[Show abstract][Hide abstract] ABSTRACT: It is now recognized that preterm infants <=28 weeks gestation can be effectively supported from the outset with nasal continuous positive airway pressure. However, this form of respiratory therapy may fail to adequately support those infants with significant surfactant deficiency, with the result that intubation and delayed surfactant therapy are then required. Infants following this path are known to have a higher risk of adverse outcomes, including death, bronchopulmonary dysplasia and other morbidities. In an effort to circumvent this problem, techniques of minimally-invasive surfactant therapy have been developed, in which exogenous surfactant is administered to a spontaneously breathing infant who can then remain on continuous positive airway pressure. A method of surfactant delivery using a semi-rigid surfactant instillation catheter briefly passed into the trachea (the "Hobart method") has been shown to be feasible and potentially effective, and now requires evaluation in a randomised controlled trial.Methods/design: This is a multicentre, randomised, masked, controlled trial in preterm infants 25-28 weeks gestation. Infants are eligible if managed on continuous positive airway pressure without prior intubation, and requiring FiO2 >= 0.30 at an age <=6 hours. Randomisation will be to receive exogenous surfactant (200 mg/kg poractant alfa) via the Hobart method, or sham treatment. Infants in both groups will thereafter remain on continuous positive airway pressure unless intubation criteria are reached (FiO2 >= 0.45, unremitting apnoea or persistent acidosis). Primary outcome is the composite of death or physiological bronchopulmonary dysplasia, with secondary outcomes including incidence of death; major neonatal morbidities; durations of all modes of respiratory support and hospitalisation; safety of the Hobart method; and outcome at 2 years. A total of 606 infants will be enrolled. The trial will be conducted in >30 centres worldwide, and is expected to be completed by end-2017.
[Show abstract][Hide abstract] ABSTRACT: To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis (CF), rather than standard therapy, was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions.
[Show abstract][Hide abstract] ABSTRACT: Aortic intima-media thickness measured by transabdominal ultrasound (aIMT) is an intermediate phenotype of cardiovascular risk. We aimed to (1) investigate the reproducibility of aIMT in a population-derived cohort of infants; (2) establish the distribution of aIMT in early infancy; (3) compare measurement by edge-detection software to that by manual sonographic calipers; and (4) assess the effect of individual and environmental variables on image quality.
[Show abstract][Hide abstract] ABSTRACT: Multiple imputation (MI) was developed as a method to enable valid inferences to be obtained in the presence of missing data rather than to re-create the missing values. Within the applied setting, it remains unclear how important it is that imputed values should be plausible for individual observations. One variable type for which MI may lead to implausible values is a limited-range variable, where imputed values may fall outside the observable range. The aim of this work was to compare methods for imputing limited-range variables, with a focus on those that restrict the range of the imputed values.
Using data from a study of adolescent health, we consider three variables based on responses to the General Health Questionnaire (GHQ), a tool for detecting minor psychiatric illness. These variables, based on different scoring methods for the GHQ, resulted in three continuous distributions with mild, moderate and severe positive skewness. In an otherwise complete dataset, we set 33% of the GHQ observations to missing completely at random or missing at random; repeating this process to create 1000 datasets with incomplete data for each scenario.For each dataset, we imputed values on the raw scale and following a zero-skewness log transformation using: univariate regression with no rounding; post-imputation rounding; truncated normal regression; and predictive mean matching. We estimated the marginal mean of the GHQ and the association between the GHQ and a fully observed binary outcome, comparing the results with complete data statistics.
Imputation with no rounding performed well when applied to data on the raw scale. Post-imputation rounding and imputation using truncated normal regression produced higher marginal means than the complete data estimate when data had a moderate or severe skew, and this was associated with under-coverage of the complete data estimate. Predictive mean matching also produced under-coverage of the complete data estimate. For the estimate of association, all methods produced similar estimates to the complete data.
For data with a limited range, multiple imputation using techniques that restrict the range of imputed values can result in biased estimates for the marginal mean when data are highly skewed.
BMC Medical Research Methodology 04/2014; 14(1):57. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to describe the distribution of magnetic resonance imaging (MRI) patterns in a large population sample of children with cerebral palsy (CP) and to examine associations between MRI patterns, and antenatal and perinatal variables.
Data were retrieved from the Victorian CP Register for 884 children (527 males, 357 females) born between 1999 and 2006. Postneonatal MRI was classified for 594 children. For 563 children (329 males, 234 females) for whom classification was to a single MRI pattern, the frequency of each variable was compared between patterns and with the population frequency.
White matter injury was the most common MRI pattern (45%), followed by grey matter injury (14%), normal imaging (13%), malformations (10%), focal vascular insults (9%), and miscellaneous patterns (7%). Parity, birth gestation, level of neonatal care, Apgar score, and time to established respiration varied between MRI patterns (p<0.01). Nulliparity was most strongly associated with focal vascular insults, whereas multiparity was associated only with malformations. Grey matter injury was not associated with birth in a tertiary unit, but was strongly associated with severe perinatal compromise. The frequency of neonatal seizures and of nursery admissions was lowest among children with malformations.
As known risk factors for CP are differentially associated with specific MRI patterns, future exploration of causal pathways might be facilitated when performed in pathogenically defined groups.
[Show abstract][Hide abstract] ABSTRACT: Most adults with common mental disorders report their first symptoms before 24 years of age. Although adolescent anxiety and depression are frequent, little clarity exists about which syndromes persist into adulthood or resolve before then. In this report, we aim to describe the patterns and predictors of persistence into adulthood.
We recruited a stratified, random sample of 1943 adolescents from 44 secondary schools across the state of Victoria, Australia. Between August, 1992, and January, 2008, we assessed common mental disorder at five points in adolescence and three in young adulthood, commencing at a mean age of 15·5 years and ending at a mean age of 29·1 years. Adolescent disorders were defined on the Revised Clinical Interview Schedule (CIS-R) at five adolescent measurement points, with a primary cutoff score of 12 or higher representing a level at which a family doctor would be concerned. Secondary analyses addressed more severe disorders at a cutoff of 18 or higher.
236 of 821 (29%; 95% CI 25-32) male participants and 498 of 929 (54%; 51-57) female participants reported high symptoms on the CIS-R (≥12) at least once during adolescence. Almost 60% (434/734) went on to report a further episode as a young adult. However, for adolescents with one episode of less than 6 months duration, just over half had no further common mental health disorder as a young adult. Longer duration of mental health disorders in adolescence was the strongest predictor of clear-cut young adult disorder (odds ratio [OR] for persistent young adult disorder vs none 3·16, 95% CI 1·86-5·37). Girls (2·12, 1·29-3·48) and adolescents with a background of parental separation or divorce (1·62, 1·03-2·53) also had a greater likelihood of having ongoing disorder into young adulthood than did those without such a background. Rates of adolescent onset disorder dropped sharply by the late 20s (0·57, 0·45-0·73), suggesting a further resolution for many patients whose symptoms had persisted into the early 20s.
Episodes of adolescent mental disorder often precede mental disorders in young adults. However, many such disorders, especially when brief in duration, are limited to the teenage years, with further symptom remission common in the late 20s. The resolution of many adolescent disorders gives reason for optimism that interventions that shorten the duration of episodes could prevent much morbidity later in life.
Australia's National Health and Medical Research Council.
[Show abstract][Hide abstract] ABSTRACT: Multiple imputation (MI) is becoming increasingly popular as a strategy for handling missing data, but there is a scarcity of tools for checking the adequacy of imputation models. The Kolmogorov-Smirnov (KS) test has been identified as a potential diagnostic method for assessing whether the distribution of imputed data deviates substantially from that of the observed data. The aim of this study was to evaluate the performance of the KS test as an imputation diagnostic.
Using simulation, we examined whether the KS test could reliably identify departures from assumptions made in the imputation model. To do this we examined how the p-values from the KS test behaved when skewed and heavy-tailed data were imputed using a normal imputation model. We varied the amount of missing data, the missing data models and the amount of skewness, and evaluated the performance of KS test in diagnosing issues with the imputation models under these different scenarios.
The KS test was able to flag differences between the observations and imputed values; however, these differences did not always correspond to problems with MI inference for the regression parameter of interest. When there was a strong missing at random dependency, the KS p-values were very small, regardless of whether or not the MI estimates were biased; so that the KS test was not able to discriminate between imputed variables that required further investigation, and those that did not. The p-values were also sensitive to sample size and the proportion of missing data, adding to the challenge of interpreting the results from the KS test.
Given our study results, it is difficult to establish guidelines or recommendations for using the KS test as a diagnostic tool for MI. The investigation of other imputation diagnostics and their incorporation into statistical software are important areas for future research.
BMC Medical Research Methodology 11/2013; 13(1):144. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Language impairment (LI) in the preschool years is known to vary over time. Stability in the diagnosis of LI may be influenced by children’s individual variability, the measurement error of commonly used assessment instruments and the cut-points used to define impairment.
To investigate the agreement between two different age-based versions of a language assessment instrument and the stability of the classification of LI using the two measures over a 12-month period.
A total of 945 participants completed the Clinical Evaluation of Language Fundamentals(CELF—Preschool 2 or 4th Edn) at 4 and 5 years of age. Agreement and stability were analysed using Bland–Altman plots, correlation and odds ratios. Sensitivity and specificity were calculated for two thresholds of the CELF-P2 using the diagnostic category on the child’s subsequent CELF-4.
For all CELF scores, mean differences for the cohort between 4 and 5 years were within 1.5 scale score units. In contrast, at the individual level variability was found across the range of scores and was of a greater magnitude than previously reported. Stability in LI classification was low, with 36% of 5-year-olds with LI (defined as a standard score below –1.25) classified as typical at 4 years, even though odds ratios calculated from classifications at the two time points suggested that 4-year-olds with LI had 23 times greater odds than their typical peers to receive a diagnosis of LI at 5 years. The CELF-P2 did not demonstrate adequate levels of diagnostic accuracy for LI at 5 years: sensitivity of 64% and specificity of 92.9%.
Substantial variability across the entire range of possible CELF scores was observed in this community cohort between the ages of 4 and 5 years. The stability of LI classification was lower than that reported in previous research conducted primarily on smaller clinical cohorts. The current study’s results suggest that the variability observed in developmental language pathways is the result of a combination of limitations in measurement instruments, individual children’s abilities and the arbitrary nature of the boundaries defining LI.
International Journal of Language & Communication Disorders 10/2013; 49(2):215-27. · 1.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Estimates of the risk of intussusception (IS) associated with currently licensed rotavirus vaccines (RV1, Rotarix®, GSK, and RV5, RotaTeq®, Merck) diverge. Contemporaneous introduction of both vaccines in Australia enabled a population-based assessment of risk. Methods. Confirmed cases of IS in infants 1-<12 months were identified from national hospitalisation databases, supplemented by active hospital-based surveillance from July 2007-June 2010. Vaccination histories were verified by the Australian Childhood Immunisation Register, which was also used to identify age-matched controls. Self-controlled case-series and case-control methods were used to assess risk of IS associated with both vaccines in pre-specified periods post-vaccination. The estimated burden of vaccine-attributable IS was compared with estimated reductions in gastroenteritis hospitalisations. Results. Based on 306 confirmed cases of IS, the relative incidence (RI) of intussusception in the 1-7 day period following the first vaccine dose, was 6.8 (95% confidence interval [CI] 2.4 to 19.0, p<0.001) for RV1, and 9.9 (95% CI 3.7 to 26.4, p<0.001) for RV5. There was a smaller increased risk 1-7 days following the second dose of each vaccine. The case-control analysis gave similar results. We estimate an excess of 18 IS cases and >6,500 fewer gastroenteritis hospitalisations in young children annually in Australia following vaccine introduction. Conclusions. We found a similarly increased risk of IS following both vaccines but the balance of benefits and risks at population level was highly favourable, a finding likely to extend to other settings despite varying incidence of IS and potentially higher morbidity and mortality from both gastroenteritis and intussusception.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to review the distribution of neuroimaging findings from a contemporary population cohort of individuals with cerebral palsy (CP) and to facilitate standardization of imaging classification.
Publications from 1995 to 2012 reporting imaging findings in population cohorts were selected through a literature search, and review of the titles, abstracts, and content of studies. Relevant data were extracted, including unpublished data from Victoria, Australia. The proportions for each imaging pattern were tabulated, and heterogeneity was assessed for all individuals with CP, and for subgroups based on gestational age, CP subtype, and Gross Motor Function Classification System level.
Studies from three geographic regions met the inclusion criteria for individuals with CP, and two additional studies reported on specific CP subtypes. Brain abnormalities were observed in 86% of scans, but were observed least often in children with ataxia (24-57%). White matter injury was the most common imaging pattern (19-45%), although the proportions showed high heterogeneity. Additional patterns were grey matter injury (21%), focal vascular insults (10%), malformations (11%), and miscellaneous findings (4-22%).
This review suggests areas where further dialogue will facilitate progress towards standardization of neuroimaging classification. Standardization will enable future collaborations aimed at exploring the relationships among magnetic resonance imaging patterns, risk factors, and clinical outcomes, and, ultimately, lead to better understanding of causal pathways and opportunities for prevention.
Developmental Medicine & Child Neurology 08/2013; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The concept of missing at random is central in the literature on statistical
analysis with missing data. In general, inference using incomplete data should
be based not only on observed data values but should also take account of the
pattern of missing values. However, it is often said that if data are missing
at random, valid inference using likelihood approaches (including Bayesian) can
be obtained ignoring the missingness mechanism. Unfortunately, the term
"missing at random" has been used inconsistently and not always clearly; there
has also been a lack of clarity around the meaning of "valid inference using
likelihood". These issues have created potential for confusion about the exact
conditions under which the missingness mechanism can be ignored, and perhaps
fed confusion around the meaning of "analysis ignoring the missingness
mechanism". Here we provide standardised precise definitions of "missing at
random" and "missing completely at random", in order to promote unification of
the theory. Using these definitions we clarify the conditions that suffice for
"valid inference" to be obtained under a variety of inferential paradigms.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effectiveness of school-based physical activity interventions on fitness, adiposity and cardiometabolic outcomes among schoolchildren. Medline, Embase, EBSCOhost CINAHL and ERIC databases were searched up to October 2012. Inclusion criteria: intervention delivered at school with controls having no intervention or usual physical education classes; participants aged 5-18 years; outcomes spanning some or all of the above. We assessed levels of evidence for identified trials based on methodological quality and sample size. Dose of the interventions (a total summary measure of intensity, frequency and duration) were considered. Eighteen randomized controlled trials (RCTs, total participants = 6,207) were included, of which six were large, higher quality trials with high dose of the intervention. The intervention was consistent in increasing fitness with large, higher quality studies and high dose of intervention providing strong evidence. Dose of school-based physical activity is an important determinant of trial efficiency. Some large, higher quality RCTs provided strong evidence for interventions to decrease skin-fold thickness, increase fitness and high-density lipoprotein cholesterol. Evidence for body mass index, body fat and waist circumference, blood pressure and triglycerides, low-density lipoprotein cholesterol and total cholesterol remain inconclusive and require additional higher quality studies with high dose of interventions to provide conclusive evidence.
[Show abstract][Hide abstract] ABSTRACT: Background: Preterm infants ≤32 weeks' gestation are increasingly being managed on continuous positive airway pressure (CPAP), without prior intubation and surfactant therapy. Some infants treated in this way ultimately fail on CPAP and require intubation and ventilation. Objectives: To define the incidence, predictors and consequences of CPAP failure in preterm infants managed with CPAP from the outset. Methods: Preterm infants 25-32 weeks' gestation were included in the study if inborn and managed with CPAP as the initial respiratory support, with division into two gestation ranges and grouping according to whether they were successfully managed on CPAP (CPAP-S) or failed on CPAP and required intubation <72 h (CPAP-F). Predictors of CPAP failure were sought, and outcomes compared between the groups. Results: 297 infants received CPAP, of which 65 (22%) failed, with CPAP failure being more likely at lower gestational age. Most infants failing CPAP had moderate or severe respiratory distress syndrome radiologically. In multivariate analysis, CPAP failure was found to be predicted by the highest FiO2 in the first hours of life. CPAP-F infants had a prolonged need for respiratory support and oxygen therapy, and a higher risk of death or bronchopulmonary dysplasia at 25-28 weeks' gestation (CPAP-F 53% vs. CPAP-S 14%, relative risk 3.8, 95% CI 1.6, 9.3) and a substantially higher risk of pneumothorax at 29-32 weeks. Conclusion: CPAP failure in preterm infants usually occurs because of unremitting respiratory distress syndrome, is predicted by an FiO2 ≥0.3 in the first hours of life, and is associated with adverse outcomes.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Early puberty has been linked to higher rates of mental health problems in adolescence. However, previous studies commencing after the initiation of puberty have been unable to explore whether early puberty is preceded by higher rates of these problems. In a large national study, we aimed to determine whether difficulties in behavior and psychosocial adjustment are evident before as well as during the early pubertal transition. METHODS: The Longitudinal Study of Australian Children recruited a nationally representative cohort of 4,983 children at age 4-5 years in 2004. This analysis includes 3,491 of these children (70.1%) followed up at ages 6-7, 8-9, and 10-11 years, with a completed parent report of stage of pubertal maturation at age 8-9 years. Parents reported behavior difficulties (Strengths and Difficulties Questionnaire) and psychosocial adjustment (Pediatric Quality of Life Inventory) at all four waves from ages 4-5 to 10-11 years. RESULTS: Both boys and girls who entered puberty early (i.e., by age 8-9 years) also experienced poorer psychosocial adjustment at this age. These psychosocial differences were already evident at ages 4-5 and 6-7 years, and persisted to at least age 10-11 years. Similar patterns were evident for behavior difficulties, but only for boys; early puberty was not related to behavior difficulties in girls. CONCLUSIONS: Children with early puberty have different patterns of behavior and social adjustment from the preschool years through early adolescence. At least in part, the association between early-onset puberty and poor mental health appears to result from processes under way well before the onset of puberty.
Journal of Adolescent Health 03/2013; · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIM: To explore the link between pre-school children's general home computer use and their letter knowledge. METHODS: As part of the Early Language in Victoria Study, a community cohort of 1539 four-year-old children was tested on letter knowledge as well as on non-verbal intelligence, oral language, articulation and phonological awareness. Performance on these measures was examined in relation to parent-questionnaire responses exploring home literacy environment and the amount of time children spent using the computer. RESULTS: A positive correlation between computer use and letter knowledge was found, and this association was still evident after controlling for other cognitive and environmental factors known to predict the development of letter knowledge in young children. CONCLUSIONS: Greater computer use in pre-school children appears to have a positive association with emerging literacy development. Future research needs to examine the nature of that association.
Journal of Paediatrics and Child Health 02/2013; · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. METHODS: Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. RESULTS: 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05). CONCLUSIONS: Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.
[Show abstract][Hide abstract] ABSTRACT: Missing data often cause problems in longitudinal cohort studies with repeated follow-up waves. Research in this area has focussed on analyses with missing data in repeated measures of the outcome, from which participants with missing exposure data are typically excluded. We performed a simulation study to compare complete-case analysis with Multiple imputation (MI) for dealing with missing data in an analysis of the association of waist circumference, measured at two waves, and the risk of colorectal cancer (a completely observed outcome).
We generated 1,000 datasets of 41,476 individuals with values of waist circumference at waves 1 and 2 and times to the events of colorectal cancer and death to resemble the distributions of the data from the Melbourne Collaborative Cohort Study. Three proportions of missing data (15, 30 and 50%) were imposed on waist circumference at wave 2 using three missing data mechanisms: Missing Completely at Random (MCAR), and a realistic and a more extreme covariate-dependent Missing at Random (MAR) scenarios. We assessed the impact of missing data on two epidemiological analyses: 1) the association between change in waist circumference between waves 1 and 2 and the risk of colorectal cancer, adjusted for waist circumference at wave 1; and 2) the association between waist circumference at wave 2 and the risk of colorectal cancer, not adjusted for waist circumference at wave 1.
We observed very little bias for complete-case analysis or MI under all missing data scenarios, and the resulting coverage of interval estimates was near the nominal 95% level. MI showed gains in precision when waist circumference was included as a strong auxiliary variable in the imputation model.
This simulation study, based on data from a longitudinal cohort study, demonstrates that there is little gain in performing MI compared to a complete-case analysis in the presence of up to 50% missing data for the exposure of interest when the data are MCAR, or missing dependent on covariates. MI will result in some gain in precision if a strong auxiliary variable that is not in the analysis model is included in the imputation model.
Emerging Themes in Epidemiology 01/2013; 10(1):6. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the prevalence of binge drinking in adolescence and its persistence into adulthood in an Australian cohort.
15-year prospective cohort study.
1943 adolescents were recruited from secondary schools at age 14-15 years.
Levels of past-week 'binge' drinking (5+ standard drinks on a day, each 10 g alcohol) and 'heavy binge' drinking (20+ standard drinks on a day for males, 11+ for females) were assessed during six adolescent waves, and across three adult waves up to age 29 years.
Half of the males (52%) and a third of the females (34%) reported past-week adolescent binge drinking. 90% of male and 70% of female adolescent-onset binge drinkers continued to binge in young adulthood; 70% of males and 48% of females who were not adolescent-onset binge drinkers reported young adult binge drinking. Past-week heavy bingeing was less common in adolescence than adulthood. Overall, 35% of the sample (95% CI 33% to 38%) reported past-week binge drinking in adolescence and young adulthood and one-third (33%; 30% to 35%) first reported binge drinking in young adulthood; only 7% of the sample (6-8%) had binge drinking in adolescence but not young adulthood. 'Heavy binge' drinking occurred in adolescence and young adulthood for 9% (8% to 10%); 8% (7% to 10%) reported it in adolescence but no longer in young adulthood; and 24% (22% to 26%) began 'heavy binge' drinking in young adulthood. Among adolescent binge drinkers (n=821), young adult binge and heavy binge drinking were predicted by being male, adolescent antisocial behaviour and adverse consequences of drinking in adolescence.
Binge alcohol use is common and persistent among young Australians. Efforts to prevent the onset of binge drinking during adolescence may substantially reduce harmful patterns of alcohol use in young adulthood.
BMJ Open 01/2013; 3(8):e003015. · 1.58 Impact Factor