Independent and Dependent Adverse Effects

Abstract

Adverse effects may be either dependent or independent of the main outcome. An adverse effect of alpha blockers is dizziness, and this occurs independently of the main outcome “alleviation of Raynaud’s phenomenon”. In contrast, the adverse effect “increased calorie intake” occurs with “increased exercise”, and this adverse effect is very dependent on the main outcome “weight loss”. Random heterogeneities, outliers, confounders, interaction factors are common in clinical trials, and all of them can be considered as kinds of adverse effects of the dependent type. Random regressions and random analyses of variance, high dimensional clustering, Bayesian methods are helpful for their analysis and many more methods are possible.

A dependent adverse effect must be significantly related not only to the intervention but also the outcome.

This chapter particularly addresses causal relationships as the underlying mechanism of a dependent adverse effect. Path statistics, path analysis, partial correlations, including d-separations, partial correlation analysis, and higher order partial correlations are particularly suitable for the purpose, but additional methods do exist.