Hermida R C, Fernández J R, Alonso I, Ayala D E, García L
Bioengineering Laboratory, E.T.S.I. Telecomunicación, Universidad de Vigo, Spain.
Chronobiol Int. 1997 Jul;14(4):409-25. doi: 10.3109/07420529709001461.
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 biological rhythms. In particular, growth hormone is characterized in children by circadian and ultradian variability, with high peaks of secretion occurring mainly during sleep. For clinical applications, the use of tolerance intervals has been recommended, and they should substitute, whenever possible, for prediction limits. In the case of hybrid data (time series of data collected from a group of subjects), such a tolerance interval could be very difficult to determine following a parametric approach similar to the procedure used for the computation of prediction intervals, especially when consideration of both within-subjects and among-subjects variances is wanted. Accordingly, we have developed a nonparametric method for the computation of such tolerance intervals. Because the method is based on bootstrap techniques, it does not require the assumption of normality or symmetry in the data and is also more appropriate when dealing with small samples. The method was used to establish time-qualified reference limits for a series of growth hormone sampled around the clock in groups of prepubertal children differentiated according to stature. The use of these tolerance intervals may eliminate many false-positive and false-negative diagnoses that might be obtained when relying on time-unspecified single samples. The provision of such tolerance limits introduces time-specification and time-structure evaluation into prevention, diagnosis, and treatment of growth disorders.
对于具有临床意义的变量而言，理想的参考区间应针对所有影响该变量的确定性因素而定，包括与生物节律相关的采样时间。特别是，儿童生长激素具有昼夜和超日节律变化的特点，其分泌高峰主要出现在睡眠期间。在临床应用中，推荐使用容许区间，并且只要有可能，它们应替代预测限。对于混合数据（从一组受试者收集的数据时间序列），按照类似于计算预测区间的参数方法来确定这样的容许区间可能非常困难，尤其是当需要同时考虑受试者内和受试者间方差时。因此，我们开发了一种用于计算此类容许区间的非参数方法。由于该方法基于自助法技术，它不需要数据服从正态分布或对称的假设，并且在处理小样本时也更合适。该方法用于为根据身材区分的青春期前儿童组中连续24小时采集的一系列生长激素建立有时间限定的参考限。使用这些容许区间可能会消除许多在依赖未指定时间的单个样本时可能出现的假阳性和假阴性诊断。提供这样的容许限将时间指定和时间结构评估引入生长障碍的预防、诊断和治疗中。
