A two-stage method for estimating the association between blood pressure variability and cardiovascular disease: An application using the ARIC Study

The association between visit-to-visit blood pressure variability and cardiovascular events has recently received a lot of attention in the cardiovascular literature. But blood pressure variability is usually estimated on a person-by-person basis, and is therefore subject to considerable measurement error. We demonstrate that hazard ratios estimated using this approach are subject to bias due to regression dilution. We propose an alternative two-stage method to reduce this bias, where in stage one repeated measurements are modelled using a mixed effects model with a random component on the residual standard deviation. The mixed effects model is used to estimate the blood pressure standard deviation for each individual, which in stage two is used as a covariate in a time-to-event model. We illustrate the methods using data from the Atherosclerosis Risk in Communities study.