ASSOCIATION OF SERUM TOTAL CHOLESTEROL WITH CORONARY-DISEASE AND ALL-CAUSE MORTALITY - MULTIVARIATE CORRECTION FOR BIAS DUE TO MEASUREMENT ERROR

Measurement error in the exposure under investigation is an important but often ignored source of bias in observational studies. The authors examined the impact of measurement error in the association between t otal serum cholesterol and 16-year coronary heart disease and all-caus e mortality in a cohort of 6,137 middle-aged men of Japanese descent i n the Honolulu Heart Program (1973-1988). A Cox regression model that enables modeling of survival time with correction for measurement erro rs in multiple covariates was employed. After controlling for age, bod y mass index, systolic blood pressure, smoking status, alcohol consump tion, dietary cholesterol, and total calorie intake, a difference of o ne standard deviation (38 mg/dL) in total cholesterol was associated w ith a significant increase in the risk of coronary disease death (unco rrected hazard ratio = 1.35). After correction for measurement errors in total cholesterol and covariates (except smoking and age), the esti mated hazard ratio increased to 1.65 (a 22% increase). A U-shaped rela tion was observed between total cholesterol levels and the risk of all -cause mortality. This association was then examined with a quadratic model and with a two-slope or V-shaped regression model. In the quadra tic fit, the magnitude of the quadratic total cholesterol term increas ed threefold after the adjustment for measurement error. In the V fit, the hazard ratio of all-cause death corresponding to a change in one standard deviation above 214 mg/dL (the nadir of the V) was 1.15, and increased to 1.49 (by 29%) after the correction. The corresponding haz ard ratio of a change in one standard deviation below 214 mg/dL was 1. 11, and increased to 1.37 (by 23%) after the correction. The authors c onclude that the impact of elevated total cholesterol on the risk of c oronary disease and all-cause mortality may be greater than previously estimated with standard methods of analysis. In addition, the correct ion for measurement error in total cholesterol and covariates did not explain the excess mortality associated with low total cholesterol. Mo re research is needed to elucidate the fundamental issues underlying t he U-shaped association, i.e., confounding versus causal implications.