Characterization of circadian blood pressure patterns using non-linear mixed effects modeling

ABSTRACT

Characterizing the time course of baseline or pre-drug blood pressure is important in acquiring unbiased estimates of antihypertensive drug effect. In this study, we recruited 23 healthy male volunteers and measured systolic (SBP) and diastolic blood pressure (DBP) over 24 hours on an hourly basis. Using a non-linear mixed effects model, circadian rhythm observed in blood pressure measurements was described by incorporating two cosine functions with periods 24 and 12 hours. A mixture model was applied to identify subgroups exhibiting qualitatively different circadian rhythms. Our results suggested that 78% of the study population, defined as ‘dippers’, demonstrated a typical circadian profile with a morning rise and a nocturnal dip. The remaining 22% of the subjects defined as ‘non-dippers’, however, were not adequately described using the typical profile and demonstrated an elevation of blood pressure during night-time. Covariate search identified weight as being positively correlated with mesor of SBP. Visual predictive checks using 1,000 simulated datasets were performed for model validation. Observations were in agreement with predicted values in ‘dippers’, but deviated slightly in ‘non-dippers’. Our work is expected to serve as a useful reference in assessing systematic intra-day blood pressure fluctuations and antihypertensive effects as well as assessing drug safety of incrementally modified drugs.