A new functional data-based biomarker for monitoring cardiovascular behavior

Cardiac safety assessment in drug development concerns the ventricular repolarization (represented by electrocardiogram (ECG) T-wave) abnormalities of a cardiac cycle, which are widely believed to be linked with torsades de pointes, a potentially life-threatening arrhythmia. The most often used biomarker for such abnormalities is the prolongation of the QT interval, which relies on the correct annotation of onset of QRS complex and offset of T-wave on ECG. A new biomarker generated from a functional data-based methodology is developed to quantify the T-wave morphology changes from placebo to drug interventions. Comparisons of T-wave-form characters through a multivariate linear mixed model are made to assess cardiovascular risk of drugs. Data from a study with 60 subjects participating in a two-period placebo-controlled crossover trial with repeat ECGs obtained at baseline and 12 time points after interventions are used to illustrate this methodology; different types of wave form changes were characterized and motivated further investigation.