On Analyzing Circadian Rhythms Data Using Nonlinear Mixed Models with Harmonic Terms

Wang, Ke, and Brown (2003, Biometrics59, 804-812) developed a smoothing-based approach for modeling circadian rhythms with random effects. Their approach is flexible in that fixed and random covariates can affect both the amplitude and phase shift of a nonparametrically smoothed periodic function. In motivating their approach, Wang et al. stated that a simple sinusoidal function is too restrictive. In addition, they stated that "although adding harmonics can improve the fit, it is difficult to decide how many harmonics to include in the model, and the results are difficult to interpret." We disagree with the notion that harmonic models cannot be a useful tool in modeling longitudinal circadian rhythm data. In this note, we show how nonlinear mixed models with harmonic terms allow for a simple and flexible alternative to Wang et al.ʹs approach. We show how to choose the number of harmonics using penalized likelihood to flexibly model circadian rhythms and to estimate the effect of covariates on the rhythms. We fit harmonic models to the cortisol circadian rhythm data presented by Wang et al. to illustrate our approach. Furthermore, we evaluate the properties of our procedure with a small simulation study. The proposed parametric approach provides an alternative to Wang et al.ʹs semiparametric approach and has the added advantage of being easy to implement in most statistical software packages.