Quality assurance of dosimetry and the impact on sample size in randomized clinical trials.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the impact of appropriate dosimetry quality assurance (QA) on patient number required in radiotherapy randomized control trials (RCT). MATERIALS AND METHODS: The steepness of clinical dose-response curves, gamma(clin.), was calculated by a convoluting a biological dose-response distribution and the distribution of technical and dosimetrical factors. Population size calculation was performed taking into account gamma(clin.) and expected difference in outcome between two arms of an RCT, for different levels of variation in dose to the patient population. RESULTS: Uncertainties in dose reduces gamma(clin.) to the largest extent when the initial gamma-value is high and less so for low gamma-value. Reduced uncertainty in dose led to a significant reduction in the number of patients required in an RCT if the expected difference between the experimental and conventional arm is small. The reduction in patient numbers is less when the differences between the conventional and experimental arm is larger. CONCLUSION: The number of patients required in an RCT may be reduced by introducing appropriate dosimetry QA as the risk of under-powering the study is minimized. Dosimetry QA in clinical studies is therefore cost-effective.

Lung function development in the first 2 yr of life is independent of allergic diseases by 2 yr.

The aim of the study was to assess if lung function at birth predicts lung function at 2 yr and secondly, if lung function development was influenced by the common phenotypes of recurrent bronchial obstruction (rBO) or atopic eczema (AE) by 2 yr. Lung function was assessed at birth (n = 802) and at 2 yr within the prospective birth cohort study 'the Environment and Childhood Asthma Study' in Oslo. The 135 children with lung function measured at birth by tidal flow volume (TFV) loops and passive respiratory mechanics, who were included in a nested case-control study were reinvestigated at 2 yr with clinical examination, TFV loops (n = 90) (mean age 26.6 (3.7 s.d.) months), skin prick test and parental interview. Children were categorized into quartiles (lower, middle two, upper) according to time to peak tidal expiratory flow/total expiratory time (t(PTEF)/t(E)) at birth as well as clinical phenotype based on the presence of rBO and/or AE (ever) by 2 yr. The observed reduction in mean t(PTEF)/t(E) from birth to 2 yr within the quartiles, were not significantly different after controlling for 'regression to the mean'. t(PTEF)/t(E) at birth correlated significantly with t(PTEF)/t(E) at 2 yr, (r = 0.475, p < 0.001). Children with both rBO and AE by 2 yr had significantly lower t(PTEF)/t(E) at 2 yr (p = 0.002) and at birth (p = 0.027), compared with children with no rBO or AE. Clinical phenotype at 2 yr did not influence the change in t(PTEF)/t(E) from birth to 2 yr. This study demonstrates a clear tracking of lung function from birth, not influenced by rBO or AE by 2 yr.

No evidence that early use of inhaled corticosteroids reduces current asthma at 10 years of age.

BACKGROUND: It is debated whether early treatment with inhaled corticosteroids (ICS) can change the natural course of childhood asthma. AIM: To assess if ICS treatment before 2 years of age in children with obstructive airways disease reduces current asthma at 10 years of age. METHODS: Children with (n=233) and without (n=219) recurrent (r) bronchial obstruction (BO) attending clinical examination at 2 years of age in the birth cohort Environment and Childhood Asthma study in Oslo, were reinvestigated at 10 years of age. Current asthma (CA) at 10 years was defined as asthma with either symptoms and/or asthma treatment during the last year, and/or 10% fall in forced expired volume in 1s after standardized treadmill run. The risk of CA was assessed by logistic regression and propensity modelling (including gender, parental atopy and severity score at 2 years) in children with rBO who received ICS or not by 2 years. RESULTS: CA was found in 97 children, more often among rBO children with (56.9%) and without ICS treatment (30.8%) compared to no-BO children (5.5%) (p<0.001). In rBO children logistic regression analyses (adjusted odds ratio aOR (95% confidence interval)) identified male gender (aOR 1.82 (1.01-3.27), p=0.046) and severity score at 2 years 1.14 (1.03-1.28), (p=0.01), as significant and ICS treatment as non-significant 2.00 (0.98-4.12) risk factors for CA. With propensity modelling adjusting for disease severity, ICS treatment by 2 years caused a non-significant increased risk aOR of CA of 1.84 (0.89-3.82). CONCLUSION: No evidence was found that early use of ICS before age two in children with rBO reduces current asthma 8 years later.

Reduced lung function at birth and the risk of asthma at 10 years of age.

BACKGROUND: Reduced lung function in early infancy has been associated with later obstructive airway diseases. We assessed whether reduced lung function shortly after birth predicts asthma 10 years later. METHODS: We conducted a prospective birth cohort study of healthy infants in which we measured lung function shortly after birth with the use of tidal breathing flow-volume loops (the fraction of expiratory time to peak tidal expiratory flow to total expiratory time [t(PTEF)/t(E)]) in 802 infants and passive respiratory mechanics, including respiratory-system compliance, in 664 infants. At 10 years of age, 616 children (77%) were reassessed by measuring lung function, exercise-induced bronchoconstriction, and bronchial hyperresponsiveness (by means of a methacholine challenge) and by conducting a structured interview to determine whether there was a history of asthma or current asthma. RESULTS: As compared with children whose t(PTEF)/t(E) shortly after birth was above the median, children whose t(PTEF)/t(E) was at or below the median were more likely at 10 years of age to have a history of asthma (24.3% vs. 16.2%, P=0.01), to have current asthma (14.6% vs. 7.5%, P=0.005), and to have severe bronchial hyperresponsiveness, defined as a methacholine dose of less than 1.0 micromol causing a 20% fall in the forced expiratory volume in 1 second (FEV1) (9.1% vs. 4.9%, P=0.05). As compared with children whose respiratory-system compliance was above the median, children with respiratory compliance at or below the median more often had a history of asthma (27.4% vs. 14.8%; P=0.001) and current asthma (15.0% vs. 7.7%, P=0.009), although this measure was not associated with later measurements of lung function. At 10 years of age, t(PTEF)/t(E) at birth correlated weakly with the maximal midexpiratory flow rate (r=0.10, P=0.01) but not with FEV1 or forced vital capacity. CONCLUSIONS: Reduced lung function at birth is associated with an increased risk of asthma by 10 years of age.

CFTR gene mutations and asthma in the Norwegian Environment and Childhood Asthma study.

BACKGROUND: Several candidate genes have been implicated in the etiology of asthma, including the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations in the CFTR gene result in derangements of mucociliary clearance. Homozygotes for CFTR mutations develop cystic fibrosis (CF), a disorder characterized mainly by lung and pancreas disease. OBJECTIVE: To investigate whether there was an increased frequency of CFTR mutations in asthma patients. METHODS: Seven hundred and three subjects aged 10-11 years from the environment and childhood asthma (ECA) study were included in the present study. Possible associations between asthma, reduced lung function, bronchial hyperresponsiveness (BHR), and increased or decreased nitrogen oxide (NO) levels (based on structural parental interview, spirometry, PD20 methacholine challenge test and exhaled NO measurements), and the five most common CFTR mutations in Norway (DeltaF508, R117H, R117C, 4005+2T-->C, 394delTT), the modulating polymorphisms IVS8(TG)mTn and the IVS8-5T were investigated. RESULTS: No association were found between asthma, reduced lung function, BHR or exhaled NO levels and CF heterozygosity. However, the IVS8(TG)11T7 haplotype was associated with normal lung function. CONCLUSIONS: Our results do not support the hypothesis that CFTR mutations or polymorphisms play a role in the pathogenesis of asthma in children. However, the distribution of Tn(TG)m haplotypes differed between individuals with reduced lung function and individuals with normal lung function.

Is bronchodilator response in 2-yr-old children associated with asthma risk factors?

Factors that might influence lung function bronchodilator response by 2 yr of age is largely unknown, thus we aimed to assess this in the 'Environment and Childhood asthma' (ECA) study in Oslo. A clinical investigation at mean age 26 months was attended by 516 (84%) children included in a nested case-control study [children with recurrent bronchial obstruction (rBO)] (n = 265) and controls without a history of lower respiratory disease (n = 251). Tidal lung function measures before and after inhaled nebulized salbutamol (bronchodilator response) (when clinically without BO) were obtained in 46%. Clinical characteristics and personal and family history of allergic/respiratory diseases (asthma risk factors) were ascertained by structured interview and clinical examination. Allergic sensitization was assessed by skin prick test/specific IgE antibody analyses to common allergens. Mean (95% CI) per cent change in time to reach peak flow/total expiratory time (t(PTEF)/t(E)) from before to after salbutamol was significantly larger in children with rBO [17.3 (9.4-25.3) than controls (-2.2 (-7.7 to 3.0)]. The bronchodilator response increased significantly (p = 0.001) with increasing number of asthma risk factors, but was not significantly associated with allergic sensitization, parental 'atopy', or maternal smoking alone. Children treated with inhaled corticosteroids had greater bronchodilator response than those treated with bronchodilators alone. Bronchodilator response in asymptomatic 2-yr-old children was most closely associated with the presence of rBO, but increasing number of asthma risk factors and treatment with inhaled corticosteroids were associated with increased bronchodilator response.