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

<p>Abstract</p> <p>Background</p> <p>Mathematical 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.</p> <p>Methods</p> <p>Growth 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.</p> <p>Results</p> <p>Using only auxological data, the model had a standard error of the residuals (SD_res), of 0.23 SDS. The model was improved when endocrine data (GH_maxprofile, IGF-I and leptin) collected before starting GH treatment were included. Inclusion of these data resulted in a decrease of the SD_resto 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 SD_resfor both types of models. Preterm children were not included in the Model group, but predictions for this group were within the expected range.</p> <p>Conclusion</p> <p>These 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.</p

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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).</p> <p>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.</p> <p>Conclusion</p> <p>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.</p> <p>These results support our previous findings that apolipoproteins and transthyretin may have a role in GH sensitivity.</p

The City Initiative for Newborn Health

This article describes the critical first steps taken to revitalize the vast public health system of Mumbai City through the active participation of personnel from within the system. It focuses on one of two components of an ambitious action-research project aimed at improving the survival and health of newborn infants and mothers living in slum communities in Mumbai

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>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 μg/kg/d.</p> <p>Methods</p> <p>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 μg/kg/d.</p> <p>Results</p> <p>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_reswas 0.13 SDS/year and for the 1–7-year prediction it was 0.57 SDS (i.e. < 0.1 SDS/year).</p> <p>Conclusion</p> <p>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.</p

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

<p>Abstract</p> <p>Background</p> <p>The 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.</p> <p>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).</p> <p>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).</p> <p>Results</p> <p>Changes 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.</p> <p>Conclusion</p> <p>Our 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.</p

Continuous growth reference from 24th week of gestation to 24 months by gender

<p>Abstract</p> <p>Background</p> <p>Growth charts and child growth assessment have become prime global instruments in child health practice over the 30 years. An updated, continuous growth standard that bridges size at birth values with postnatal growth values can improve child growth screening and monitoring.</p> <p>Methods</p> <p>This novel growth chart was constructed from two sources of information. Size at birth (weight, length and head circumference) reference values were updated based on information of normal deliveries (i.e. singleton live births without severe congenital malformation, with healthy mothers and born vaginally) from the Swedish Medical Birth Registry, 1990–1999 (n = 810393). Weight was evaluated using logarithmic transformation as for postnatal weight. Standard deviations were estimated from data within the empirical mean ± 1.0 SD for each gestational week and gender. These values were smoothed by empirical curve-fitting together with values from our recently published postnatal growth reference including 3650 longitudinally followed children from birth to final height <abbrgrp><abbr bid="B9">9</abbr></abbrgrp>. Timescale and weight axes were made logarithmic in order to magnify the early time part of the graph.</p> <p>Results</p> <p>This study presents the first continuous gender specific growth chart from birth irrespective of gestational age at birth until 2 years of age for weight, length and head circumference. Birth weight at 40 weeks of gestation increased approximately 100 gram and length increased only 1 mm compared with earlier Swedish reference from 1977–81. The curve is now less S-shaped as compared with earlier curves and compared with 4 curves from other countries and with more constant variation over the whole range.</p> <p>Conclusion</p> <p>Our values picture the unrestricted pattern of growth improving the detection of a deviating growth pattern, when the growth of an individual infant is plotted on the charts. Especially for very preterm infants age corrected growth can be more easily evaluated although it must be recognized that the early comparison is with what is estimated as normal growth in uterus. The reference values are useful in child health care systems for population screening, but also in research or in the clinic for evaluating various growth promoting interventions – either nutritional, surgical or therapeutic – that might affect a child in early life.</p

Evaluation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) in a randomised controlled trial aiming for prevention of severe ROP : A substudy of the Mega Donna Mega trial

Objective The current grading of retinopathy of prematurity (ROP) does not sufficiently discriminate disease severity for evaluation of trial interventions. The published ROP Activity Scales (original: ROP-ActS and modified: mROP-ActS), describing increasing severity of ROP, versus the categorical variables severe ROP, stage, zone and plus disease were evaluated as discriminators of the effect of an ROP preventive treatment. Methods and analysis The Mega Donna Mega trial investigated ROP in infants born <28-week gestational age (GA), randomised to arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation or no supplementation. Of 207 infants, 86% with finalised ROP screening were included in this substudy. ROP-ActS versus standard variables were evaluated using Fisher’s non-parametric permutation test, multivariable logistic and linear regression and marginal fractional response models. Results The AA:DHA group (n=84) and the control group (n=93) were well balanced. The maximum ROP-ActS measurement was numerically but not significantly lower in the AA:DHA group (mean: 4.0 (95% CI 2.9 to 5.0)) versus the control group (mean: 5.3 (95% CI 4.1 to 6.4)), p=0.11. In infants with any ROP, the corresponding scale measurements were 6.8 (95% CI 5.4 to 8.2) and 8.7 (95% CI 7.5 to 10.0), p=0.039. Longitudinal profiles of the scale were visually distinguished for the categories of sex and GA for the intervention versus control. Conclusions The preventive effect of AA:DHA supplementation versus no supplementation was better discriminated by the trial’s primary outcome, severe ROP, than by ROP-ActS. The sensitivity and the linear qualities of ROP-ActS require further validations on large data sets and perhaps modifications. Trial registration number NCT03201588

Evaluation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) in a randomised controlled trial aiming for prevention of severe ROP: A substudy of the Mega Donna Mega trial

Objective The current grading of retinopathy of prematurity (ROP) does not sufficiently discriminate disease severity for evaluation of trial interventions. The published ROP Activity Scales (original: ROP-ActS and modified: mROP-ActS), describing increasing severity of ROP, versus the categorical variables severe ROP, stage, zone and plus disease were evaluated as discriminators of the effect of an ROP preventive treatment. Methods and analysis The Mega Donna Mega trial investigated ROP in infants born &lt;28-week gestational age (GA), randomised to arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation or no supplementation. Of 207 infants, 86% with finalised ROP screening were included in this substudy. ROP-ActS versus standard variables were evaluated using Fisher\u27s non-parametric permutation test, multivariable logistic and linear regression and marginal fractional response models. Results The AA:DHA group (n=84) and the control group (n=93) were well balanced. The maximum ROP-ActS measurement was numerically but not significantly lower in the AA:DHA group (mean: 4.0 (95% CI 2.9 to 5.0)) versus the control group (mean: 5.3 (95% CI 4.1 to 6.4)), p=0.11. In infants with any ROP, the corresponding scale measurements were 6.8 (95% CI 5.4 to 8.2) and 8.7 (95% CI 7.5 to 10.0), p=0.039. Longitudinal profiles of the scale were visually distinguished for the categories of sex and GA for the intervention versus control. Conclusions The preventive effect of AA:DHA supplementation versus no supplementation was better discriminated by the trial\u27s primary outcome, severe ROP, than by ROP-ActS. The sensitivity and the linear qualities of ROP-ActS require further validations on large data sets and perhaps modifications. Trial registration number NCT03201588

The Public Domain

Background/Aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m(2) BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m(2) equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m(2) BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m(2) BSA. Conclusion: Dosing GH per m(2) BSA is at least as efficacious as dosing per kg BW, and is more cost-effective. (c) 2014 S. Karger AG, Basel