Discrepant Inferences When Modeling Associations Between Time-Varying Exposures and Linear Growth Trajectories in Infancy Using Length-For-Age Z Scores Versus Raw Length

Abstract

Abstract Objectives To compare inferences from longitudinal models of the relationships between biomarkers of interest and linear growth outcomes in infancy using length-for-age z-scores (LAZ) based on age- and sex-specific growth standards, or raw length. Methods This was a secondary analysis of data from a study of the association between bone-related biomarkers and infant linear growth trajectories up to 1 year of life in a subset of infants (n = 820) enrolled in the Maternal Vitamin D for Infant Growth trial. The linear growth outcome (LAZ or raw length) was modelled as a function of the interaction between each biomarker and age using linear mixed effect models with restricted cubic splines. Models were specified to obtain the best fit and reconcile discrepancies in results from LAZ and length models. Inferences from marginal effects at birth, 3 months, 6 months, and 12 months were compared, for a total 4 effect estimates from each of 10 pairs of LAZ and length models, resulting in 40 pairs of estimates. The following biomarkers were included: fibroblast growth factor 21 (FGF21), fibroblast growth factor 23 (FGF23), N-terminal propeptide of C-type natriuretic peptide (NT-proCNP), osteocalcin, osteoprotegerin, receptor activator of nuclear activator kappa-b ligand (RANKL), 25-hydroxyvitamin D (25OHD), C-reactive protein (CRP), Interleukin 6 (IL6), and insulin-like growth factor-1 (IGF1). Biomarkers were time-varying, measured in cord blood and at 3 and 6 months of age. Results The best fitting model for LAZ had 3 knots with random slopes, and the best fitting model for raw length had 5 knots, random slopes, and an exponential residual covariance structure. Comparisons of the pairs of marginal estimates from the LAZ vs length models resulted in discrepant inferences for 25% of effect estimates (10/40). Results were consistently concordant only for FGF23, 25OHD, CRP, and IL6. Conclusions Length and LAZ represent the same biological construct but their use in longitudinal modelling may lead to different inferences about associations between time-varying exposures and infant growth, possibly due to residual confounding by age. These findings raise concerns about the reliability of studies of determinants or markers of infant linear growth based on longitudinal modelling of growth trajectories. Funding Sources Bill and Melinda Gates Foundation.