Andreas F. M. Nierop

Validated Multivariate Models Predicting the Growth Response to GH Treatment in Individual Short Children with a Broad Range in GH Secretion Capacities

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.

Population-based waist circumference and waist-to-height ratio reference values in preschool children

Aim:  To establish new reference values for measurements of waist circumference and waist‐to‐height ratio in preschool children.

Models predicting the growth response to growth hormone treatment in short children independent of GH status, birth size and gestational age

BackgroundMathematical models can be used to predict individual growth responses to growth hormone (GH) therapy. The aim of this study was to construct and validate high-precision models to predict the growth response to GH treatment of short children, independent of their GH status, birth size and gestational age. As the GH doses are included, these models can be used to individualize treatment.MethodsGrowth data from 415 short prepubertal children were used to construct models for predicting the growth response during the first years of GH therapy. The performance of the models was validated with data from a separate cohort of 112 children using the same inclusion criteria.ResultsUsing only auxological data, the model had a standard error of the residuals (SDres), of 0.23 SDS. The model was improved when endocrine data (GHmax profile, IGF-I and leptin) collected before starting GH treatment were included. Inclusion of these data resulted in a decrease of the SDres to 0.15 SDS (corresponding to 1.1 cm in a 3-year-old child and 1.6 cm in a 7-year old). Validation of these models with a separate cohort, showed similar SDres for both types of models. Preterm children were not included in the Model group, but predictions for this group were within the expected range.ConclusionThese prediction models can with high accuracy be used to identify short children who will benefit from GH treatment. They are clinically useful as they are constructed using data from short children with a broad range of GH secretory status, birth size and gestational age.

A proteomic approach identified growth hormone-dependent nutrition markers in children with idiopathic short stature

BackgroundThe broad range in growth observed in short prepubertal children receiving the same growth hormone (GH) dose is due to individual variation in GH responsiveness. This study used a pharmaco-proteomic approach in order to identify novel biomarkers that discriminate between short non-GH-deficient (GHD) children who show a good or poor growth response to GH treatment.A group of 32 prepubertal children with idiopathic short stature (ISS) were included in the study. Children were classified on the basis of their first year growth velocity as either good (high responders, n = 13; range, 0.9–1.3 standard deviation score (SDS) or poor (low responders, n = 19; range, 0.3–0.5 SDS) responders to GH treatment (33 μg/kg daily).Serum protein expression profiles before, and after 1 year of GH treatment, were analyzed on a weak cationic exchange array (CM10) using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS).ResultsChanges in the intensity of two protein peaks (13.788 kDa and 17.139 kD) during the study period allowed the correct classification of 82% of children as high and low responders, respectively. The 13.788 kD peak, transthyretin, decreased in the high-responder group and increased in the low-responder group during 1 year of GH treatment, whereas the 17.139 kDa peak, apolipoprotein A-II (Apo A-II) decreased in the high-responder group and remained unchanged in the low-responder group. These peaks were identified by the consistency of peak pattern in the spectra, serum depletion experiments using specific antibodies and mass spectrometry.ConclusionOur results suggest that transthyretin and apolipoprotein A-II may have a role in GH sensitivity and could be used as markers to predict which short prepubertal children with ISS will show a good or poor response to GH treatment.

Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency

Context  Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.

Proteins related to lipoprotein profile were identified using a pharmaco-proteomic approach as markers for growth response to growth hormone (GH) treatment in short prepubertal children

BackgroundThe broad range in growth observed in response to growth hormone (GH) treatment is mainly caused by individual variations in both GH secretion and GH sensitivity. Individual GH responsiveness can be estimated using evidence-based models that predict the response to GH treatment; however, these models can be improved. High-throughput proteomics techniques can be used to identify proteins that may potentially be used as variables in such models in order to improve their predictive ability. Previously we have reported that proteomic analyses can identify biomarkers that discriminate between short prepubertal children with idiopathic short stature (ISS) who show good or poor growth in response to GH treatment. In this study we used a pharmaco-proteomic approach to identify novel factors that correlate with the growth response to GH treatment in prepubertal children who are short due to GH deficiency or ISS. The study included 128 short prepubertal children receiving GH treatment, of whom 39 were GH-deficient and 89 had ISS. Serum protein expression profiles at study start and after 1 year of GH treatment were analyzed using SELDI-TOF. Cross-validated regression and random permutation analyses were performed to identify significant correlations between protein expression patterns and the 2-year growth response to GH treatment.ResultsAt start of treatment we identified a combination of seven protein peaks that correlated with the 2-year growth response in the GH-deficient group (R2 = 0.73). After 1 year of treatment, a combination of four peaks in the GH-deficient group (R2 = 0.64), eight peaks in the ISS group R2 = 0.47) and eight peaks in the total study group correlated with the 2-year growth response R2 = 0.38).The peaks identified corresponded to apolipoproteins A-I, A-II, C-I, C-III, transthyretin and serum amyloid A 4, which are all part of the high-density lipoprotein.ConclusionUsing a proteomic approach we identified biomarkers related to the lipoprotein profile that could be used to predict growth response to GH treatment in prepubertal children who are short as a result of GH-deficiency or who have ISS.These results support our previous findings that apolipoproteins and transthyretin may have a role in GH sensitivity.

Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children

BackgroundIn addition to stimulating linear growth in children, growth hormone (GH) influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. Hypothesis: There are different dose-dependent thresholds for metabolic effects in response to GH treatment.MethodA randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a) individualized GH dose including six different dose groups ranging from 17–100 μg/kg/day (n=87) and (b) fixed GH dose of 43 μg/kg/day (n=41). The individualized GH dose group was used for finding dose–response effects, where the effective GH dose (ED 50%) required to achieve 50% Δ effect was calculated with piecewise linear regressions.ResultsDifferent thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval) was calculated as 33(±24.4) μg/kg/day for Δ left ventricular diastolic diameter (cm), 39(±24.5) μg/kg/day for Δ alkaline phosphatase (μkat/L), 47(±43.5) μg/kg/day for Δ lean soft tissue (SDS), 48(±35.7) μg/kg/day for Δ insulin (mU/L), 51(±47.6) μg/kg/day for Δ height (SDS), and 57(±52.7) μg/kg/day for Δ insulin-like growth factor I (IGF-I) SDS. Even though lipolysis was seen in all subjects, there was no dose–response effect for Δ fat mass (SDS) or Δ leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial.ConclusionsDose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.

Protein profiling identified dissociations between growth hormone-mediated longitudinal growth and bone mineralization in short prepubertal children

Growth hormone (GH) promotes longitudinal growth and bone mineralization. In this study, a proteomic approach was used to analyze the association between serum protein expression pattern and height-adjusted bone mineralization in short prepubertal children receiving GH treatment. Patterns of protein expression were compared with those associated with longitudinal bone growth. Specific protein expression patterns associated with changes in height-adjusted bone mineralization in response to GH treatment were identified. Out of the 37 peaks found in significant regression models, 27 were uniquely present in models correlated with changes in bone mineralization and 7 peaks were uniquely present in models correlated with changes in height. The peaks identified corresponded to apolipoproteins, transthyretin, serum amyloid A4 and hemoglobin beta. We conclude that a proteomic approach could be used to identify specific protein expression patterns associated with bone mineralization in response to GH treatment and that height-adjusted bone mineralization and longitudinal bone growth are regulated partly by the same and partly by different mechanisms. Protein isoforms with different post-translational modifications might be of importance in the regulation of these processes. However, further validation is needed to assess the clinical significance of the results.

Modelling individual longitudinal human growth from fetal to adult life − QEPS I

BACKGROUND Only one mathematical model to date describes human growth and its different phases from fetal life until adult height. AIM To develop a model describing growth from fetal life to adult height taking maturation/biological tempo into consideration. METHODS SUBJECTS The model was developed based on longitudinal mean height values obtained from published growth references for a cohort of 3650 healthy Swedish children followed from birth circa 1974 until adult height combined with birth-length for circa 400 000 healthy infants born 1990-1995. RESULTS The QEPS-model for individual growth was constructed with a combination of four basic shape-invariant growth functions: a quadratic Q-function and a negative exponential E-function, both started during fetal life, 8 months before birth; the E-function levelled off after birth, whereas the Q-function continued until end of growth. A specific nonlinear pubertal P-function started at onset of puberty, and a stop S-function ended growth according to both the Q-function continuing during puberty and the specific P-function. For each function, an individual height-scale parameter was defined, and for the E- and P-functions, a time-scale parameter; giving six modifying parameters in total. In addition standardized proportional scores were used for biological interpretations. The QEPS-model was used to fit and generate mathematical functions suitable to describe the growth of the healthy population of Swedish children; thereafter, the model was modified using four height-scale parameters to model individual height in cm, and two time-scale parameters to adjust for the individual tempo of growth. Individual confidence intervals were calculated for all parameters. CONCLUSIONS A new shape-invariant growth model, QEPS, was developed, that requires only four basic growth functions to describe the total pattern of growth in height from fetal life to adult height, with addition of height- and time-scale parameters describing individual growth. The model can describe a wide variety of growth curves. Moreover, it is the first model to provide confidence intervals which enable us to describe the precision/quality of individual parameters.

ORIGINAL ARTICLE: Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency

Context  Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.