Novel type of references for BMI aligned for onset of puberty - using the QEPS growth model.

OBJECTIVES: Despite inter-individual variations in pubertal timing, growth references are conventionally constructed relative to chronological age (C-age). Thus, they are based on reference populations containing a mix of prepubertal and pubertal individuals, making them of limited use for detecting abnormal growth during adolescence. Recently we developed new types of height and weight references, with growth aligned to age at onset of the pubertal growth spurt (P-age). Here, we aim to develop a corresponding reference for pubertal BMI. METHODS: The QEPS-height and weight models were used to define a corresponding QEPS-BMI model. QEPS-BMI was modified by the same individual, constitutional weight-height-factor (WHF) as computed for QEPS-weight. QEPS-BMI functions were computed with QEPS weight and height functions fitted on longitudinal measurements from 1418 individuals (698 girls) from GrowUp1990Gothenburg cohort. These individual BMI functions were used to develop BMI references aligned for height at AgeP5; when 5% of specific puberty-related (P-function) height had been attained. Pubertal timing, stature at pubertal onset, and childhood BMI, were investigated in subgroups of children from the cohort GrowUp1974Gothenburg using the new references. RESULTS: References (median, standard deviation score (SDS)) were generated for total BMI (QEPS-functions), for ongoing prepubertal growth (QE-function) vs C-age, and for total BMI and separated into BMI specific to puberty (P-function) and BMI gain from ongoing basic growth (QES-functions), allowing individual growth to be aligned based on P-age. Growth in basic BMI was greater than average for children categorized as tall and/or with high-BMI at puberty-start. In children categorized as short at puberty-start, P-function-related-BMI was greater than average. CONCLUSIONS: Use of these new pubertal BMI references will make it possible for the first time to consider individual variations owing to pubertal timing when evaluating BMI. This will improve the detection of abnormal changes in body composition when used in combination with pubertal height and weight references also abnormal growth. Other benefits in the clinic will include improved growth monitoring during treatment for children who are overweight/obese or underweight. Furthermore, in research settings these new references represent a novel tool for exploring human growth.

Growth pattern evaluation of the Edinburgh and Gothenburg cohorts by QEPS height model.

BACKGROUND: The QEPS-growth-model, developed and validated in GrowUp-Gothenburg cohorts, used for developing growth references and investigating healthy/pathological growth, lacks external validation from other longitudinal cohorts of healthy individuals. AIM: To investigate if the QEPS-model can fit the longitudinal Edinburgh growth study of another design than GrowUp-Gothenburg cohorts, and to compare growth patterns in the individuals born in mid-1970s in North-Western Europe. METHODS: Longitudinal growth data were obtained from the Edinburgh and the GrowUp1974Gothenburg cohorts. The QEPS-model was used to describe length/height from birth to adult height with confidence interval, and the multivariable regression model for estimating the contribution of the different QEPS-functions to adult height. RESULTS: The QEPS-model fitted the Edinburgh cohort well, with high accuracy, and low confidence intervals indicating high precision. Despite 3 cm shorter stature (less QE-function growth) in Scottish children, the growth patterns of the cohorts were similar, especially for specific pubertal growth. The contribution to adult height from different QEPS functions was similar. CONCLUSION: The QEPS-model is validated for the first time in a longitudinal study of healthy individuals of another design and found to fit with high accuracy and precision. The Scottish and Western-Swedish cohorts born in mid-1970s showed similar growth patterns for both sexes, especially pubertal growth. IMPACT: For the first time, the QEPS height model was used and found to fit another longitudinal cohort of healthy individuals other than the Swedish longitudinal cohorts. With large numbers of individual measurements in each growth phase, the QEPS model calculates growth estimates with narrow confidence intervals (high precision) and high accuracy. The two different cohorts born in the mid-1970s from Scotland and Western Sweden have similar growth patterns, despite a 3 cm difference in adult height.

Novel type of references for weight aligned for onset of puberty - using the QEPS growth model.

BACKGROUND: Growth references are traditionally constructed relative to chronological age, despite inter-individual variations in pubertal timing. A new type of height reference was recently developed allowing growth to be aligned based on onset of pubertal height growth. We here aim to develop a corresponding reference for pubertal weight. METHODS: To model QEPS-weight, 3595 subjects (1779 girls) from GrowUp1974Gothenburg and GrowUp1990Gothenburg were used. The QEPS-height-model was transformed to a corresponding QEPS-weight-model; thereafter, QEPS-weight was modified by an individual, constitutional weight-height-factor. Longitudinal weight and length/height measurements from 1418 individuals (698 girls) from GrowUp1990Gothenburg were then used to create weight references aligned for height at pubertal onset (the age at 5% of P-function growth, AgeP5). GrowUp1974Gothenburg subgroups based on pubertal timing, stature at pubertal onset, and childhood body composition were assessed using the references. RESULTS: References (median, SDS) for total weight (QEPS-functions), weight specific to puberty (P-function), and weight gain in the absence of specific pubertal growth (basic weight, QES-functions), allowing alignment of individual growth based on age at pubertal onset. For both sexes, basic weight was greater than average for late maturing, tall and high-BMI subgroups. The P-function-related weight was greater than average in short and lower than average in tall children, in those with high BMI, and in girls but not boys with low BMI. CONCLUSIONS: New pubertal weight references allow individual variations in pubertal timing to be taken into consideration when evaluating growth. When used together with the comparable pubertal height reference, this will improve growth monitoring in clinical practice for identifying abnormal growth and serve as a valuable research tool providing insight into human growth.

Swedish references for weight, weight-for-height and body mass index: The GrowUp 1990 Gothenburg study.

AIM: To update the Swedish references for weight, weight-for-height and body mass index (BMI) considering the secular trend for height but not including that for weight. METHODS: Longitudinal measures of height and weight were obtained (0-18 years) from 1418 (698 girls) healthy children from the GrowUp 1990 Gothenburg cohort born at term to non-smoking mothers and Nordic parents. A total of 145 individuals with extreme BMI value vs GrowUp 1974 BMI SDS reference were excluded (0-2 years: ±4SDS, 2 < years: -3SDS, +2.3SDS). References were constructed using the LMS method. RESULTS: The updated weight reference became similar to the GrowUp 1974 Gothenburg reference: BMI increased rapidly up to lower levels in the 1990 cohort during infancy/early childhood, similar in both groups in late childhood/adolescence, despite lower values at +2SDS. Compared with the WHO weight standard, median and -2SDS weight values were higher for the 1990 cohort, whereas +2SDS values were lower, resulting in narrower normal range. Median values were greater and ±2SDS narrower for the 1990 vs the WHO weight-for-height reference. International Obesity Task force (IOTF) BMI lines for definitions for over- and underweight were added. CONCLUSION: We present updated references for weight, weight-for-height and BMI, providing a healthy goal for weight development when monitoring growth within healthcare settings.

A new type of pubertal height reference based on growth aligned for onset of pubertal growth.

Objectives Growth references of today traditionally describe growth in relation to chronological age. Despite the broad variation in age of pubertal maturation, references related to biological age are lacking. To fill this knowledge gap, we aimed to develop a new type of pubertal height reference for improved growth evaluation during puberty, considering individual variation in pubertal timing. Methods Longitudinal length/height measures were obtained from birth to adult height in 1,572 healthy Swedish children (763 girls) born at term ∼1990 to nonsmoking mothers and Nordic parents, a subgroup of GrowUp1990Gothenburg cohort. A total height reference was constructed from Quadratic-Exponential-Puberty-Stop (QEPS)-function-estimated heights from individual height curves that had been aligned for time/age at onset of pubertal growth (5% of P-function growth). References that separated growth into specific pubertal heightSDS (P-function growth) and basic heightSDS (QES-function growth) were also generated. Results References (cm and SDS) are presented for total height, and height subdivided into that specific to puberty and to basic growth arising independently of puberty. The usefulness of the new pubertal growth reference was explored by identifying differences in the underlying growth functions that translate into differences in pubertal height gain for children of varying body mass, height, and with different pubertal timings. Conclusions A new type of height reference allowing alignment of individual growth curves, based on the timing of the pubertal growth spurt was developed using QEPS-model functions. This represents a paradigm shift in pubertal growth research and growth monitoring during the adolescent period.

A new Swedish reference for total and prepubertal height.

AIM: We aimed to develop up-to-date references with standard deviation scores (SDS) for prepubertal and total height. METHODS: Longitudinal length/height measures from 1572 healthy children (51.5% boys) born at term in 1989-1991 to non-smoking mothers and Nordic parents were obtained from the GrowUp 1990 Gothenburg cohort. A total height SDS reference from birth to adult height was constructed from Quadratic-Exponential-Pubertal-Stop (QEPS) function estimated heights based on individual growth curves. A prepubertal height SDS reference, showing growth trajectory in the absence of puberty, was constructed using the QE functions. RESULTS: The total height reference showed taller prepubertal mean heights (for boys 1-2 cm; for girls 0.5-1.0 cm) with a narrower normal within ± 2SDS range vs the GrowUp 1974 Gothenburg reference. Adult height was increased by + 0.9 cm for women (168.6 cm) and by + 1.6 cm for men (182.0 cm). Height in children growing at -2SDS (the cut-off used for referrals) differed up to 2 cm vs the GrowUp 1974 Gothenburg reference, 3 cm vs Swedish 1981 references and World Health Organisation (WHO) 0-5 years standard, and 6-8 cm vs the WHO 5-19 years reference. CONCLUSION: Up-to-date total and prepubertal height references offer promise of improved growth monitoring compared with the references used in Sweden today.

Use of Multivariate Immune Reconstitution Patterns to Describe Immune Reconstitution after Allogeneic Stem Cell Transplantation in Children.

Immune reconstitution after hematopoietic stem cell transplantation (HSCT) is a complex process. Impacts of the reconstitution of different immune cells over time are complex and difficult to understand. New mathematical models are needed to better understand this process. In this study, we used principal component analysis to better analyze the process of immune reconstitution after HSCT. Forty-six consecutive patients receiving HSCT for malignant and nonmalignant disorders were included in the study. All patients were followed for at least 24 months after transplantation with regular blood sampling for analysis of lymphocyte subset numbers and function. Exponentially transformed lymphocyte subset counts and lymphocyte functional markers were analyzed to identify major trends in the reconstitution process. Using our multivariate model for mapping immune reconstitution after HSCT, we showed that dysfunctional reconstitution patterns precede severe complications, such as chronic graft-versus-host disease, relapse, and death.

Estimating secular changes in longitudinal growth patterns underlying adult height with the QEPS model: the Grow Up Gothenburg cohorts.

BACKGROUND: Over the past 150 years, humans have become taller, and puberty has begun earlier. It is unclear if these changes are continuing in Sweden, and how longitudinal growth patterns are involved. We aimed to evaluate the underlying changes in growth patterns from birth to adulthood by QEPS estimates in two Swedish cohorts born in 1974 and 1990. METHODS: Growth characteristics of the longitudinal 1974 and 1990-birth cohorts (n = 4181) were compared using the QEPS model together with adult heights. RESULTS: There was more rapid fetal/infancy growth in girls/boys born in 1990 compared to 1974, as shown by a faster Etimescale and they were heavier at birth. The laterborn were taller also in childhood as shown by a higher Q-function. Girls born in 1990 had earlier and more pronounced growth during puberty than girls born in 1974. Individuals in the 1990 cohort attained greater adult heights than those in the 1974 cohort; 6 mm taller for females and 10 mm for males. CONCLUSION: A positive change in adult height was attributed to more growth during childhood in both sexes and during puberty for girls. The QEPS model proved to be effective detecting small changes of growth patterns, between two longitudinal growth cohorts born only 16 years apart.

Insight into human pubertal growth by applying the QEPS growth model.

BACKGROUND: Computerized mathematical models describing absolute and relative individual growth during puberty in both cm and standard deviation (SD)-scores are lacking. The present study aimed to fill this gap, by applying the QEPS-model that delineates mathematically the specific pubertal functions of the total growth curve. METHODS: Study population used was the individual growth curves of the longitudinally followed cohort GrowUp1974 Gothenburg (n = 2280). The QEPS-model describes total height as (T)otal-function: a combination of four shape-invariant growth functions, modified by time-scale and height-scale parameters: a (Q)uadratic-function for the continuous growth from fetal life to adulthood; a negative (E)xponential-function adds the rapid, declining fetal/infancy growth; a (P)ubertal-function the specific pubertal growth spurt; a (S)top-function the declining growth until adult height. A constructed variable, MathSelect, was developed for assessing data-quality. CIs and SD-scores for growth estimates were calculated for each individual. QEPS-model estimates used for pubertal growth; from the T-function: onset of puberty as minimal height velocity (AgeT ONSET ); mid-puberty as peak height velocity (AgeT PHV ); end of puberty as height velocity decreased to 1 cm/year (AgeT END ); duration of different intervals and gain (AgeT ONSET-END and Tpubgain); from the P-function: onset of puberty, estimated as growth at 1% or 5% (AgeP1 , AgeP5); mid-puberty as 50% (AgeP50) and PHV (AgeP PHV ); end of pubertal growth at 95 or 99% (AgeP95, AgeP99); duration of different intervals and pubertal gain (Ppubgain; P max ); from the QES-function: gain (QESpubgain) . RESULTS: Application of these mathematical estimates for onset, middle and end of puberty of P-function, QES-function, and T-function during puberty showed: the later the onset of puberty, the greater the adult height; pubertal gain due to the P-function growth was independent of age at onset of puberty; boys had higher total gain during puberty due to P-function growth than to QES-function growth; for girls it was reversed. CONCLUSIONS: QEPS is the first growth model to provide individualized estimates of both the specific pubertal growth function and the total growth during puberty, with accompanying SD-scores and Cis for each individual. These QEPS-derived estimates enable more in-depth analysis of different aspects of pubertal growth than previously possible.

Pubertal height gain is inversely related to peak BMI in childhood.

BACKGROUND: Childhood BMI may influence subsequent growth in height as well as the timing of puberty. The aim of the present study was to investigate associations between BMI in childhood and subsequent height gain/pubertal growth. METHODS: Longitudinal growth data were used (GrowUp1990Gothenburg cohort, n = 1,901). The QEPS growth-model was used to characterize height gain in relation to the highest BMISDS value between 3.5 and 8 y of age. Children were defined as overweight/obese (OwOb) or normal weight/underweight (NwUw), using the 2012 International Obesity Task Force criteria. RESULTS: A negative association between childhood BMISDS and pubertal height gain was observed. Already at birth, OwOb children were heavier than NwUw children, and had a greater height velocity during childhood. Onset of puberty was 3.5/3.0 mo earlier in OwOb girls/boys, and they had 2.3/3.1 cm less pubertal height gain from the QEPS-models specific P-function than NwUw children. Adult height was not related to childhood BMI. CONCLUSION: We found that pubertal height gain was inversely related to peak BMI in childhood. Higher childhood BMISDS was associated with more growth before onset of puberty, earlier puberty, and less pubertal height gain, resulting in similar adult heights for OwOb and NwUw children.

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. 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.

Fatty acid profiles and antioxidants of organic and conventional milk from low- and high-input systems during outdoor period.

BACKGROUND: Intensification of organic dairy production leads to the question of whether the implementation of intensive feeding incorporating maize silage and concentrates is altering milk quality. Therefore the fatty acid (FA) and antioxidant (AO) profiles of milk on 24 farms divided into four system groups in three replications (n = 71) during the outdoor period were analyzed. In this system comparison, a differentiation of the system groups and the effects of the main system factors 'intensification level' (high-input versus low-input) and 'origin' (organic versus conventional) were evaluated in a multivariate statistical approach. RESULTS: Consistent differentiation of milk from the system groups due to feeding-related impacts was possible in general and on the basis of 15 markers. The prediction of the main system factors was based on four or five markers. The prediction of 'intensification level' was based mainly on CLA c9,t11 and C18:1 t11, whereas that of 'origin' was based on n-3 PUFA. CONCLUSION: It was possible to demonstrate consistent differences in the FA and AO profiles of organic and standard conventional milk samples. Highest concentrations of nutritionally beneficial compounds were found in the low-input organic system. Adapted grass-based feeding strategies including pasture offer the potential to produce a distinguishable organic milk product quality.

Protein markers predict body composition during growth hormone treatment in short prepubertal children.

OBJECTIVE: A high-throughput pharmaco-proteomic approach has previously been successfully used to identify lipoprotein biomarkers related to changes in longitudinal growth and bone mass in response to growth hormone (GH) treatment. The aim of this study was to identify protein markers involved in the diverse anabolic and lipolytic remodelling of body composition during GH treatment. DESIGN, PATIENTS AND MEASUREMENTS: The study population consisted of 128 prepubertal children receiving GH treatment. Thirty-nine were short as a result of GH deficiency, and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after 1 year of GH treatment were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Body composition was analysed by dual-energy X-ray absorptiometry (DXA), reliably estimating muscle mass from appendicular (arms and legs) lean soft tissue mass (LST). DXA was also used to estimate appendicular bone mineral content (BMC) and fat mass for the total body. RESULTS: Specific protein expression patterns associated with GH response in different body compartments were identified. Among identified proteins, different isoforms of nutrition markers such as apolipoproteins (Apo) were recognized: Apo C-I, Apo A-II, serum amyloid A4 (SAA4) and transthyretin (TTR). In addition, unidentified peaks were associated with GH effects on specific body compartments. CONCLUSIONS: Our results suggest that unique protein markers are associated with remodelling of different body compartments during GH treatment, which in the future might be useful to optimize GH treatment not only with regard to longitudinal growth.

Development of systems biology-oriented biomarkers by permuted stepwise regression for the monitoring of seasonal allergic rhinitis treatment effects.

BACKGROUND: The immune system, a complex set of integrated responses, often cannot be explained, predicted, or monitored by examining its separate components as biomarkers. Combining different components may therefore be a suitable approach to develop relevant biomarkers reflecting immune system functioning in an appropriate way. METHODS: Here we compute and test pattern variables that should reflect immune system functioning on the systems level. Computation was based on a dataset (from a randomized controlled trial comparing two routes of administration) of allergen-specifically induced expression levels of cytokines (IL-1ß, IL-5, IL-10, IL-12, IL-13, IL-17, IFN-γ and TNF-α) and symptom severity scores from 22 seasonal allergic rhinitis (SAR) patients measured before and after six weeks of treatment with medicinal products containing Citrus and Cydonia. By means of stepwise regression analyses we explored and tested pattern variables of the immunological data using permuted stepwise regression (PStR) to distinguish optimally between (immunological) baseline and post-baseline data for the whole treatment group (22 patients) and the two separate treatment groups (11 patients in each group). The validity of the stepwise selection method for the computed pattern variables was tested by means of random permutation tests and evaluated with the cross-validated correct rate of classification (CV correct). RESULTS: For the total group a pattern variable was computed with three variables: IL-10 (day 7), TNF-α (day 1) and IL-10 (day 1) (CV correct: 0.91; p<0.001; R(2)=0.66), demonstrating a small improvement from the model with IL-10 (day 7) only (CV correct: 0.84; p<0.001; R(2)=0.47). For the subcutaneous injection group a pattern variable was computed with four variables: IL-10 (day 7), IL-10 (day 1), IL-17 (day 7) and IFN-γ (day 7) (CV correct: 0.90; p<0.01; R(2)=0.78), demonstrating a very small improvement from the model with IL-10 (day 7) only (CV correct: 0.86; p<0.01; R(2)=0.58). For the nasal spray group a pattern variable was computed with three variables: IL-10 (day 7), TNF-α (day 1) and IL-10 (day 1) (CV correct: 0.95; p<0.01; R(2)=0.79), demonstrating a moderate improvement from the model with IL-10 (day 7) only (CV correct: 0.79; p<0.05; R(2)=0.37). CONCLUSION/DISCUSSION: In this study three robust systems biology-oriented biomarkers for the monitoring of SAR were computed that demonstrated small to moderate improvement compared to monitoring of a single cytokine (IL-10 (day 7)) (CV correct improvement: 0.07 (total group), 0.04 (subcutaneous injection group), 0.16 (nasal spray group)). Further computation and biomarker validation with larger datasets, including data from healthy persons and SAR patients, are indicated.

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.

Citrus/Cydonia Compositum Subcutaneous Injections versus Nasal Spray for Seasonal Allergic Rhinitis: A Randomized Controlled Trial on Efficacy and Safety.

UNLABELLED: Background. Clinical experiences in vitro and clinical studies have demonstrated the curative potency and safety of Citrus/Cydonia compositum in seasonal allergic rhinitis treatment. Objectives. To compare the efficacy and safety of two routes of administration (nasal spray versus subcutaneous injections). METHODOLOGY: Design. a national, randomised, comparative clinical trial with two parallel groups. Participants. 23 patients fulfilled the study requirements. Intervention. after a one- or two-week wash-out period, 23 patients were randomized, to a 6-week treatment period. Outcomes. immunological and symptom severity changes and safety. Immunologic outcome assessments were blinded to group assignment. 23 patients were randomized and from 22/23 patients (11 in each group) blood samples were analyzed before and after treatment. Conclusion. Both routes of administration demonstrate immunological and clinical effects, with larger inflammatory and innate immunological effects of the nasal spray route and larger allergen-specific clinical effects of the subcutaneous route, and are safe.

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. DESIGN: Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 microg/kg/day) or a standard dose (43 microg/kg/day). OBJECTIVE: To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD. HYPOTHESIS: Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD. RESULTS: We observed a narrower variation for fasting insulin (-34.2%) and for homoeostasis model assessment (HOMA) (-38.9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Delta) height SDS correlated with Deltainsulin-like growth factor I (IGF-I), Deltaleptin and Deltabody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Deltalean body mass (LBM) SDS and DeltaIGF-I SDS] clustered together and correlated strongly with Deltaheight SDS and GH dose, whereas lipolytic variables [Deltafat mass (FM) SDS and Deltaleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for DeltaLBM SDS and Deltaheight SDS, but not for changes in FM. CONCLUSIONS: Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

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.

BACKGROUND: The 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. RESULTS: At 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. CONCLUSION: Using 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.

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. METHODS: A population-based, cross-sectional study of 4502 children aged 0-5 years derived from child health care in a Swedish county. Measurements of weight, height and waist circumference were recorded using a standardized procedure. RESULTS: New reference values for waist circumference and waist-to-height ratio for preschool children are presented. Reference charts were constructed and are presented. Waist circumference increased with age (r = 0.80, p < 0.001). After adjustment to the individual height, expressed as waist-to-height ratio, there was an inverse correlation to age during the first 5 years of age (r = -0.87, p < 0.001). CONCLUSION: The new reference values for waist circumference and waist-to-height ratio for Swedish preschool children enable future identification of new risk populations for childhood obesity. For clinicians, new reference charts for these two variables are provided for practical use.

The first-year growth response to growth hormone treatment predicts the long-term prepubertal growth response in children.

BACKGROUND: Pretreatment auxological variables, such as birth size and parental heights, are important predictors of the growth response to GH treatment. For children with missing pretreatment data, published prediction models cannot be used. The objective was to construct and validate a prediction model for children with missing background data based on the observed first-year growth response to GH. The accuracy and reliability of the model should be comparable with our previously published prediction model relying on pretreatment data. The design used was mathematical curve fitting on observed growth response data from children treated with a GH dose of 33 microg/kg/d. METHODS: Growth response data from 162 prepubertal children born at term were used to construct the model; the group comprised of 19% girls, 80% GH-deficient and 23% born SGA. For validation, data from 205 other children fulfilling the same inclusion and treatment criteria as the model group were used. The model was also tested on data from children born prematurely, children from other continents and children receiving a GH dose of 67 microg/kg/d. RESULTS: The GH response curve was similar for all children, but with an individual amplitude. The curve SD score depends on an individual factor combining the effect of dose and growth, the 'Response Score', and time on treatment, making prediction possible when the first-year growth response is known. The prediction interval (+/- 2 SD res) was +/- 0.34 SDS for the second treatment year growth response, corresponding to +/- 1.2 cm for a 3-year-old child and +/- 1.8 cm for a 7-year-old child. For the 1-4-year prediction, the SD res was 0.13 SDS/year and for the 1-7-year prediction it was 0.57 SDS (i.e. < 0.1 SDS/year). CONCLUSION: The model based on the observed first-year growth response on GH is valid worldwide for the prediction of up to 7 years of prepubertal growth in children with GHD/ISS, born AGA/SGA and born preterm/term, and can be used as an aid in medical decision making.