Construction of time-specified reference limits for growth hormone secretion in prepuberal children

The ideal reference interval for a variable of clinical interest would be specific for all deterministic factors affecting that variable, including the time of sampling in relation to biologic rhythms. In particular, growth hormone is characterized in children by circadian and ultradian variability, with high peaks of secretion occurring mainly during sleep. This pattern of growth hormone secretion can be modelled by multiple linear least-squares analysis, allowing the concomitant fit of several significant harmonics. With the aim to investigate rhythmic changes in growth hormone secretion and to derive tolerance limits for its circadian variability, while also studying possible differences in rhythmic characteristics between children with short versus standard stature, the authors analyzed data sampled around the clock in groups of prepuberal children differentiated according to stature. Original data were used to compute time-specified tolerance limits for the circadian variability of growth hormone. The method, derived on the basis of bootstrap techniques, does not need to assume normality or symmetry in the data and, therefore, it is highly appropriate to describe the circadian pattern of growth hormone secretion. These tolerance intervals, computed from hybrid time series, may take into account both inter- and intra-individual variability. The provision of such tolerance limits introduces time-specification and time-structure evaluation into prevention, diagnosis and treatment of growth disorders