Abstract
The aim of the study was to develop and validate models that could predict the growth responses to GH therapy of individual children. Models for prediction of the initial one and 2-y growth response were constructed from a cohort of 269 prepubertal children (Model group) with isolated GH deficiency or idiopathic short stature, using a nonlinear multivariate data fitting technique. Five sets of clinical information were used. The “Basic model” was created using auxological data from the year before the start of GH treatment and parental heights. In addition to Basic model data, the other four models included growth data from the first 2 y of life, or IGF-I, or GH secretion estimated during a provocation test (AITT) or a spontaneous GH secretion profile.
The performance of the models was validated by calculating the differences between predicted and observed growth responses in 149 new GH treated children (Validation group) who fulfilled the inclusion criteria used in the original cohort. The SD of these differences (SDres) in the validation group was compared with the SDres for the model group. For the 1st y, the SDres for the Basic model was 0.28 SDscores. The lowest SDres (0.19 SDscores), giving the most narrow prediction interval, was achieved adding the 24h GH profile and data on growth from the first 2 y of life to the Basic model. The models presented permit estimation of GH responsiveness in children over a broad range in GH secretion, and with an accuracy of the models substantially better than when using maximal GH response during an provocation test. The predicted individual growth response, calculated using a computer program, can serve as a guide for evidence-based decisions when selecting children to GH treatment.
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Abbreviations
- GHD:
-
GH deficiency
- GHI:
-
GH insensitivity
- ISS:
-
idiopathic short stature
- IGFBP-3:
-
IGF binding protein 3
- AITT:
-
arginin-insulin tolerance test
- GHmax:
-
the estimated maximal GH level
References
Saggese G, Ranke MB, Saenger P, Rosenfeld RG, Tanaka T, Chaussain JL, Savage MO 1998 Diagnosis and treatment of growth hormone deficiency in children and adolescents: Towards a consensus. Horm Res 50: 320–340
Ranke MB 1996 Towards a consensus on the definition of idiopathic short stature. Horm Res 45: 64
Wit JM, Boersma B, de Muinck Keizer-Schrama SMPF, Nienhuis HE, Oostdijk W, Otten BJ, Delemarre-van de Waal HA 1995 Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Clin Endocrinol Oxf 42: 365–372
Goddard AD, Covello R, Luoh S-M, Clackson T, Attie KM, Gesundheit N, Rundle AC, Wells JA, Carlsson LMS 1995 Mutations of the growth hormone receptor in children with idiopatic short stature. N Engl J Med 333: 1093–1098
Attie MK, Carlsson LMS, Rundle AC, Sherman BM 1995 Evidence for partial growth hormone insensitivity among patients with idiopatic short stature. J Pediatr 127: 244–250
Laron Z 1995 Prismatic cases: Laron Syndrome (Primary Growth Hormone Resistance) from patient to laboratory to patient. J Clin Endocrinol Metab 80: 1526–1531
Savage MO, Woods KA 1996 The investigation of growth hormone insensitivity. Clin Endocrinol Oxf 45: 257–260
Wyatt DT, Mark D, Slyper A 1995 Survey of growth hormone treatment practices by 251 pediatric endocrinologists. J Clin Endocrinol Metab 80: 3292–3297
Ranke MB, Haber P 1996 Growth hormone stimulation tests. In: Ranke MB (ed) Diagnostics of endocrine function in children and adolescents. Johann Ambrosius Barth Verlag, Heidelberg Leipzig, pp 134–148
Kriström B, Karlberg J, Albertsson Wikland K 1995 Prediction of the growth response of short prepubertal children treated with growth hormone. Acta Paediatr Scand 84: 51–57
Rosenfeld RG, Albertsson Wikland K, Cassorla F, Frasier DS, Hasegawa Y, Hintz RL, Lafranchi S, Lippe B, Loriaux L, Melmed S, Preece MA, Ranke MB, Reiter EO, Rogol AD, Underwood LE, Werther GA 1995 Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 80: 1532–1540
Kriström B, Jansson C, Rosberg S, Albertsson Wikland K 1997 Growth response to growth hormone (GH) treatment relates to serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in short children with various GH secretion capacities. J Clin Endocrinol Metab 82: 2889–2898
Kriström B, Carlsson B, Carlsson LMS, Albertsson Wikland K 1998 Short term changes in serum leptin levels provide a strong metabolic marker for the growth response to growth hormone treatment in children. J Clin Endocrinol Metab 83: 2735–2741
Altman DG, Royston P 2000 What do we mean by validating a prognostic model?. Stat Med 19: 453
Kriström B, Jansson C, Svensson B, Rosberg S, Nierop AFM, Albertsson Wikland K 1997 Growth response to growth hormone treatment is possible to predict. Horm Res 48: 74
Tanner JM, Whitehouse RM 1976 Clinical longitudinal standards for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 51: 170–202
Zachmann M, Prader A, Kind HP, Häflinger H, Budlinger H 1974 Testicular volume during adolescence. Helv Paediatr Acta 29: 61–72
Karlberg J, Engström I, Karlberg P, Fryer JG 1987 Analysis of linear growth using a mathematical model. Acta Paediatr Scand 76: 478–488
Albertsson Wikland K, Rosberg S 1988 Analyses of 24-hour growth hormone profiles in children: relation to growth. J Clin Endocrinol Metab 67: 493–500
Karlberg P, Taranger J, Engström I, Karlberg J, Landström T, Lichtenstein H, Lindström B, Svennberg-Redegren I 1976 Physical growth from birth to 16 years and longitudinal outcome of the study during the same age period. Acta Paediatr Scand 258: 7–76
Karlberg J, Albertsson Wikland K 1996 Nutrition and linear growth in childhood. In: Bindels JG, Goedhardt AC, Visser HKA (eds) Recent Developments in Infant Nutrition. Kluwer Academic Publishers, London, p 112–127
Albertsson Wikland K, Jansson C, Rosberg S, Novamo A 1993 Time-resolved immunometric assay of human growth hormone. Clin Chem 39: 1620–1625
Albertsson Wikland K, Rosberg S, Karlberg J, Groth T 1994 Analysis of 24-hour growth hormone profiles in healthy boys and girls of normal stature: relation to puberty. J Clin Endocrinol Metab 78: 1195–1201
Jansson C, Boguszewski C, Rosberg S, Carlsson LMS, Albertsson Wikland K 1997 Growth hormone (GH) assays: influence of standard preparations, GH isoforms, assay characteristics, and GH-binding protein. Clin Chem 43: 950–956
Merriam GR, Wachter KW 1982 Algorithms for the study of episodic hormone secretion. Am J Physiol 243: E310
Albertsson Wikland K, Rosberg S, Libre E, Lundberg LO, Groth T 1989 Growth hormone secretory rates in children as estimated by deconvolution analysis of 24-h plasma concentration profiles. Am J Physiol 257: E809
Albertsson Wikland K, Rosberg S 1996 Methods of evaluating spontaneous growth hormone secretion. In: Ranke MB (ed) Diagnostics of Endocrine Function in Children and Adolescents. Johann Ambrosius Barth Verlag, Heidelberg Leipzig, pp 149–175
Blum WF, Breier BH 1994 Radioimmunoassays for IGFs and IGFBPs. Growth Regul 4: 11–19
Boguszewski M, Jansson C, Rosberg S, Albertsson Wikland K 1996 Changes in serum insulin-like growth factor I and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. J Clin Endocrinol Metab 81: 3902–3908
Gifi A 1990 Nonlinear Multivariate Analysis. Wiley, Chichester, pp 58
Bradley J 1968 Distribution Free Statistical Test. Prentice-Hall, Inc, London, pp 76–78
Karlberg J 1989 A biologically-oriented mathematical model (ICP) for human growth. Acta Paediatr Scand Suppl 350: 70–94
Tassoni P, Cacciari E, Cau M, Colli C, Tosi M, Zucchini S, Cicognani A, Pirazzoli P, Salaradi S, Balsamo A, Frejaville E, Cassio A, Zappulla F 1990 Variability of growth hormone response to pharmacological and sleep tests performed twice in short children. J Clin Endocrinol Metab 71: 230–234
Albertsson Wikland K, Rosberg S 1992 Reproducibility of 24-h growth hormone profiles in children. Acta Endocrinol 126: 109–112
Martha PM, Rogol AD, Veldhuis JD, Blizzard RM 1996 A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. J Clin Endocrinol Metab 81: 4068–4074
Gelander L, Albertsson Wikland K 1989 Growth hormone (GH) release after administration of GH-releasing hormone in relation to endogenous 24-h GH secretion in short children. J Endocrinol 122: 61–68
Hindmarsh P, Smith PJ, Brook CGD, Matthews DR 1987 The relationship between height velocity and growth hormone secretion in short prepubertal children. Clin Endocrinol Oxf 27: 581–591
Mauras N, Blizzard RM, Link K, Johnson ML, Rogol AD, Veldhuis JD 1987 Augmentation of growth hormone secretion during puberty. J Clin Endocrinol Metab 64: 596–601
Ranke MB, Guilbaud O, Lindberg A, Cole T 1993 Prediction of the growth response in children with various growth disorders treated with growth hormone: analysis of data from the Kabi Pharmacia International Growth Study. Acta Paediatr 82S391: 82–88
Blethen SL, Compton P, Lippe BM, Rosenfeld RG, August GP, Johanson A 1993 Factors predicting the response to growth hormone (GH) therapy in children with GH deficiency. J Clin Endocrinol Metab 76: 574–579
Spagnoli A, Spadoni GL, Cianfarani S, Pasquino AM, Troiani S, Boscherini B 1995 Prediction of the outcome of growth hormone therapy in children with idiopatic short stature. J Pediatr 126: 905–909
Ranke MB, Guilbaud O 1991 Growth response in prepubertal children with idiopathic growth hormone deficiency during the first two years of treatment with human growth hormone. Acta Paediatr Scand 379: 109–115
Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson Wikland K, Price DA 1999 Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. J Clin Endocrinol Metab 84: 1174–1183
Damen GM, Boersma B, Wit JM, Heymans HSA 1994 Catch-up growth in 60 children with coeliac disease. J Pediatr Gastroenterol Nutr 19: 394–400
Ranke MB, Schwarze CP, Mohnike K, von Mühlendahl KE, Keller E, Willgerodt H, Kiess W 1998 Catch-up growth after childhood-onset substitution in primary hypothyroidism: is it a guide towards optimal growth hormone treatment in idiopathic growth hormone deficiency?. Horm Res 50: 264
Ranke MB, Lindberg A, Guilbaud O 1994 Prediction of growth in response to treatment with growth hormone. In: Ranke MB, Gunnarsson R (eds) Progress in Growth Hormone Therapy - 5 Years of KIGS. J & J Verlag, Mannheim, pp 97–111
Rikken B, Massa GG, Wit JM 1995 Final height in a large cohort of Dutch patients with growth hormone deficiency treated with growth hormone. Horm Res 43: 135–137
Blethen SL, Baptista J, Kuntze J, Foley T, LaFranchi S, Johanson A 1997 Adult height in growth hormone (GH) deficient children treated with biosynthetic GH. J Clin Endocrinol Metab 82: 418–420
Acknowledgements
The authors thank their colleagues in the Swedish Study Group for GH Treatment for fruitful discussions, for caring for the patients, and for providing the reports from clinical trials on GH treatment in short children in Sweden. The Swedish Study Group for GH Treatment consists of: K. Albertsson Wikland, J. Alm, S. Aronsson, J. Gustafsson, L. Hagenäs, A. Häger, S. Ivarsson, B. Kriström, C. Marcus, C. Moëll, K.O. Nilsson, M. Ritzén, T. Tuvemo, U. Westgren, O. Westphal, and J. Åman. We also thank our colleagues participating in the National Registry for GH treatment. Special thanks are due to our pediatric colleagues in the region of Western Sweden: Drs S. Adolfsson, M. Bergström, H. Fors, U. Jansson, P.O. Lübeck, and H. Tollig for collaboration and referring most of the patients who underwent complete investigations, and to our colleagues at the GP-GRC, collaborating in the clinical work: O. Westphal, R. Bjarnason, J. Dahlgren, L. Gelander, and E. Norjavaara; in the laboratory, C. Löfqvist and L. Larsson; and in the ward, C Axelson. We also thank Dr. W. Blum for the IGF-I and IGFBP-3 assays.
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This work was supported by grants from Swedish Medical Research Council (7509), Barnhusfonden, The Jerring Foundation, The Samariten Foundation, The Medical Faculties in Umeå and Göteborg Universities, Wilhelm and Martina Lundgrens Foundation, The May Flower Foundation, West Sweden Region (3160) and Pharmacia.
Part of this study has been presented at the 5th joint meeting of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society, Stockholm 1997.
APPENDIX
APPENDIX
Predicted Change in Height SDscore (ΔHSDS) during GH Treatment TABLE
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Wikland, K., Kriström, B., Rosberg, S. et al. Validated Multivariate Models Predicting the Growth Response to GH Treatment in Individual Short Children with a Broad Range in GH Secretion Capacities. Pediatr Res 48, 475–484 (2000). https://doi.org/10.1203/00006450-200010000-00010
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DOI: https://doi.org/10.1203/00006450-200010000-00010
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