Using lifetime risk estimates in personal genomic profiles: estimation of uncertainty

Abstract

Personal genome tests are now offered direct-to-consumer (DTC) via genetic variants identified by genome-wide association studies (GWAS) for common diseases. Tests report risk estimates (age-specific and lifetime) for various diseases based on genotypes at multiple loci. However, uncertainty surrounding such risk estimates has not been systematically investigated. With breast cancer as an example, we examined the combined effect of uncertainties in population incidence rates, genotype frequency, effect sizes, and models of joint effects among genetic variants on lifetime risk estimates. We performed simulations to estimate lifetime breast cancer risk for carriers and noncarriers of genetic variants. We derived population-based cancer incidence rates from Surveillance, Epidemiology, and End Results (SEER) Program and comparative international data. We used data for non-Hispanic white women from 2003 to 2005. We derived genotype frequencies and effect sizes from published GWAS and meta-analyses. For a single genetic variant in FGFR2 gene (rs2981582), combination of uncertainty in these parameters produced risk estimates where upper and lower 95% simulation intervals differed by more than 3-fold. Difference in population incidence rates was the largest contributor to variation in risk estimates. For a panel of five genetic variants, estimated lifetime risk of developing breast cancer before age 80 for a woman that carried all risk variants ranged from 6.1% to 21%, depending on assumptions of additive or multiplicative joint effects and breast cancer incidence rates. Epidemiologic parameters involved in computation of disease risk have substantial uncertainty, and cumulative uncertainty should be properly recognized. Reliance on point estimates alone could be seriously misleading.

Figure 1

Effect of Epidemiologic Parameters on Lifetime Risk of Developing Breast Cancer from Birth among Carriers and Noncarriers of FGFR2 Variant Figures show the effect of breast cancer incidence rates, risk ratio, genotype frequency, and combinations of these parameters on lifetime risk of developing breast cancer from birth among carriers and noncarriers of FGFR2 (rs2981582) genetic variant. (A) Effect of 3-fold lower breast cancer incidence rates; blue solid line with squares indicates lifetime risk of developing breast cancer among non-Hispanic white women; red solid line with squares indicates lifetime risk of developing breast cancer among non-Hispanic white women who carried FGFR2 genetic variant; red dashed line indicates lifetime risk of developing breast cancer among carriers of FGFR2 genetic variant assuming a 3-fold lower breast cancer incidence rates; green solid line with squares indicates lifetime risk of developing breast cancer among noncarriers of non-Hispanic white women; green dashed line indicates lifetime risk of developing breast cancer among noncarriers assuming a 3-fold lower breast cancer incidence rates. (B) Effect of lower and upper 95% prediction interval (PI) of risk ratio; blue solid line with squares indicates lifetime risk of developing breast cancer among non-Hispanic white women; red solid line with squares indicates effect of using upper 95% PI risk ratio on lifetime risk among non-Hispanic white women who carried FGFR2 genetic variant; red dashed line indicates effect of using lower 95% PI risk ratio on lifetime risk among non-Hispanic white women who carried FGFR2 genetic variant; green solid line with square indicates effect of using upper 95% PI risk ratio on lifetime risk among noncarriers of non-Hispanic white women; green dashed line indicates effect of using lower 95% PI risk ratio on lifetime risk among noncarriers of non-Hispanic white women. (C) Effect of lower and upper 95% confidence interval (CI) of genotype frequency; blue solid line with square indicates lifetime risk of developing breast cancer among non-Hispanic white women; red solid line with squares indicates effect of using lower 95% CI genotype frequency on lifetime risk among non-Hispanic white women who carried FGFR2 genetic variant; red dashed line indicates effect of using upper 95% CI genotype frequency on lifetime risk among non-Hispanic white women who carried FGFR2 genetic variant; green solid line with squares indicates effect of using lower 95% CI genotype frequency on lifetime risk among noncarriers of non-Hispanic white women; green dashed line indicates effect of using upper 95% CI genotype frequency on lifetime risk among noncarriers of non-Hispanic white women. (D) Effect of combination of these parameters; blue solid line with square indicates lifetime risk of developing breast cancer among non-Hispanic white women; red solid line with square indicates combination effect of lower 95% CI genotype frequency and upper 95% PI risk ratio on lifetime risk among non-Hispanic white women who carried FGFR2 genetic variant; red dashed line indicates combination effect of upper 95% CI genotype frequency and lower 95% PI risk ratio on lifetime risk among carriers of FGFR2 genetic variant assuming a 3-fold lower breast cancer incidence rates; green solid line with square indicates combination effects of lower 95% CI genotype frequency and lower 95% PI risk ratio on lifetime risk among noncarriers of non-Hispanic white women; green dashed line indicates combination effects of upper 95% CI genotype frequency and upper 95% PI risk ratio on lifetime risk among noncarriers assuming a 3-fold lower breast cancer incidence rates.

Figure 2

Effects of Varying Genotype Frequency and Risk Ratio on Lifetime Risk of Developing Breast Cancer from Birth among Carriers of FGFR2 Variant Figures show the effect of assuming 10% or 20% lower or higher values than the point estimates of genotype frequency and risk ratio of FGFR2 (rs2981582) genetic variant on lifetime risk of developing breast cancer from birth among carriers of U.S. non-Hispanic white women in 2003–2005. (A) Effect assuming 10% or 20% lower or higher genotype frequency; blue solid line with squares indicates lifetime risk of developing breast cancer among non-Hispanic white women; red solid line with squares indicates lifetime risk among carriers of FGFR2 genetic variant assuming 20% lower genotype frequency; red dashed line indicates lifetime risk among carriers of FGFR2 genetic variant assuming 10% lower genotype frequency; green solid line with squares indicates lifetime risk among carriers of FGFR2 genetic variant assuming 20% higher genotype frequency; and green dashed line indicates lifetime risk among carriers of FGFR2 genetic variant assuming 10% higher genotype frequency. (B) Effect assuming 10% or 20% lower or higher genotype risk ratio; blue solid line with squares indicates lifetime risk among non-Hispanic white women; red solid line with squares indicates lifetime risk among carriers of FGFR2 genetic variant assuming 20% higher genotype risk ratio; red dashed line indicates lifetime risk among carriers of FGFR2 genetic variant assuming 10% higher genotype risk ratio; green solid line with squares indicates lifetime risk among carriers of FGFR2 genetic variant assuming 10% lower genotype risk ratio; and green dashed line indicates lifetime risk among carriers of FGFR2 genetic variant assuming 20% lower genotype risk ratio.