A multilevel modelling solution to mathematical coupling.

Owing to mathematical coupling, statistical analyses relating change to baseline values using correlation or regression are erroneous, where the statistical procedure of testing the null hypothesis becomes invalid. Alternatives, such as Oldham's method and the variance ratio test, have been advocated, although these are limited in the presence of measurement errors with non-constant variance. Furthermore, such methods prohibit the consideration of additional covariates (e.g., treatment group within trials) or confounders (e.g., age and gender). This study illustrates the more sophisticated approach of multilevel modelling (MLM) which overcomes these limitations and provides a comprehensive solution to the analysis of change with respect to baseline values. Although mathematical coupling is widespread throughout applied research, one particular area where several studies have suggested a strong relationship between baseline disease severity and treatment effect is guided tissue regeneration (GTR) within dental research. For illustration, we use GTR studies where the original data were found to be available in the literature for reanalysis. We contrast the results from an MLM approach and Oldham's method with the standard (incorrect) approach that suffers from mathematical coupling. MLM provides a robust solution when relating change to baseline and is capable of simultaneously dealing with complex error structures and additional covariates and/or potential confounders.