Regression of calculated variables in the presence of shared measurement error

To test hypotheses regarding relations between meaningful parameters, it is often necessary to calculate these parameters from other directly measured variables. For example, the relationship between O2 consumption and O2 delivery may be of interest, although these may be computed from measurements of cardiac output and blood O2 contents. If a measured variable is used in the calculation of two derived parameters, error in the measurement will couple the calculated parameters and introduce a bias, which can lead to incorrect conclusions. This paper presents a method of correcting for this bias in the linear regression coefficient and the Pearson correlation coefficient when calculations involve the nonlinear and linear combination of the measured variables. The general solution is obtained when the first two terms of a Taylor series expansion of the function can be used to represent the function, as in the case of multiplication. A significance test for the hypothesis that the regression coefficient is equal to zero is also presented. Physiological examples are provided demonstrating this technique, and the correction methods are also applied in simulations to verify the adequacy of the technique and to test for the magnitude of the coupling effect. In two previous studies of O2 consumption and delivery, the effect of coupled error is shown to be small when the range of O2 deliveries studied is large, and measurement errors are of reasonable size.