Heterogeneity in coronary heart disease risk

There is large inter-individual heterogeneity in risk of coronary heart disease (CHD). Risk factors traditionally used in primary risk assessment only partially explain this heterogeneity. Residual, unobserved heterogeneity leads to age-related attenuation of hazard rates and underestimation of hazard ratios. Its magnitude is unknown. Therefore, we aimed to estimate a lower and an approximate upper bound. Heterogeneity was parametrized by a log-normal distribution with shape parameter sigma. Analysis was based on published data. From concordance indices of studies including traditional risk factors and additional diagnostic imaging data, we calculated the part of heterogeneity explained by imaging data. For traditional risk assessment, this part typically remains unexplained, thus constituting a lower bound on unobserved heterogeneity. Next, the potential impact of heterogeneity on CHD hazard rates in several large countries was investigated. CHD rates increase with age but the increase attenuates with age. Presuming this attenuation to be largely caused by heterogeneity, an approximate upper bound on sigma was derived. Taking together both bounds, unobserved heterogeneity in studies without imaging information can be described by a shape parameter in the range sigma = 1-2. It substantially contributes to observed age-dependences of hazard ratios and may lead to underestimation of hazard ratios by a factor of about two. Therefore, analysis of studies for primary CHD risk assessment should account for unobserved heterogeneity.