotypes; and
determining the cross-traits PRS model based at least in part on the plurality of PRS models.
2 . The method of claim 1 , wherein the set of genetic correlations comprises p-values between the phenotype of interest and each candidate phenotype, and filtering the plurality of candidate phenotypes based on the set of genetic correlations is further based on a p-value threshold.
3 . The method of claim 2 , wherein the p-value threshold is less than about 1e-3.
4 . The method of claim 1 , further comprising determining a genetic correlation between the phenotype of interest and a candidate phenotype based on the set of summary statistics for the phenotype of interest and the set of summary statistics for the candidate phenotype.
5 . The method of claim 1 , wherein the set of summary statistics from a GWAS comprise a p-value for each of a plurality of single nucleotide polymorphism (SNP) sites.
6 . The method of claim 5 , further comprising determining a genetic correlation between the phenotype of interest and a candidate phenotype based on determining a genetic covariance between the plurality of single nucleotide polymorphism sites for the phenotype of interest and the candidate phenotype.
7 . The method of claim 6 , wherein the genetic correlation is determined based on a function of the genetic covariance among the plurality of single nucleotide polymorphism sites for the phenotype of interest and the candidate phenotype and a heritability of the phenotype of interest and the candidate phenotype.
8 . The method of claim 7 , wherein the genetic correlation is determined according to the following formula:
r g ( y 1 ,y 2 )=ρ g ( y 1 ,y 2 )/√{square root over ( h g 2 ( y 1 ) h g 2 ( y 2 )))}
where r g is the genetic correlation between the phenotype of interest (y 1 ) and a candidate phenotype (y 2 ), ρ g is the genetic covariance among SNPs of the two phenotypes, and h g 2 is the heritability for each respective phenotype.
9 . The method of claim 1 , wherein the plurality of candidate phenotypes comprises more than about 100 phenotypes.
10 . The method of claim 1 , wherein the cross-traits PRS model comprises a weight factor for each PRS model of the plurality of PRS models.
11 . The method of claim 10 , further comprising determining the weight factor by a penalized linear or logistic regression.
12 . The method of claim 11 , wherein the penalized linear or logistic regression includes elastic net regularization.
13 . The method of claim 1 , wherein each PRS model outputs a PRS, and the cross-traits PRS is a linear or logistic combination of the PRS from the plurality of PRS models.
14 . The method of claim 1 , further comprising executing the cross-trait PRS model to generate a PRS for the phenotype of interest.
15 . The method of claim 1 , wherein each PRS model is based at least in part on the set of summary statistics from the corresponding GWAS.
16 . The method of claim 1 , wherein the plurality of PRS models includes a PRS model for the phenotype of interest.
17 . The method of claim 1 , further comprising generating each of the plurality of PRS models.
18 . The method of claim 17 , wherein generating one or more of the plurality of PRS models by a stacked clumping and thresholding (SCT) method.
19 . The method of claim 1 , wherein each of the plurality of PRS models includes greater than about 50,000 SNPs.
20 . (canceled)
21 . A method for generating a cross-traits polygenic risk score (PRS) model, comprising:
obtaining, for a phenotype of interest, GWAS statistical data relating the phenotype of interest to genetic information;
identifying one or more filtered candidate phenotypes to form a cohort of filtered candidate phenotypes, wherein each filtered candidate phenotype has GWAS statistical data, and wherein each filtered candidate phenotype has a genetic correlation with the phenotype of interest and the genetic correlation exceeds a defined threshold;
retrieving a plurality of PRS models, each PRS model corresponding to a phenotype of the cohort of filtered candidate phenotypes; and
determining the cross-traits PRS model based at least in part on the plurality of PRS models.
22 . A method for generating a transethnic polygenic risk score (PRS) model, comprising:
selecting a target population of interest having genotype data available for individuals within the target population;
analyzing the genotype data for the target population and one or more population-specific genetic datasets to determine one or more sets of SNPs that are statistically associated with a phenotype of interest, wherein the population-specific genetic datasets are for populations other than the target population,
applying SNP filtering criteria to the one or more set of SNPs to generate a plurality of training SNP sets with each training SNP set corresponding to a different population of the one or more population-specific genetic datasets;
training a plurality of PRS models based on the genotype data for the one or more population-specific genetic datasets and the plurality of training SNP sets to generate a PRS model for each of the one or more populations in the one or more population specific genetic datasets; and
determining the transethnic PRS model based at least in part on training the plurality of PRS models using the target population training set to generate the transethnic PRS model.
23 .- 45 . (canceled)