Laboratory Tests Into the Model

Laboratory tests may also show a high degree of correlation amongst each other. For example, aspartate aminotransferase (AST) is correlated with alanine aminotransferase (ALT) with a correlation coefficient of about 0.6 and total protein is correlated with albumin, also with a correlation coefficient of about 0.6. Caution needs to be exercised when two or more correlated laboratory values enter in the covariate model simultaneously because of the possible collinearity that may occur (Bonate, 1999). Like in the linear regression case, inclusion of correlated covariates may result in an unstable model leading to inflated standard errors and deflated Type I error rate. 

Sometimes, rather than treating the covariate as a continuous variable, the covariate will be categorized and the categorical variable will be used in the model instead of the original value. For example, de Maat et al. (2002) in a population analysis of nevirapine categorized baseline laboratory markers of hepatic function into dichotomous covariates. Patients were coded as V if their laboratory value was 1.5 times higher than the upper limit of normal and 0 otherwise. Patients with an aspartate aminotransferase 1.5 times higher than normal had a 13% decrease in nevirapine clearance than patients with normal values. 

In practice, using a normal chemistry panel and complete blood count it is not unusual to have 30 potential covariates, everything from sodium ion concentration to alkaline phosphatase activity. Early in PopPK analyses it was not unusual to screen every single covariate for their impact on the model. But a model might end up having a volume of distribution as a function of chloride ion concentration or clearance that is a function of glucose concentration. Physiologically, these covariates are nonsensical. Ideally at the end of model 

Weight, an intrinsic covariate, is probably the most frequently identified covariate in a PopPK analysis. All structural model parameters, except absorption related 

The most frequently used surrogate for weight is BSA and there are many different equations that can be used to calculate a person s BSA. In the absence of height measurements, Livingston and Lee (2001) developed the following equations for BSA 

---