Two-stage functional mixed models for evaluating the effect of longitudinal covariate profiles on a scalar outcome

Biometrics. 2007 Jun;63(2):351-62. doi: 10.1111/j.1541-0420.2006.00713.x.

Abstract

The Daily Hormone Study, a substudy of the Study of Women's Health Across the Nation (SWAN) consisting of more than 600 pre- and perimenopausal women, includes a scalar measure of total hip bone mineral density (BMD) together with repeated measures of creatinine-adjusted follicle stimulating hormone (FSH) assayed from daily urine samples collected over one menstrual cycle. It is of scientific interest to investigate the effect of the FSH time profile during a menstrual cycle on total hip BMD, adjusting for age and body mass index. The statistical analysis is challenged by several features of the data: (1) the covariate FSH is measured longitudinally and its effect on the scalar outcome BMD may be complex; (2) due to varying menstrual cycle lengths, subjects have unbalanced longitudinal measures of FSH; and (3) the longitudinal measures of FSH are subject to considerable among- and within-subject variations and measurement errors. We propose a measurement error partial functional linear model, where repeated measures of FSH are modeled using a functional mixed effects model and the effect of the FSH time profile on BMD is modeled using a partial functional linear model by treating the unobserved true subject-specific FSH time profile as a functional covariate. We develop a two-stage nonparametric regression calibration method using period smoothing splines. Using the connection between smoothing splines and mixed models, we show that a key feature of our approach is that estimation at both stages can be conveniently cast into a unified mixed model framework. A simple testing procedure for constant functional covariate effect is also proposed. The proposed methods are evaluated using simulation studies and applied to the SWAN data.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Biometry
  • Bone Density / physiology
  • Female
  • Follicle Stimulating Hormone / urine
  • Humans
  • Likelihood Functions
  • Linear Models
  • Longitudinal Studies
  • Menopause
  • Menstrual Cycle
  • Models, Statistical*
  • Regression Analysis
  • Statistics, Nonparametric

Substances

  • Follicle Stimulating Hormone