Adding a genome-wide polygenic risk score to a traditional risk factor model marginally improved CHD risk discrimination in young adults (ΔC index 0.03; 95% CI 0.001-0.05) but not in midlife adults.
Cohort (n=9,757)
Yes
Does the addition of a polygenic risk score to a traditional risk factor model improve long-term prediction of incident coronary heart disease in young and middle-aged adults?
A polygenic risk score provides minimal additive clinical utility beyond traditional risk factors for predicting long-term coronary heart disease risk in young and middle-aged adults.
Effect estimate: ΔC index 0.03 (95% CI 0.001-0.05)
BACKGROUND: Understanding the predictive utility of previously derived polygenic risk scores (PRSs) for long-term risk of coronary heart disease (CHD) and its additive value beyond traditional risk factors can inform prevention strategies. METHODS: Data from adults 20 to 59 years of age who were free of CHD from the FOS (Framingham Offspring Study) and the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Because the PRS was derived from samples of predominantly European ancestry, individuals who self-reported White race were included. The sample was stratified by age and cohort: young (FOS, 20-39 years median, 30 years of age), early midlife (FOS, 40-59 years median, 43 years of age), and late midlife (ARIC, 45-59 years median, 52 years of age). Two previously derived and validated prediction tools were applied: (1) a 30-year traditional risk factor score and (2) a genome-wide PRS comprising >6 million genetic variants. Hazard ratios for the association between each risk estimate and incident CHD were calculated. Predicted and observed rates of CHD were compared to assess discrimination for each model individually and together with the optimism-corrected C index (95% CI). RESULTS: Among 9757 participants, both the traditional risk factor score (hazard ratio per 1 SD, 2.60 95% CI, 2.08-3.27, 2.09 95% CI, 1.83-2.40, and 2.11 95% CI, 1.96-2.28) and the PRS (hazard ratio, 1.98 95% CI, 1.70-2.30, 1.64 95% CI, 1.47-1.84, and 1.22 95% CI, 1.15-1.30) were significantly associated with incident CHD in young, early midlife, and late midlife, respectively. Discrimination was similar or better for the traditional risk factor score (C index, 0.74 95% CI, 0.70-0.78, 0.70 95% CI, 0.67-0.72, and 0.72 95% CI, 0.70-0.73) compared with an age- and sex-adjusted PRS (0.73 95% CI, 0.69-0.78, 0.66 95% CI, 0.62-0.69, and 0.66 95% CI, 0.64-0.67) in young, early-midlife, and late-midlife participants, respectively. The ΔC index when PRS was added to the traditional risk factor score was 0.03 (95% CI, 0.001-0.05), 0.02 (95% CI, -0.002 to 0.037), and 0.002 (95% CI, -0.002 to 0.006) in young, early-midlife, and late-midlife participants, respectively. CONCLUSIONS: Despite a statistically significant association between PRS and 30-year risk of CHD, the C statistic improved only marginally with the addition of PRS to the traditional risk factor model among young adults and did not improve among midlife adults. PRS, an immutable factor that cannot be directly intervened on, has minimal clinical utility for long-term CHD prediction when added to a traditional risk factor model.
Khan et al. (Mon,) conducted a cohort in Coronary Heart Disease (n=9,757). Polygenic risk score (PRS) vs. Traditional risk factor score was evaluated on Incident coronary heart disease (ΔC index 0.03, 95% CI 0.001-0.05). Adding a genome-wide polygenic risk score to a traditional risk factor model marginally improved CHD risk discrimination in young adults (ΔC index 0.03; 95% CI 0.001-0.05) but not in midlife adults.