A new explained-variance based genetic risk score for predictive modeling of disease risk

Abstract

The goal of association mapping is to identify genetic variants that predict disease, and as the field of human genetics matures, the number of successful association studies is increasing. Many such studies have shown that for many diseases, risk is explained by a reasonably large number of variants that each explains a very small amount of disease risk. This is prompting the use of genetic risk scores in building predictive models, where information across several variants is combined for predictive modeling. In the current study, we compare the performance of four previously proposed genetic risk score methods and present a new method for constructing genetic risk score that incorporates explained variance information. The methods compared include: a simple count Genetic Risk Score, an odds ratio weighted Genetic Risk Score, a direct logistic regression Genetic Risk Score, a polygenic Genetic Risk Score, and the new explained variance weighted Genetic Risk Score. We compare the methods using a wide range of simulations in two steps, with a range of the number of deleterious single nucleotide polymorphisms (SNPs) explaining disease risk, genetic modes, baseline penetrances, sample sizes, relative risks (RR) and minor allele frequencies (MAF). Several measures of model performance were compared including overall power, C-statistic and Akaike's Information Criterion. Our results show the relative performance of methods differs significantly, with the new explained variance weighted GRS (EV-GRS) generally performing favorably to the other methods.

Figure 1

Model comparisons in Step 1 Scenario 1-1 (SNP=2, MAF=0.25).

Figure 2

Model comparisons in Step 1 Scenario 1-2 (SNP=2, MAF=0.5).

Figure 3

Model comparisons in Step 1 Scenario 1-3 (SNP=2, MAF=0.25/0.5).

Figure 4

Model comparisons in Step 1 Scenario 2-1 (SNP=6, MAF=0.25).

Figure 5

Model comparisons in Step 1 Scenario 2-2 (SNP=6, MAF=0.5).

Figure 6

Model comparisons in Step 1 Scenario 2-3 (SNP=6, RR=1.25/1.5/1.75).

Figure 1

Relative risk and minor allele frequency specifications in the simulation design.

Figure 2. Model comparisons in Step 2 Scenario 1

(different relative risk and same minor allele frequency, baseline penetrance=0.1, n=200).

Figure 3. Model comparisons in Step 2 Scenario 2

(same relative risk and different minor allele frequency, baseline penetrance=0.1, n=200).

Figure 4. Model comparisons in Step 2 Scenario 2

(same relative risk and different minor allele frequency, baseline penetrance=0.1, n=500).

Figure 5. Model comparisons in Step 2 Scenario 3

(different relative risk and different minor allele frequency, baseline penetrance=0.1, n=200).

Figure 6. Model comparisons in Step 2 Scenario 3

(different relative risk and different minor allele frequency, baseline penetrance=0.1, n=500).