Alkaline phosphatase in pediatric patients with genu varum caused by vitamin D-deficient rickets.

An elevated serum alkaline phosphatase (ALP) level is one of the markers for the presence of rickets in children, but it is also associated with bone formation. However, its role in diagnosing genu varum in pediatric patients with vitamin D-deficient rickets is still unknown. To clarify the role of the serum ALP level in assessing the severity of genu varum, we retrospectively investigated this issue statistically using data on rickets such as serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, ALP, the level of creatinine as the percentage of the median according to age (%Cr), and the metaphyseal diaphyseal angle (MDA) in the lower extremities as an index of the severity of genu varum. A multiple regression analysis revealed that log ALP and %Cr values were negatively associated with MDA values. The former association was also confirmed by a linear mixed model, while iPTH was positively associated with MDA by path model analysis. To elucidate the association of ALP with MDA in the presence of iPTH, we investigated three-dimensional figures by neural network analysis. This indicated the presence of a biphasic association of ALP with MDA: the first phase increases while the second decreases MDA. The latter phenomenon is considered to be associated with the increase in bone formation due to the mechanical stress loaded on the lower extremities. These findings are important and informative for pediatricians to understand the significance of the serum ALP level in pediatric patients with genu varum caused by vitamin D deficiency.

Tongue function and its influence on masticatory performance in patients treated for oral cancer: a five-year prospective study.

PURPOSE: The purpose of this study was to observe the impact of oral oncological treatment, including the recovery of several tongue functions (force, mobility, and sensory functions), and to determine the influence of these functions on masticatory performance. MATERIALS AND METHODS: Masticatory performance and tongue force, mobility, and sensory functions were determined in 123 patients with oral cavity cancer. The assessments were performed 4 weeks before treatment and 4 to 6 weeks, 6 months, 1 year, and 5 years after treatment. Generalized estimation equations and mixed model analyses were performed, correcting for previously identified factors in the same population. RESULTS: A significant deterioration in tongue mobility and sensory function was observed in patients with mandible and tongue and/or floor-of-mouth tumors. Better tongue force and sensory function (thermal and tactile) positively influenced masticatory performance, and this effect was stronger where fewer occlusal units were present. The effect of both the tongue force and maximum bite force was weaker in dentate patients in comparison with patients with full dentures. A web-based application was developed to enable readers to explore our results and provide insight into the coherence between the found factors in the mixed model. CONCLUSIONS: Tongue function deteriorates after oral oncological treatment, without statistically significant recovery. Adequate bite and tongue forces are especially important for patients with a poor prosthetic state. Patients with sensory tongue function deficits especially benefit from the presence of more occluding pairs.

Leiter-3 generalizability in Scandinavia.

The Leiter-3 is a nonverbal assessment that evaluates cognitive abilities and has been adapted for use in Scandinavia. Generalizability of United States-based normative scoring for use with the Scandinavian population was evaluated. Leiter-3 scores from a sample of Scandinavian students were compared with scores obtained from the Leiter-3 standardization sample, controlling for confounding variables, across ages, using mixed-methods analysis. A Scandinavian-population-based sample was created from Leiter-3 standardization data and norms were constructed and were used to generate standardized scores from the sample data. Results suggest that overall the Scandinavian test-takers score higher than American test-takers, but that differences between groups were minimized when controlling for factors that may influence cognitive performance. Creating Scandinavian based scores was not effective at reducing gaps in performance, suggesting that differences in performance between the different populations may be attributable to factors other than those typically controlled for when constructing standardized tests. Implications of these results and recommendations for Leiter-3 adaptation are reviewed.

Flexible semiparametric joint modeling: an application to estimate individual lung function decline and risk of pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Epidemiologic surveillance of lung function is key to clinical care of individuals with cystic fibrosis, but lung function decline is nonlinear and often impacted by acute respiratory events known as pulmonary exacerbations. Statistical models are needed to simultaneously estimate lung function decline while providing risk estimates for the onset of pulmonary exacerbations, in order to identify relevant predictors of declining lung function and understand how these associations could be used to predict the onset of pulmonary exacerbations. METHODS: Using longitudinal lung function (FEV1) measurements and time-to-event data on pulmonary exacerbations from individuals in the United States Cystic Fibrosis Registry, we implemented a flexible semiparametric joint model consisting of a mixed-effects submodel with regression splines to fit repeated FEV1 measurements and a time-to-event submodel for possibly censored data on pulmonary exacerbations. We contrasted this approach with methods currently used in epidemiological studies and highlight clinical implications. RESULTS: The semiparametric joint model had the best fit of all models examined based on deviance information criterion. Higher starting FEV1 implied more rapid lung function decline in both separate and joint models; however, individualized risk estimates for pulmonary exacerbation differed depending upon model type. Based on shared parameter estimates from the joint model, which accounts for the nonlinear FEV1 trajectory, patients with more positive rates of change were less likely to experience a pulmonary exacerbation (HR per one standard deviation increase in FEV1 rate of change = 0.566, 95% CI 0.516-0.619), and having higher absolute FEV1 also corresponded to lower risk of having a pulmonary exacerbation (HR per one standard deviation increase in FEV1 = 0.856, 95% CI 0.781-0.937). At the population level, both submodels indicated significant effects of birth cohort, socioeconomic status and respiratory infections on FEV1 decline, as well as significant effects of gender, socioeconomic status and birth cohort on pulmonary exacerbation risk. CONCLUSIONS: Through a flexible joint-modeling approach, we provide a means to simultaneously estimate lung function trajectories and the risk of pulmonary exacerbations for individual patients; we demonstrate how this approach offers additional insights into the clinical course of cystic fibrosis that were not possible using conventional approaches.

Income and health-related quality of life among prostate cancer patients over a one-year period after radical prostatectomy: a linear mixed model analysis.

PURPOSE: To examine income-related disparities in health-related quality of life (HRQOL) over a one-year period after surgery (radical prostatectomy) and its contributory factors in a longitudinal perspective. Evidence of associations between income and HRQOL among patients with prostate cancer (PCa) is sparse and their explanations still remain unclear. METHODS: 246 males of two German hospitals filled out a questionnaire at the time of acute treatment, 6 and 12 months later. Age, partnership status, baseline disease and treatment factors, physical and psychological comorbidities, as well as treatment factors and adverse effects at follow-up were additionally included in the analyses to explain potential disparities. HRQOL was assessed with the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 core questionnaire and the prostate-specific QLQ-PR25. A linear mixed model for repeated measures was calculated. RESULTS: The fixed effects showed highly significant income-related inequalities regarding the majority of HRQOL scales. Less affluent PCa patients reported lower HRQOL in terms of global quality of life, all functional scales and urinary symptoms. After introducing relevant covariates, some associations became insignificant (physical, cognitive and sexual function), while others only showed reduced estimates (global quality of life, urinary symptoms, role, emotional and social function). In particular, mental disorders/psychological comorbidity played a relevant role in the explanation of income-related disparities. CONCLUSIONS: One year after surgery, income-related disparities in various dimensions of HRQOL persist. With respect to economically disadvantaged PCa patients, the findings emphasize the importance of continuous psychosocial screening and tailored interventions, of patients' empowerment and improved access to supportive care.

Recommendations for analysis of repeated-measures designs: testing and correcting for sphericity and use of manova and mixed model analysis.

PURPOSE: A common experimental design in ophthalmic research is the repeated-measures design in which at least one variable is a within-subject factor. This design is vulnerable to lack of 'sphericity' which assumes that the variances of the differences among all possible pairs of within-subject means are equal. Traditionally, this design has been analysed using a repeated-measures analysis of variance (RM-anova) but increasingly more complex methods such as multivariate anova (manova) and mixed model analysis (MMA) are being used. This article surveys current practice in the analysis of designs incorporating different factors in research articles published in three optometric journals, namely Ophthalmic and Physiological Optics (OPO), Optometry and Vision Science (OVS), and Clinical and Experimental Optometry (CXO), and provides advice to authors regarding the analysis of repeated-measures designs. RECENT FINDINGS: Of the total sample of articles, 66% used a repeated-measures design. Of those articles using a repeated-measures design, 59% and 8% analysed the data using RM-anova or manova respectively and 33% used MMA. The use of MMA relative to RM-anova has increased significantly since 2009/10. A further search using terms to select those papers testing and correcting for sphericity ('Mauchly's test', 'Greenhouse-Geisser', 'Huynh and Feld') identified 66 articles, 62% of which were published from 2012 to the present. SUMMARY: If the design is balanced without missing data then manova should be used rather than RM-anova as it gives better protection against lack of sphericity. If the design is unbalanced or with missing data then MMA is the method of choice. However, MMA is a more complex analysis and can be difficult to set up and run, and care should be taken first, to define appropriate models to be tested and second, to ensure that sample sizes are adequate.

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. RESULTS: We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers. CONCLUSIONS: The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.

Rhinoviruses significantly affect day-to-day respiratory symptoms of children with asthma.

BACKGROUND: Viruses are frequently associated with acute exacerbations of asthma, but the extent to which they contribute to the level of day-to-day symptom control is less clear. OBJECTIVE: We sought to explore the relationship between viral infections, host and environmental factors, and respiratory symptoms in children. METHODS: Sixty-seven asthmatic children collected samples twice weekly for an average of 10 weeks. These included nasal wash fluid and exhaled breath for PCR-based detection of viral RNA, lung function measurements, and records of medication use and asthma and respiratory symptoms in the previous 3 days. Atopy, mite allergen exposure, and vitamin D levels were also measured. Mixed-model regression analyses were performed. RESULTS: Human rhinoviruses (hRVs) were detected in 25.5% of 1232 nasal samples and 11.5% of breath samples. Non-hRV viruses were detected in less than 3% of samples. hRV in nasal samples was associated with asthma symptoms (cough and phlegm: odds ratio = 2.0; 95% CI = 1.4-2.86, P = .0001; wheeze and chest tightness: odds ratio = 2.34, 95% CI = 1.55-3.52, P < .0001) and with cold symptoms, as reported concurrently with sampling and 3 to 4 days later. No differences were found between the 3 hRV genotypes (hRV-A, hRV-B, and hRV-C) in symptom risk. A history of inhaled corticosteroid use, but not atopic status, mite allergen exposure, or vitamin D levels, modified the association between viruses and asthma symptoms. CONCLUSION: The detection of nasal hRV was associated with a significantly increased risk of day-to-day asthma symptoms in children. Host, virus genotype, and environmental factors each had only a small or no effect on the relationship of viral infections to asthma symptoms.

Sleep Health and Anxiety Symptoms in Midlife Women: The Study of Women's Health Across the Nation (SWAN).

Purpose: To investigate the associations between anxiety symptoms in midlife women and sleep features later in life, the aim is to test the hypothesis that poor sleep, as measured by each of six individual dimensions (4 objective actigraphy measures, 2 self-reports) of sleep health, is associated with higher levels of anxiety symptoms in midlife women. Participants and Methods: The participants in this longitudinal analysis included women from the SWAN Sleep I Study, a subcohort of the community-dwelling midlife women participating in the core Study of Women's Health Across the Nation (SWAN), which was initiated in 1996. Of the 370 participants enrolled in the Sleep Study, 270 were included in the analytic sample, and 100 who did not meet the inclusion criteria were excluded. Baseline measures of six dimensions of multidimensional sleep health (actigraphy measures: efficiency, duration, mid-sleep timing, regularity; self-report measures: alertness, satisfaction) were obtained between 2003 and 2005, corresponding to SWAN core annual/biennial assessments 5-8. Associations of each dimension with self-reported anxiety symptoms (Generalized Anxiety Disorder - 7-item scale; GAD-7), collected during visits 12 (2009-2011), 13 (2011-2013), and 15 (2015-2017), were examined using mixed models. The GAD-7 outcome was measured both continuously and as a categorical variable due to its skewed distribution. Results: No statistically significant associations were found between any of the six baseline sleep health dimensions and the GAD-7 score after adjustment for covariates. Conclusion: The reasons for the lack of support for our hypothesis, despite previous evidence supporting an association between sleep and anxiety, are unclear. There is considerable overlap between anxiety and sleep symptoms, which may complicate the interpretation of our the findings. Thus, the failure to identify associations is likely multifactorial, and more studies with shorter follow-up intervals are warranted to better understand these relationships.

Predation affects body shape in the knife livebearer Alfaro cultratus (Cyprinodontiformes: Poeciliidae).

Livebearing fishes are a common model for studying the effects of predation on prey biology. Numerous studies have found differences in life history, sexual selection, behavior, and morphology between populations of the same species that co-occur with predators and those that do not. Alfaro cultratus is a livebearing fish with populations in different predation environments, but unlike other livebearers, this species also has an extreme body shape that is laterally compressed. Given this unusual morphology, we asked if predation environment would still predict overall body shape, as has been documented in other species. We collected specimens from both predator and no predator sites in Costa Rica and used a geometric morphometrics analysis to determine if body shape is affected by predation environment, while controlling for size and river gradient. Body shape does indeed differ between predation environments; however, the observed differences contrast with the patterns found in other livebearer systems. Alfaro cultratus in predation environments had deeper and shorter bodies and deeper caudal peduncles than those found in environments without dominant fish predators.

Body Mass Index and Exercise Effort Influences Changes in Motor Symptoms After High-Cadence Dynamic Cycling in Parkinson's Disease.

High-cadence dynamic cycling improves motor symptoms of Parkinson's disease (PD), such as tremor and bradykinesia. However, some participants experience greater benefits than others. To gain insight into how individual characteristics and cycling performance affects functional changes, data from two previous studies were used to build several preliminary predictive models. The purpose was to examine which variables contribute to greater improvement in symptoms after high-cadence dynamic cycling. We hypothesized that individuals with higher body mass index (BMI), increased age, more severe symptoms, and higher PD medication dosages were less likely to contribute effort during cycling. UPDRS-III was assessed before and after each session, and cadence and power were recorded every second. Entropy of cadence was calculated, and data were analyzed using analysis of variance and multiple linear regression. The multiple linear regression model of post UPDRS significantly (R2 = 0.81, p < 0.001) explained its variance, with pre UPDRS as the main predictor (p < 0.0001). The binomial logistic model of mean effort did not significantly (R2 = 0.36, p = 0.14) explain the variance. Post-hoc analysis found a significant (ß = 0.28, p = 0.03) moderating effect of different levels of BMI on the association between mean effort and post UPDRS. These results suggest that BMI, effort, and baseline UPDRS levels can potentially predict individual responses to high-cadence dynamic cycling.

Potential estimation model in French alpine skiing - Individual evolution curve and progression typology.

Estimating the potential of alpine skiers is an unresolved question, especially because of the complexity of sports performance. We developed a potential estimation model based solely on the evolution of performance as a function of age. A bayesian mixed model allowed to estimate the potential curve and the age at peak performance for the population (24.81 ± 0.2) and for each individual as the uncertainty around this curve. With Gaussian mixtures, we identified among all the estimates four types of curves, clustered according to the performance level and the progression per age. Relying on the uncertainty calculated on the progression curve the model created also allow to estimate a score and an uncertainty associated with each cluster for all individuals. The results allows to: i) describe and explain the relationship between age and performance in alpine skiing from a species point of view (at 0.87%) and ii) to provide to sport staffs the estimation of the potential of each individual and her/his typology of progression to better detect sports potential. The entire methodology is based on age and performance data, but the progression identified may depend on parameters specific to alpine skiing.

Analysis of a Multi-Environment Trial for Black Raspberry (Rubus occidentalis L.) Quality Traits.

U.S. black raspberry (BR) production is currently limited by narrowly adapted, elite germplasm. An improved understanding of genetic control and the stability of pomological traits will inform the development of improved BR germplasm and cultivars. To this end, the analysis of a multiple-environment trial of a BR mapping population derived from a cross that combines wild ancestors introgressed with commercial cultivars on both sides of its pedigree has provided insights into genetic variation, genotype-by-environment interactions, quantitative trait loci (QTL), and QTL-by-environment interactions (QEI) of fruit quality traits among diverse field environments. The genetic components and stability of four fruit size traits and six fruit biochemistry traits were characterized in this mapping population following their evaluation over three years at four distinct locations representative of current U.S. BR production. This revealed relatively stable genetic control of the four fruit size traits across the tested production environments and less stable genetic control of the fruit biochemistry traits. Of the fifteen total QTL, eleven exhibited significant QEI. Closely overlapping QTL revealed the linkage of several fruit size traits: fruit mass, drupelet count, and seed fraction. These and related findings are expected to guide further genetic characterization of BR fruit quality, management of breeding germplasm, and development of improved BR cultivars for U.S. production.

Deciphering Genotype-By-Environment Interaction for Target Environmental Delineation and Identification of Stable Resistant Sources Against Foliar Blast Disease of Pearl Millet.

Once thought to be a minor disease, foliar blast disease of pearl millet, caused by Magnaporthe grisea, has recently emerged as an important biotic constraint for pearl millet production in India. The presence of a wider host range as well as high pathogenic heterogeneity complicates host-pathogen dynamics. Furthermore, environmental factors play a significant role in exacerbating the disease severity. An attempt was made to unravel the genotype-by-environment interactions for identification and validation of stable resistant genotypes against foliar blast disease through multi-environment testing. A diversity panel consisting of 250 accessions collected from over 20 different countries was screened under natural epiphytotic conditions in five environments. A total of 43 resistant genotypes were found to have high and stable resistance. Interestingly, most of the resistant lines were late maturing. Combined ANOVA of these 250 genotypes exhibited significant genotype-by-environment interaction and indicated the involvement of crossover interaction with a consistent genotypic response. This justifies the necessity of multi-year and multi-location testing. The first two principal components (PCs) accounted for 44.85 and 29.22% of the total variance in the environment-centered blast scoring results. Heritability-adjusted genotype plus genotype × environment interaction (HA-GGE) biplot aptly identified "IP 11353" and "IP 22423, IP 7910 and IP 7941" as "ideal" and "desirable" genotypes, respectively, having stable resistance and genetic buffering capacity against this disease. Bootstrapping at a 95% confidence interval validated the recommendations of genotypes. Therefore, these genotypes can be used in future resistance breeding programs in pearl millet. Mega-environment delineation and desirability index suggested Jaipur as the ideal environment for precise testing of material against the disease and will increase proper resource optimization in future breeding programs. Information obtained in current study will be further used for genome-wide association mapping of foliar blast disease in pearl millet.

Intention-to-treat analysis when only a baseline value is available.

OBJECTIVES: How to perform an intention to treat (ITT) analysis when a patient has a baseline value but no follow-up measurements is problematic. The purpose of this study was to compare different methods that deal with this problem, i.e. no imputation (standard and alternative mixed model analysis), single imputation (i.e. baseline value carried forward), and multiple imputation (selective and non-selective). STUDY DESIGN AND SETTING: We used a simulation study with different scenarios regarding 1) the association between missingness and the baseline value, 2) whether the patients did or did not receive the treatment, and 3) the percentage of missing data, and two real life data sets. RESULTS: Bias and coverage were comparable between the two mixed model analyses and multiple imputation in most situations including the real life data examples. Only in the situation when the patients in the treatment group were simulated not to have received the treatment, selective imputation using this information outperformed all other methods. CONCLUSIONS: In most situations a standard mixed model analysis without imputation is appropriate as ITT analysis. However, when patients with missing follow-up data allocated to the treatment group did not received treatment, it is advised to use selective imputation, using this information, although the results should be interpreted with caution.

Masticatory function and related factors after oral oncological treatment: A 5-year prospective study.

BACKGROUND: Chewing ability is often compromised in patients with oral cancer. The aim of this study was to identify which factors affect masticatory performance in these patients. METHODS: Patients with primary oral cancer were assessed for up to 5 years after primary treatment. Healthy controls were assessed once. A mixed-model analysis was performed, with masticatory performance as outcome measure. RESULTS: A total of 123 patients were included in the study. Factors positively associated with masticatory performance were number of occlusal units (OU), having functional dentures, and maximum mouth opening (MMO). The impact of tumor location and maximum bite force (MBF) differed per assessment moment. Masticatory performance declined for up to 1 year but recovered at 5 years after treatment. CONCLUSION: Masticatory performance in patients treated for oral cancer is affected by MBF, MMO, number of OU, and dental status. These should be the focus of posttreatment therapy.

Analysis of Heritability Using Genome-Wide Data.

Most analyses of genome-wide association data consider each variant independently without considering or adjusting for the genetic background present in the rest of the genome. New approaches to genome analysis use representations of genomic sharing to better account for confounding factors like population stratification or to directly approximate heritability through the estimated sharing of individuals in a dataset. These approaches use mixed linear models, which relate genotypic sharing to phenotypic sharing, and rely on the efficient computation of genetic sharing among individuals in a dataset. This unit describes the principles and practical application of mixed models for the analysis of genome-wide association study data. © 2016 by John Wiley & Sons, Inc.

The effects of perceived stigma on quality of life outcomes in persons with early-stage dementia: Longitudinal findings: Part 2.

This article is the second report from a study examining perceived stigma in persons with dementia with findings regarding the association between stigma and quality of life outcomes being reported here. Fifty persons with dementia and 47 family caregivers were sampled, with data being collected at baseline and six, 12, and 18 months. The modified Stigma Impact Scale measured perceived stigma. Quality of life outcomes included: depression, anxiety, behavioral symptoms, personal control, physical health, self-esteem, social support, and activity participation. Linear mixed model or generalized linear mixed model (for depression) analyses revealed that some aspect of perceived stigma was associated with each outcome. Social rejection was associated with anxiety, behavioral symptoms, health, and activity participation. Internalized shame was associated with anxiety, personal control, health, self-esteem, social support understanding and assistance, and activity participation. Finally, social isolation was associated with depression, anxiety, personal control, health, self-esteem, social support understanding, and activity participation. The complexity of relationships between perceived stigma and quality of life outcomes is evident from these findings.

Different modes of GH administration influence gene expression in the male rat brain.

The endogenous secretion pattern in males of GH is episodic in rats and in humans, whereas GH administration is usually even. Different types of GH administration have different effects on body mass, longitudinal bone growth, and liver metabolism in rodents, whereas possible effects on brain plasticity have not been investigated. In this study, GH was administered as a continuous infusion or as two daily injections in hypophysectomized male rats. Thirteen transcripts previously known to respond to GH in the hippocampus and parietal cortex (cortex) were assessed by RT-PCR. To investigate the effects of type of GH administration on several transcripts with different variations, and categories of transcripts (neuron-, glia-, and GH-related), a mixed model analysis was applied. Accordingly, GH injections increased overall transcript abundance more than GH infusions (21% in the hippocampus, P<0.001 and 10% in the cortex, P=0.09). Specifically, GH infusions and injections robustly increased neuronal hemoglobin beta (Hbb) expression significantly (1.8- to 3.6-fold), and GH injections were more effective than GH infusions in increasing Hbb in the cortex (41%, P=0.02), whereas a 23% difference in the hippocampus was not significant. Also cortical connexin 43 was higher in the group with GH injections than in those with GH infusions (26%, P<0.007). Also, there were differences between GH injections and infusions in GH-related transcripts of the cortex (23%, P=0.04) and glia-related transcripts of the hippocampus (15%, P=0.02). Thus, with the exception of Hbb there is a moderate difference in responsiveness to different modes of GH administration.