Research Article

Mixed modeling and sample size calculations for identifying housekeeping gene

Exploring factors impacting early childhood health among Aboriginal and Torres Strait Islander families and communities: Protocol for a population-based cohort study using data linkage (the 'Defying the Odds' study)

Introduction: Empirical evidence on family and community risk and protective factors influencing the comparatively high rates of potentially preventable hospitalisations and deaths among Aboriginal and Torres Strait Islander infants and children is limited. As is evidence on geographical variation in these risks. The ‘Defying the Odds’ study aims to explore the impact of perinatal outcomes, maternal social and health outcomes and level of culturally secure service availability on the health outcomes of Western Australian (WA) Aboriginal infants and children aged 0–5 years. Methods and analysis: The study combines a retrospective cohort study that uses state-wide linked health and administrative data from 12 data sources for multiple generations within Aboriginal families in WA, with specifically collected survey data from health and social services supporting Aboriginal families in regions of WA. Data sources include perinatal/birth registration, hospital, emergency department, mental health services, drug and alcohol service use, mortality, infectious disease notifications, and child protection and family services. Multilevel regression models will be used to examine the intensity of admissions and presentations, mortality, intensity of long stays and morbidity-free survival (no admissions) for Aboriginal children born in WA in 2000–2013. Relationships between maternal (and grand-maternal) health and social factors and child health outcomes will be quantified. Community-level variation in outcomes for Aboriginal children and factors contributing to this variation will be examined, including the availability of culturally secure services. Online surveys were sent to staff members at relevant services to explore the scope, reach and cultural security of services available to support Aboriginal families across selected regions of WA. Ethics and dissemination: Ethics approvals have been granted for the study. Interpretation and dissemination are guided by the study team’s Aboriginal leadership and reference groups. Dissemination will be through direct feedback and reports to health services in the study and via scientific publications and policy recommendations.Funding for the Defying the Odds study has been provided by National Health and Medical Research Council of Australia (project grant 1078214). BM was supported by a National Health and Medical Research Council of Australia Training Fellowship (586736). Baker Heart and Diabetes Institute is supported in part by the Victorian Government OIS Programme

Offending outcomes for Māori and non-Māori, an investigation of ethnic bias in the criminal justice system : evidence from a New Zealand birth cohort.

Māori have been overrepresented in the New Zealand criminal justice system for decades. Māori are significantly more likely to be disadvantaged by risk factors which are linked to criminal offending behaviours. Overseas research suggests that there may be a bias from officials against minority groups within criminal justice systems around the world, in which minorities are more likely to be arrested or receive harsher sentences given equivalent behaviour. However, limited research on this issue has been conducted in New Zealand. The current study updates Fergusson, Horwood and Lynskey (1993) who found that Māori/Pacific Island children were 2.9 times more likely than Pākehā children to come to the attention of the Police. The present study used the same longitudinal sample as the 1993 study, followed from adolescence through to age 35 (N = 995). The present study examined the associations between rates of offending and ethnicity (Māori versus non-Māori) both before and after controlling for disadvantageous social, family and individual risk factors which have previously been linked to offending behaviours. Specifically, the study investigated whether there is any evidence of an ethnic bias against Māori within the criminal justice system after controlling for these factors. Generalised estimating equation (GEE) models were fitted to repeated measures data to examine the strength of the associations between Māori ethnicity and rates of offending. The GEE models were then extended in a series of adjustments to control for social, family and individual risk factors, and again to include self-reported rates of violent, property and other offences. Results found that Māori offend at a significantly higher rate compared to non-Māori, and that even when known risk factors of offending and self-reported rates of offending were controlled for, a small residual bias was evident. Although results were not statistically significant after adjusting for risk factors, the consistency of the results (with several different measures showing similar trends) suggests that there may be an ethnic bias against Māori within the criminal justice system. These findings may aid in addressing the issue of Māori being overrepresented and consequently reduce the number of Māori in the New Zealand criminal justice system

Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) (n = 10) among genes (HDC, HNMT, ABP1, HRH1, HRH4) within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Results: Genotyping and HILD response profiles were completed for 163 children. ABP1 47 C/T, ABP1 4107, and HNMT-1639 C/Twere associated with Emax (ABP1 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, p = 0.04; ABP1 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, p = 0.005; HNMT-1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, p = 0.02). In a stratified analysis among African American children only, ABP1 and HNMT SNPs were also associated with PD response; HRH4 413 CC genotype was associated with lower Emax, p = 0.009. Conclusions: We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more personalized treatments

Population Pharmacokinetic/Pharmacodynamic Modeling of Histamine Response Measured by Histamine Iontophoresis Laser Doppler

The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40 Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; Emax, 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively

Population Pharmacokinetic/Pharmacodynamic Modeling of Histamine Response Measured by Histamine Iontophoresis Laser Doppler

The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40 Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; Emax, 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively

Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) (n = 10) among genes (HDC, HNMT, ABP1, HRH1, HRH4) within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Results: Genotyping and HILD response profiles were completed for 163 children. ABP1 47 C/T, ABP1 4107, and HNMT-1639 C/Twere associated with Emax (ABP1 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, p = 0.04; ABP1 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, p = 0.005; HNMT-1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, p = 0.02). In a stratified analysis among African American children only, ABP1 and HNMT SNPs were also associated with PD response; HRH4 413 CC genotype was associated with lower Emax, p = 0.009. Conclusions: We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more personalized treatments

Variability of Histamine Pharmacodynamic Response in Children With Allergic Rhinitis

Histamine iontophoresis with laser Doppler monitoring (HILD) is a robust and dynamic surrogate for histamine microvasculature response. We characterized histamine pharmacodynamics in children using HILD. HILD was performed in 54 children with allergic rhinitis. A non‐compartmental analysis and non‐linear mixed‐effects model with a linked effect PK/PD model was used to provide estimates for area under the effect curve (AUEC), maximal response over baseline (EffmaxNT), and time of EffmaxNT (Tmax). Data were placed in sub‐groups by visualization of time vs. response relationships. ANOVA and regression analyses were used for sub‐group comparisons. Three histamine response phenotypes were identified. One group demonstrated a hyper‐responsive phenotype (higher Tmax, EffmaxNt and AUEC, P \u3c .01). AUEC and EffmaxNT were more strongly associated in this group (r2 = 0.86) than the entire cohort (r2 = 0.64). These data demonstrate a hyper‐responsive histamine phenotype via HILD. This finding is important to future pharmacologic studies of antihistamines

Variability of Histamine Pharmacodynamic Response in Children With Allergic Rhinitis

Histamine iontophoresis with laser Doppler monitoring (HILD) is a robust and dynamic surrogate for histamine microvasculature response. We characterized histamine pharmacodynamics in children using HILD. HILD was performed in 54 children with allergic rhinitis. A non‐compartmental analysis and non‐linear mixed‐effects model with a linked effect PK/PD model was used to provide estimates for area under the effect curve (AUEC), maximal response over baseline (EffmaxNT), and time of EffmaxNT (Tmax). Data were placed in sub‐groups by visualization of time vs. response relationships. ANOVA and regression analyses were used for sub‐group comparisons. Three histamine response phenotypes were identified. One group demonstrated a hyper‐responsive phenotype (higher Tmax, EffmaxNt and AUEC, P \u3c .01). AUEC and EffmaxNT were more strongly associated in this group (r2 = 0.86) than the entire cohort (r2 = 0.64). These data demonstrate a hyper‐responsive histamine phenotype via HILD. This finding is important to future pharmacologic studies of antihistamines