Department of Pediatrics (B.K., C.L., S.R., K.A.W.), Göteborg Pediatric Growth Research Center, Göteborg University, S-41685 Göteborg; and Department of Pediatrics (B.K.), Umeå University, S-90195 Umeå, Sweden
Address all correspondence and requests for reprints to: Berit Kriström, University of Göteborg, Göteborg Pediatric Growth Research Center, The Queen Silvias Childrens Hospital, Sahlgrenska University Hospital, East, S-416 85 Göthenburg, Sweden. E-mail: berit.kristrom{at}pediatri.umu.se
WE HAVE recently shown and validated (1) that the initial 1- and 2-yr growth responses to GH treatment can be accurately predicted with the use of mathematical algorithms, so-called "prediction models." The patient group consisted of prepubertal short (<-2 SD score) children aged 315 yr and diagnosed as having GH deficiency (GHD) or idiopathic short stature (ISS). The treatment GH dose was 0.1 IU/kg·d (0.033 mg/kg·d). Five prediction models were constructed, using increasing amounts of pretreatment data and a nonlinear multivariate approach. The first model included exclusively auxology from the start of GH treatment (Basic model), and the second was constructed with the addition of growth data from the first 2 yr of life (Basic+Early growth model). The third and fourth models included the maximum GH level (GHmax) from provocation tests or the IGF-I SD score from the start of treatment, respectively. The best prediction model (i.e. the model with the most narrow prediction interval) included all the auxological data and data from the spontaneous 24-h GH secretion profile. The best predictor from the profile was the single maximum GH value. However, it is well known that the spontaneous maximum GH level usually occurs during nighttime and the 24-h GH profile is laborious to perform.
The aim of this study was, therefore, to determine whether the accuracy of prediction could be maintained if the GH sampling period was shortened, but still using all the auxological data (i.e. using the best prediction model).
To be able to answer this question data from a large group of children were required with a wide range of GH levels.
Data from a total of 279 prepubertal short children (94 with GHD and 185 with ISS, diagnosed according to results from two provocation tests, and aged 315 yr) were therefore studied. Data from children used in the construction and validation of the models were included as well as data from children later diagnosed as having GHD or ISS.
The studies were approved by the Ethics Committees of the Medical Faculties of the Universities of Göteborg, Lund, Linköping, Uppsala, and Umeå and of the Karolinska Institute. Informed consent was obtained from the parents of each child and from the child, where appropriate.
Results
The GHmax values were distinctly clustered
around two time points, 2400 h and 0500 h, irrespective of
the actual serum GHmax level. The period
2000 h to 0800 h contained 89% of the
GHmax values, and the period 2000 h to
0200 h contained 53% (Fig. 1). Guided by the timing of the
GHmax values over 24 h, with the aim of
including as many GHmax values as possible, the
periods 2000 h to 0800 h and 2000 h to 0200 h were
selected for comparison with the prediction result from the full 24-h
GH sampling period.
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The performance of a prediction model is estimated by the differences
(residuals) between the predicted and the observed outcomes, here
height SD score. Results are presented as the
SD for the residuals,
SDres, a measurement of the model
accuracy. The lower the SDres, the
better.
For the total group of 279 children, the prediction accuracy for the
first year height was estimated by the
SDres, using the prediction based on
the GHmax from the 12-h and 6-h sampling periods.
When data on growth in early life were included in the estimates, the
SDres were 0.194 and 0.207 for
12 h and 6 h, respectively, and 0.202 and 0.214 for 12 h
and 6 h, respectively, if early growth data were not included. As
expected, the SDres for these shorter
GH sampling periods were higher than those obtained using the true
GHmax over 24 h (0.191 with data on growth
in early life included and 0.199 if early growth data were not
included; Ref. 1), but still lower (i.e.
better) than the corresponding values achieved using models using the
GHmax from an arginine-insulin tolerance test
(GHmaxAITT) or levels of IGF-I before the start
of treatment (0.268 and 0.239) (1), respectively.
Discussion and Conclusion
Overnight blood sampling for estimation of spontaneous GH secretion may be regarded as laborious and stressful for the child, but compared with a provocation test it has many advantages: it is physiological, induces no discomfort, and, with the use of a withdrawal pump, is convenient and almost risk free. In addition, the resulting GH estimate used in the prediction model is a good predictor of the growth response to GH treatment and can be used to aid in the selection of children for an expensive treatment that may continue for many years. Thus, the expense of the investigation in terms of costs, time, discomfort, and risk should be compared with the reliability of the results achieved, together with the expense of treatment.
The GHmax obtained during a sampling period limited to 12 h at night results in an acceptable prediction level for 97% of the children and is still a better predictor of the growth response than the GHmax AITT or IGF-I levels when used in our prediction models. When considering GH treatment in a short child, we suggest that this work-up procedure, with the use of a computerized prediction model, may ultimately replace the hazardous provocation test that is such a poor predictor of the growth response to treatment.
Acknowledgments
Footnotes
Abbreviations: GHD, GH deficiency; ISS, idiopathic short stature.
Received June 22, 2000.
Accepted July 3, 2001.
References
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