Background
In a clinical setting, when considering prescribing growth hormone (GH) treatment for a short or slowly growing child, tools that reliably predict the growth response to treatment are welcome. Published prediction models rely on pretreatment auxological variables and often on parental heights
Most prediction models give information on the estimated growth response for only the first or the first 2 years of treatment
The aim of this project was to develop a prediction model for growth in response to GH in prepubertal children, relying only on data that could be obtained in different health settings, and also in adopted and immigrant children (i.e. where information on birth size, gestational age, growth during early life and parental heights are missing). However, accuracy and reliability should not be reduced compared with our previously published prediction model relying on pretreatment data
It is an empirical finding that first year growth in response to GH is an indicator of the growth response in subsequent years of treatment, a finding confirmed in models predicting growth response on a yearly basis in children with GH deficiency (GHD)
The hypothesis in the present study was that the observed first-year growth response to a certain dose of GH in prepubertal children would provide enough information with which to construct a prediction model with a model error low enough to be useful in clinical practice for the prediction of future prepubertal growth response on GH treatment. By this, it should be possible to individualize the GH dose and thereby the growth outcome until the onset of puberty.
Patients and Methods
Patients
Growth response data until puberty were used from prepubertal children on GH treatment in Sweden retrieved from the National Registry or from clinical trials. Every 3 months, the dose of GH was adjusted according to weight, height was measured with a standardized technique, and pubertal status and compliance were checked.
Model group
Growth data during GH treatment were obtained from 162 prepubertal children born at term (19% girls; 80% GH-deficient; 23% born SGA) and for whom 2 years or more of prepubertal growth data were available and age was 2.5 years or more at the start of treatment (Table
The characteristics of the children included in the model group (n = 162) and in the validation group (n = 205).
Model group
(30 girls, 132 boys)
Validation group
(58 girls, 147 boys)
Variables
Median
Min
Max
n
Median
Min
Max
n
At birth
Gestational age (weeks)
40
37
42
162
40
37
42
205
Height at birth SDS
-1.07
-2.65
2.6
162
-1.48
-5.75
1.9
205
Weight at birth SDS
-0.88
-2.75
3.24
162
-1.28
-4.5
1.81
205
At GH start
Age at start of GH treatment (yrs)
8.3
2.78
13.92
162
7.78
2.51
12.53
205
Height SDS
-2.91
-4.59
-1.54
162
-2.84
-4.76
-1.29
205
Weight SDS
-2.58
-4.29
0.73
162
-2.5
-5.28
1.28
205
Weight for height SDS
-0.54
-3.31
3.85
162
-0.61
-3.08
4.09
205
Body mass index (kg/m2)
15.4
12.88
23.98
162
15.19
12.25
23.76
205
Change in height SDS during pre-treatment year
0.02
-0.85
0.58
144
0.01
-0.71
0.68
186
Target height SDS
-0.75
-2.4
1.26
162
-0.66
-2.71
0.94
205
Fathers height SDS
-1.13
-4.93
1.91
162
-0.83
-3.86
2.02
205
Mothers height SDS
-1,25
-3.55
1.22
162
-1.25
-3.55
1.55
205
Diff MPH SDS
-2.26
-4.98
-0.8
162
-2.27
-5.11
-0.41
205
GHmax during AITT (mU/L)
19.8
1.7
229.4
160
21
2.4
124.88
181
GHmax of 24 h profile (mU/L)
34.65
3.88
81.08
64
32.8
7.55
235.37
94
IGF-I at GH start
96.25
11.68
219
68
80
8
330
150
IGF-I SDS
-0.6
-6.69
1.38
68
-1.1
-7.43
3.03
150
GH dose (ug/kg.day)
0.033
0.027
0.04
162
0.033
0.023
0.043
205
During treatment
Change in height SDS first yr
0.72
0.3
2.26
162
0.74
0.07
2.56
205
Change in height SDS during 2 yrs
1.15
0.4
2.88
162
1.14
0.23
3.12
205
Growth hormone (mU/L) levels were analysed at GP-GRC, GU, with Delfia monoclonal assay, Wallac, Finland, standard WHO IRP 80/505,
Insulin-like growth factor I (IGF-I) (μg/L) were analysed according to Blum and Breier
Validation group
Data from 205 children (28% girls; 74% GH-deficient; 43% born SGA), fulfilling the same inclusion and treatment criteria as the model group, were used to validate the model (Table
Test groups
Children born prematurely
The model was applied to data from a separate group of 19 children born prematurely with a gestational age of 30–36 weeks (68% SGA) and given GH at a dose of 33 μg/kg/d (Table
The characteristics of the children included in the test groups of children born prematurely (n = 19) and in children from other continents (n = 78).
Preterm
(6 girls, 13 boys)
From foreign continents
(27 girls, 51 boys)
Variables
Median
Min
Max
n
Median
Min
Max
n
At birth
Gestational age (weeks)
35
32
36
19
38.5
27
41
28
Height at birth SDS
-2.55
-8.09
1.43
19
-1.76
-3.91
0.38
6
Weight at birth SDS
-2.25
-6.12
0.11
19
-1.27
-3.95
0.63
8
At GH start
Age at start of GH treatment (yrs)
6.38
3.02
10.1
19
8.35
3.13
13.47
78
Height SDS
-2.81
-4.08
-2.01
19
-3.27
-6.31
-0.74
78
Weight SDS
-2.78
-5.15
-1.56
19
-3.11
-5.66
1.12
78
Weight for height SDS
-0.97
-3.29
0.71
19
-0.71
-3.8
4.23
78
BMI (kg/m2)
14.5
12.18
16.5
19
15.35
11.49
22.23
78
Change in height SDS during pre-treatment year
0
-0.45
0.52
17
0.07
-0.73
0.59
69
Target height SDS
-0.58
-1.89
1.26
19
-1.23
-3.72
0.5
39
Father height SDS
-1.13
-3.41
1.3
19
-2.04
-4.62
0.54
39
Mother height SDS
-0.84
-3.39
1.55
19
-2.07
-5.85
0.4
41
Diff MPH SDS
-2.23
-3.43
-1.27
19
-1.76
-4.35
1.27
39
GHmax during AITT (mU/L)
24.15
11
70.4
18
20.72
1.09
135.57
30
GHmax of 24 h profile (mU/L)
19.95
14.3
48.05
11
42.69
12.37
88.79
43
IGF-I at GH-start
60
19
187
18
78
12
259
19
IGF-I SDS
-1.57
-5.42
0.72
18
-1.35
-7.02
1.75
19
GH dose (ug/kg.day)
0.037
0.027
0.043
19
0.033
0.023
0.047
78
During treatment
Change in height SDS first yr
0.67
0.47
1.16
19
0.68
-0.1
1.74
78
Change in height SDS during 2 yrs
0.92
0.63
1.69
19
1.06
0.11
2.79
78
Children from non-European continents
Growth data for 78 children from non-European continents (four from Africa, 24 from Asia, 24 from other continents and 26 who had parents from different continents) given GH at a dose of 33 μg/kg/d were also tested in the model. Out of these 78 children, 28 had a diagnosis of GHD and 24 a diagnosis of ISS; in 26 children a GH-provocation test had not been performed. Birth data were missing in the majority of these patients (Table
Children treated with a higher GH dose
In order to study the robustness of the model, growth data from 15 children treated with a GH dose of 67 μg/kg/d, but otherwise fulfilling all inclusion criteria for the model, were assessed.
Methods
Auxology
Birth weight SDS and birth length SDS used in the algorithms were calculated according to Niklasson et al.
Curve fitting for a non-linear growth-response curve
During our earlier work for the prediction of the 0–1 year and 0–2-year growth responses to GH treatment in prepubertal children with GHD and ISS, models were constructed based exclusively on data that could be obtained from before the start of GH treatment, heavily relying on auxological data at birth and during the first 2 years of life and parental heights
Measurements of growth response were obtained at different treatment times; for adequate correction of these differences a non-linear growth-response curve was computed by curve-fitting. It was based on observed longitudinal measurements from a subset of the model group of patients reported previously
Furthermore, the old complex equations, Fa(t) and Fb(t), were reparameterized to facilitate more simple clinical interpretation, especially for equation Fb(t) (Figure
Graphic illustration of the two equations that, when combined, produce the non-linear growth response curve
Graphic illustration of the two equations that, when combined, produce the non-linear growth response curve. The hyperbolic equation FCU(t) can be regarded as a 'catch-up' equation, (by multiplying with the individual parameter MModel) asymptotically modulating individual amplitude with time. The "1" on the y-axis gives the asymptotic value of the FCU(t), and the Equation FBG(t) can be interpreted as a 'baseline growth' equation that introduces a delayed general growth response with a greater relative impact on individuals with low levels of catch-up growth than on individuals with high levels of catch-up growth.
Our previous equation, Fa(t)
The accuracy of this reparameterization was assessed by evaluating the maximum absolute deviation between the old
The individual growth-response curves can be computed by adding the two equations, where only FCU(t) is multiplied by an individual factor, a model parameter MModel
The clinical concept 'Response Score' (RS)
The MModel(Individual) *FCU(t) part of the equation provides an individual predicted catch-up growth curve over the prepubertal years, approaching an asymptotic value (Figure
The total growth response during time 't' can be expressed by the growth response equation: Δheight SDS (t) = FBG(t) + RSpred * FCU(t) (Figure
GH response chart for visualization of Response Scores (RS) on different levels (i.e. growth responses for children with variable individual responsiveness to GH)
GH response chart for visualization of Response Scores (RS) on different levels (i.e. growth responses for children with variable individual responsiveness to GH). Left panel: The RS chart is given with 'isolines' ('channels') for RS = 1, 2, 3 and 4 which is indicated in the figure. For the individual child at treatment time 1 year (x-axis), the observed growth response (Δheight SDS) is found on the y-axis to the left and following the corresponding curve the individual RS can be found to the right. Middle panel: Observed first-year Δheight SDS on treatment for three prepubertal children from the validation group (filled circles). The individual calculated Response Score (dotted line) is found on the right axis. The function for the Response score is: RS(t) = (Δheight SDSobs - FBG(t))/FCU(t), where FBG(t) = elog (1 + t*(0.205 - 1/(1 + 2.1*t))) and FCU(t) = t/(t + 0.894); t = GH treatment time in years. Right panel: Individual Response Scores from the same three children, based on observed Δheight SDS on treatment at different time points (filled circles at treatment time 2, 3, 4, 5 and 6 years) in comparison with the predicted (dotted line). Response Score was consistent over time within an individual child, and the inclusion in the model of measurements made later than 1 year after the start of GH treatment are acceptable.
Using the observed Response Score (RS) for prediction
For each observed measurement of individual growth response on GH treatment (Δheight SDSobs), it is possible to estimate the individual RS by defining the following Response Score equation: RS(t) = (Δheight SDSobs - FBG(t))/FCU(t) (Figure
This gives the prediction model: Δheight SDS(t) = FBG(t) + RS1 yr * FCU(t)
where FBG(t) = elog (1 + t*(0.205 - 1/(1 + 2.1*t))) and FCU(t) = t/(t + 0.894); t = GH treatment time in years.
For each child, the RS(t) value that is calculated from an observed change in height SDS (Δheight SDStobs) should remain constant during GH treatment, as long as no concomitant distress interferes with growth.
Ethics
The study was approved by the Ethics Committee 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 parent(s) or person(s) with custody of the child and from the child, where appropriate.
Results
Observed response score for prediction
Figure
Validation of long-term growth in response to GH on data from children born AGA/SGA at term
The observed individual growth responses to GH in 205 children during 1–7 years of prepubertal growth were used to validate the predictions made based on the observed first-year growth and the corresponding Response Score. The validation group was examined both in total and subdivided into children born AGA and SGA; data are presented in Table
Model error for the prediction of the 1–7-year GH growth response expressed in Dheight SD scores for the model group and the validation group separately: for the total group and subdivided into children born AGA or SGA.
Model group
Validation group
Total group:
n
SDres
SDstudRes
Total group:
n
SDres
SDstudRes
1–2 year
162
0.17
1.00
1–2 year
205
0.19
1.11
1–3 years
97
0.29
1.00
1–3 years
111
0.28
0.97
1–4 years
53
0.38
1.00
1–4 years
58
0.35
0.90
1–5 years
34
0.43
1.00
1–5 years
40
0.45
1.04
1–6 years
17
0.48
1.00
1–6 years
29
0.40
0.84
1–7 years
7
0.57
1.00
1–7 years
9
0.43
0.75
AGA:
AGA:
1–2 year
125
0.17
0.99
1–2 year
117
0.19
1.12
1–3 years
69
0.28
0.96
1–3 years
63
0.26
0.90
1–4 years
39
0.39
1.02
1–4 years
31
0.31
0.82
1–5 years
21
0.44
1.03
1–5 years
18
0.39
0.92
1–6 years
8
0.45
0.95
1–6 years
15
0.42
0.88
1–7 years
7
0.57
1.00
1–7 years
3
0.26
0.45
SGA:
SGA:
1–2 year
37
0.18
1.05
1–2 year
88
0.19
1.09
1–3 years
28
0.31
1.08
1–3 years
48
0.30
1.05
1–4 years
14
0.36
0.93
1–4 years
27
0.37
0.98
1–5 years
13
0.41
0.96
1–5 years
22
0.49
1.13
1–6 years
9
0.50
1.04
1–6 years
14
0.37
0.79
1–7 years
0
-
-
1–7 years
6
0.49
0.87
SDres = root mean square error of the residuals.
SD stud Res = SDres/SDresModelgroup
For a reliable model, the SDres should be similar, or lower, for the validation group compared with the SDres from the model group.
Group validation of estimated Response Scores
The values for the Response Scores over treatment time t (RS(t)) were calculated for 51 of the 162 children on GH treatment in the model group for whom prepubertal growth measurements were available at precise annual intervals during the first 4 years of treatment (Figure
The group mean values ± SEM for the Response Score calculated at 1, 2, 3 and 4 years of GH treatment
The group mean values ± SEM for the Response Score calculated at 1, 2, 3 and 4 years of GH treatment. The equation was applied to data from children who have values from all four annual measurements on GH treatment: the model group (n = 51) and validation group (n = 54). The observed height at the yearly measurement is used for estimation of the RS (1–4 years). This shows that a reliable model gives constant RS values during 4 years of GH treatment.
The similarity with respect to mean growth in response to GH over all years shows that the model and validation groups are clinically comparable with respect to the average growth response; the difference between group mean yearly changes in height SDS is a maximum of 0.02 SDS. The model and validation groups were also studied after subdivision into quartiles according to the RS1 yr level; the mean and range at each yearly measurement remained the same for each quartile (data not shown).
Test on data from children born prematurely
The prediction model based on RS1 yr was tested on a separate group of 19 children born prematurely at a gestational age of 30–36 weeks, Table
Test of growth in response to GH treatment in different cohorts of children: born preterm from other countries or treated with 67 μg/kg/d of GH in children born preterm or at term.
Children born preterm (30–36 w)
GH dose 33 μg/kg/d
n
SDres
SDstudRes
1–2 year
19
0.16
0.93
1–3 years
15
0.31
1.07
1–4 years
7
0.44
1.15
1–5 years
5
0.27
0.63
1–6 years
4
0.51
1.07
1–7 years
2
0.47
0.83
Children from other continents
GH dose 33 μg/kg/d
n
SDres
SDstudRes
1–2 year
78
0.18
1.07
1–3 years
42
0.25
0.88
1–4 years
20
0.35
0.9
1–5 years
10
0.34
0.79
GH dose of 67 μg/kg/d
Born at term
n
SDres
SDstudRes
1–2 year
15
0.19
1.13
1–3 years
7
0.31
1.09
1–4 years
2
0.37
0.95
GH dose of 67 μg/kg/d
Born preterm
n
SDres
SDstudRes
1–2 year
7
0.17
1.01
1–3 years
2
0.26
0.90
SDres = root mean square error of the residuals.
SD stud Res = SDres/SDresModelgroup
Test on data from children coming from other continents
The prediction model was tested, and found to be valid on growth data from 78 children from other continents who seldom had complete data on birth size, pre-treatment growth and/or parental heights (Table
Test on data from children treated with an increased GH dose
In order to study the robustness of the model for differences in GH dosing, data from children fulfilling the inclusion criteria but being treated with a higher GH dose (67 μg/kg/d) were checked in the prediction model. The results are presented in Table
Discussion
The hypothesis for the present study was confirmed, i.e. the observed first-year growth response on GH treatment contained enough information to be used for prediction of up to 7 years of prepubertal growth on GH treatment with a model error below 0.1 SDS/year for the entire 7-year period. The validated model is accurate and reliable and only needs information on four variables: gender, age, height at start of GH treatment, and observed first-year growth response to GH. This information is easily obtained in a clinical setting. The model can also be used for the children of immigrants for whom early growth data and parental height data are missing, as no pre-treatment investigations are necessary. Information on first-year growth in response to GH treatment makes it possible to estimate an individual Response Score, which can be used in the model in place of the pre-treatment data used in our previous prediction models to give equally accurate growth predictions
A prerequisite for construction of the model is that we can demonstrate that the growth response to GH treatment can be fully described by a common equation for prepubertal non-syndromic children, clinically classified as GH-deficient/ISS, AGA/SGA and born later than 30 weeks of gestation. Using growth-response equations which are modulated by an individual parameter depending on individual responsiveness and GH dose, we show that the model works on empirical data from an independent group of 205 children fulfilling the inclusion criteria for the model group and also on data from more than 100 children with short stature as a result of other diagnoses. Thus, the present model was demonstrated to be valid on independent data from children classified as GH-deficient/ISS, born AGA/SGA, born at term/preterm (> 30 weeks gestational age), of Swedish or non-Swedish origin and receiving a GH dose close to 33 ug/kg/d or 67 ug/kg/d. Although these results are valid for the model, the groups of children treated with higher dose or born preterm are limited in number and data from more children are needed for further validation.
The performance of the present model, demonstrated by the SDres for the second year, is 0.17 SDS, corresponds to a 95% prediction interval of ± 0.34 SDS with very similar results for the model group and the validation group. This gives a second year prediction interval of ± 1.2 cm for a 3-year-old child and ± 1.8 cm for a child aged 7 years. For 1–4 years of treatment, the SDres is as low as 0.38 SDS (i.e. 0.13 SDS/year) and for the period from 1–7 years, the SDres is 0.57 SDS (i.e. < 0.1 SDS/year). Thus, knowing only the first-year growth response to GH treatment makes it possible to predict the total growth response for up to 7 prepubertal years (i.e. until the start of puberty). This is of great clinical significance as height at the onset of puberty has an important influence on adult height
In this project a new concept was introduced: the individual Response Score at 1 year which is dependent on both the GH dose and the GH responsiveness of the child. For each child, it is now possible to calculate an individual Response Score value using the observed change in height SDS during a given treatment time period. Due to seasonal variation in both spontaneous growth and growth during GH treatment
In many children, information on heredity (parental heights), gestational age, birth size and/or pre-treatment growth are missing and are impossible to retrieve. For such children, a test-treatment year is often used to evaluate GH responsiveness. Therefore, a model that is accurate for use in patients with many different diagnoses of short stature is crucial as otherwise insufficient information precludes the use of any prediction model. The prediction model presented can be used in such children with the same degree of accuracy as the model that includes pretreatment data
The variation in mean GH responsiveness between groups of children with different diagnosis is well known
Conclusion
In conclusion, data are presented showing that the growth response to GH treatment can be described by a common algorithm for prepubertal non-syndromic children from different ethnic and geographic backgrounds, clinically classified as GHD/ISS, AGA/SGA and born later than 30 weeks of gestation. For each child, there is an individual parameter modulating the amplitude and timing of the response that depends on the child's GH responsiveness (constant) and treatment dose (here named Response Score). The observed first-year growth response to GH treatment reveals this value.
We provide a prediction model that is valid for the majority of short children worldwide in whom growth-supportive therapies are considered, despite the lack of historical auxological data on the child and without the need for any extensive investigations. The advantage of the present model is the 7-year reliability (i.e. the entire prepubertal period). The drawbacks are that an observed first-year GH growth response is needed and that the model is currently only validated for a GH dose close to 33 μg/kg/d. In order to increase the applicability of the mode, a collaborative study will be needed. This will be of importance in order to add a dose module for improved individualizing of the GH dose. Using this decision-making tool, it is possible to make reliable evidence-based decisions on whether, or how, to continue GH treatment in the individual child.
The model presented here can be used in non-syndromic short children, independently of birth size, and provides the best prediction accuracy available
Abbreviations
AGA: appropriate for gestational age; AITT: arginine-insulin tolerance test; DIFF MPH SDS: difference in SDS between child and target height; GHD: growth hormone deficiency; IGF-I: insulin-like growth factor I; ISS: idiopathic short stature; RS: response score; SDS: standard deviation score; SDres: root mean square error of the residuals; SGA: small for gestational age.
Competing interests
Kerstin Albertsson Wikland (KAW) declares that she had until 2005 an unrestricted research grant from Pharmacia/Pfizer. Berit Kristrom (BK) and Jovanna Dahlgren (JD) have received reimbursement for expert consultant work for Pfizer and JD has shares in the company. Aimon Niklasson (AN) has nothing to declare. Andreas FM Nierop (AFMN) works for Muvara, Multivariate Analysis of Industrial and Research Data Statistical Consultation, The Netherlands.
Authors' contributions
BK, JD, AN, AFMN and KAW have all given substantial contribution to conception and design, analysis and interpretation of these data. AFMN has performed all of the modeling work. BK, JD, AN, AFMN and KAW have been involved in drafting the manuscript and have revised it critically for intellectual content. BK, JD, AN, AFMN and KAW have given final approval of the version to be published.