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Background: Indigenous populations have high rates of disease and premature mortality. Most Indigenous communities are young, and adolescence (age 10-24 years) provides great opportunities for population health gain. However, the absence of a comprehensive account of Indigenous adolescents' health has been a barrier to effective policy. We aimed to report a national health profile for Indigenous adolescents in Australia., Methods: We undertook a systematic synthesis of population data to report the health and wellbeing of Indigenous adolescents in Australia. A reporting framework for Indigenous adolescent health in Australia was defined to measure health outcomes, health risks, and sociocultural determinants. Available data (primary data from national surveys and administrative datasets, and available published data) were mapped against the defined reporting framework, and the quality graded, with the highest quality data selected to report a health profile for Indigenous adolescents. Comparison with non-Indigenous adolescents was made where possible, and estimates (disaggregated by age, sex, and remoteness) were reported as relative risks. A national advisory group (six Indigenous young people, three Indigenous adult community members, three researchers, three policy makers, and two service providers, all aged ≥16 years) provided input about the reporting framework, interpretation of findings, and policy recommendations., Findings: Data were available for 184 (79%) of 234 elements of the reporting framework. All-cause mortality for Indigenous adolescents (70 per 100 000) was more than twice that of non-Indigenous adolescents, with about 60% of deaths due to intentional self-harm and road traffic injury. 80% of all deaths among Indigenous adolescents were considered as potentially avoidable in the current health system. Communicable diseases (particularly sexually transmitted infections) were leading contributors to morbidity. Almost a third of Indigenous adolescents aged 18-24 years reported high levels of psychological distress (twice the non-Indigenous rate). There was an excess burden of mental disorders and substance use, alongside emerging type 2 diabetes and ischaemic heart disease. Additionally, there were excess intentional and unintentional injuries. Many aspects of this health profile differed markedly from that of non-Indigenous adolescents: rates of acute rheumatic fever, pneumococcal infection, gonorrhoea, and type 2 diabetes resulting in admission to hospital were ten times higher; rates of assault and childbirth in those aged 15-19 years were five times higher; whereas rates of eating disorders, melanoma and other skin cancers, and anaphylaxis were significantly lower. Risks for future ill-health were common; 43% of 15-24 year olds were current tobacco smokers and about 45% had high body mass (overweight or obese). Disadvantage across sociocultural health determinants also emerged, particularly around education., Interpretation: Despite Australia's adolescents having one of the best health profiles globally, Indigenous adolescents have largely been left behind. Adequate responses will require intersectoral actions, including a health system responsive to the needs of Indigenous adolescents. Without a specific focus on adolescents, Australia will not redress Indigenous health inequalities., Funding: Australia's National Health and Medical Research Council, Sidney Myer Foundation, and the Murdoch Children's Research Institute., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In cross-population comparisons of disease occurrence (prevalence, incidence), a common public health question is the extent to which variations in the distribution of risk factors for the disease explain observed differences. Limited work has been done on formalizing this problem, which is conceptually tantamount to quantifying the degree of confounding for the 'population effect' induced by different factors. A common approach is to compare 'unadjusted' and 'adjusted' regression-based estimates of that parameter, but the interpretation of the resulting 'contribution' measures may be hindered by other confounding sources and non-collapsibility issues. Interactions also raise interpretational challenges., Methods: We formalized this problem using directed acyclic graphs and the potential outcomes framework, on the basis of which we defined a series of estimands that address specific questions and are identifiable under certain causal assumptions. We subsequently determined possible estimators. A study of regional differences in egg allergy prevalence in 1-year-olds was used for illustration., Results: The main estimands defined were: the change in the prevalence or incidence difference induced by compositional variations in measured risk factors, all at once and individually, relative to a reference population; and the proportion of the crude difference that remains unexplained by measured factors. Standardization (g-computation), inverse probability weighted (IPW) and doubly robust IPW estimators of these estimands were considered., Conclusions: This work provides a causal theoretical basis for studying disease occurrence differences between populations. The proposed measures can be used to answer the questions that arise in this context under a set of clearly stated assumptions., (© The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Background: Excess adiposity and adiposity-related inflammation are known risk factors for cardiovascular disease in adults; however, little is known regarding the determinants of adiposity-related inflammation at birth., Objectives: The aim of this study was to investigate the association between maternal pre-pregnancy BMI and newborn adiposity and inflammation., Methods: Paired maternal (28-week gestation) and infant (umbilical cord) blood samples were collected from a population-derived birth cohort (Barwon Infant Study, n = 1074). Data on maternal comorbidities and infant birth anthropomorphic measures were compiled, and infant aortic intima-media thickness was measured by trans-abdominal ultrasound. In a selected subgroup of term infants (n = 161), matched maternal and cord lipids, high-sensitivity C-reactive protein (hsCRP) and maternal soluble CD14 were measured. Analysis was completed by using pairwise correlation and linear regression. Because of their non-normal distribution, pathology blood measures were log transformed prior to analysis., Results: Maternal pre-pregnancy BMI was positively associated with increased birth weight (mean difference 17.8 g per kg m -2 , 95% CI 6.6 to 28.9; p = 0.002), newborn mean skin-fold thickness (mean difference 0.1 mm per kg m -2 , 95% CI 0.0 to 0.1; p < 0.001) and cord blood hsCRP (mean difference of 4.2% increase in hsCRP per kg m -2 increase in pre-pregnancy BMI, 95% CI 0.6 to 7.7%, p = 0.02), but not cord blood soluble CD14. Inclusion of maternal hsCRP as a covariate attenuated the associations between pre-pregnancy BMI and both newborn skin-fold thickness and cord blood hsCRP., Conclusion: Higher maternal pre-pregnancy BMI is associated with increased newborn adiposity and inflammation. These associations may be partially mediated by maternal inflammation during pregnancy., (© 2016 World Obesity Federation.)

Background: Lipid metabolism is vital to fetal development and cardiometabolic health and the final weeks of gestation are known to be a time of intense metabolic activity. New techniques such as lipidomics allow investigation of a complex lipidomic profile in infants., Objectives: This research aimed to (1) describe variations in lipidomic profile in late preterm and term infants and (2) compare variations to an adult lipidomic profile with known clinical implications., Methods: The Barwon Infant Study (n = 1,074) is a population-derived pre-birth cohort study. The lipidomic profile of cord blood was measured by liquid chromatography-mass spectrometry in 225 participants and the association between gestational age and lipidomic profile was investigated using multiple linear regression adjusting for birth weight, exposure to labour, and infant sex. Patterns of association with gestational age across the lipidomic profile were compared with associations between body mass index (BMI) and lipidomic profile observed among adults in the San Antonia Family Heart Study (n = 994)., Results: Gestational age was independently associated with the abundances of 39% of lipid species. Variations in the lipidomic profile with increasing gestational age were comparable to some variations observed in association with increasing BMI among adults., Conclusion: There is a strong relationship between gestational age and the cord blood lipid profile at birth, providing further evidence for the importance of metabolic changes of late gestation. A number of the variations in the lipid profile with increasing gestational age are analogous to differences observed in the adult lipid profile with an increasing BMI., (© 2018 S. Karger AG, Basel.)

Background: Multiple imputation has become very popular as a general-purpose method for handling missing data. The validity of multiple-imputation-based analyses relies on the use of an appropriate model to impute the missing values. Despite the widespread use of multiple imputation, there are few guidelines available for checking imputation models., Analysis: In this paper, we provide an overview of currently available methods for checking imputation models. These include graphical checks and numerical summaries, as well as simulation-based methods such as posterior predictive checking. These model checking techniques are illustrated using an analysis affected by missing data from the Longitudinal Study of Australian Children., Conclusions: As multiple imputation becomes further established as a standard approach for handling missing data, it will become increasingly important that researchers employ appropriate model checking approaches to ensure that reliable results are obtained when using this method.

Background: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy., Objective: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year., Methods: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D 3 (25(OH)D 3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D 3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding., Results: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year., Conclusions: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Conjunctival ultraviolet autofluorescence (CUVAF) area detected from UVAF photographs is a recently developed potential marker for past sun exposure, but its relationship with sun-related factors has not been fully investigated. Methods: The study included 339 healthy children ages 5 to 15 years in Melbourne, Australia. Data were collected by questionnaire and examination at school. CUVAF area was measured using a computer program and analyzed as a continuous and dichotomous outcome (any/none). Results: Fifty-three children (15.6%) had detectable CUVAF, and the youngest age at which a child showed sun damage was 8 years. Compared with silicone skin cast score, there was good inter-grader agreement on CUVAF grading, with Cohen kappa 0.85 [95% confidence interval (CI), 0.65-1.00] for total CUVAF area using both eye photographs. Perfect intra-grader agreement was achieved. Fairer pigmentation, including medium/fair skin color [adjusted odds ratio (AOR), 3.42; 95% CI, 1.02-11.48 vs. dark/olive] and blue/gray eye color (AOR, 4.07; 95% CI, 1.73-9.55 vs. brown) was associated with increased odds of CUVAF. Increasing lifetime sunburn number (e.g., AOR, 2.89; 95% CI, 1.14-7.35 and 4.29; 1.04-17.76 for sunburns 2 to 4 and ≥ 5 times, respectively, vs. no sunburns, trend P = 0.004) and freckling by the end of last summer were associated with increased odds of CUVAF. Conclusions: CUVAF area can be an a priori objective measure of past sun exposure in pediatric populations for future research. Impact: To our knowledge, this is the first pediatric study that evaluated associations of sun-related risk factors with CUVAF. Cancer Epidemiol Biomarkers Prev; 26(7); 1146-53. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objectives: To describe 24-hour time-use patterns and their association with health-related quality of life (HRQoL) in early adolescence., Methods: The Child Health CheckPoint was a cross-sectional study nested between Waves 6 and 7 of the Longitudinal Study of Australian Children. The participants were 1455 11- to 12-year-olds (39% of Wave 6; 51% boys). The exposure was 24-hour time use measured across 259 activities using the Multimedia Activity Recall for Children and Adolescents. "Average" days were generated from 1 school and 1 nonschool day. Time-use clusters were derived from cluster analysis with compositional inputs. The outcomes were self-reported HRQoL (Physical and Psychosocial Health [PedsQL] summary scores; Child Health Utility 9D [CHU9D] health utility)., Results: Four time-use clusters emerged: "studious actives" (22%; highest school-related time, low screen time), "techno-actives" (33%; highest physical activity, lowest school-related time), "stay home screenies" (23%; highest screen time, lowest passive transport), and "potterers" (21%; low physical activity). Linear regression models, adjusted for a priori confounders, showed that compared with the healthiest "studious actives" (mean [SD]: CHU9D 0.84 [0.14], PedsQL physical 86.8 [10.8], PedsQL psychosocial 79.9 [12.6]), HRQoL in "potterers" was 0.2 to 0.5 SDs lower (mean differences [95% confidence interval]: CHU9D -0.03 [-0.05 to -0.00], PedsQL physical -5.5 [-7.4 to -3.5], PedsQL psychosocial -5.8 [-8.0 to -3.5])., Conclusions: Discrete time-use patterns exist in Australian young adolescents. The cluster characterized by low physical activity and moderate screen time was associated with the lowest HRQoL. Whether this pattern translates into precursors of noncommunicable diseases remains to be determined., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Multiple imputation (MI) is becoming increasingly popular for handling missing data. Standard approaches for MI assume normality for continuous variables (conditionally on the other variables in the imputation model). However, it is unclear how to impute non-normally distributed continuous variables. Using simulation and a case study, we compared various transformations applied prior to imputation, including a novel non-parametric transformation, to imputation on the raw scale and using predictive mean matching (PMM) when imputing non-normal data. We generated data from a range of non-normal distributions, and set 50% to missing completely at random or missing at random. We then imputed missing values on the raw scale, following a zero-skewness log, Box-Cox or non-parametric transformation and using PMM with both type 1 and 2 matching. We compared inferences regarding the marginal mean of the incomplete variable and the association with a fully observed outcome. We also compared results from these approaches in the analysis of depression and anxiety symptoms in parents of very preterm compared with term-born infants. The results provide novel empirical evidence that the decision regarding how to impute a non-normal variable should be based on the nature of the relationship between the variables of interest. If the relationship is linear in the untransformed scale, transformation can introduce bias irrespective of the transformation used. However, if the relationship is non-linear, it may be important to transform the variable to accurately capture this relationship. A useful alternative is to impute the variable using PMM with type 1 matching. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: The maternal and infant microbiome may influence infant cardiovascular risk through immune programming. The maternal vagino-enteric microbiome is often sampled for group B streptococcus (GBS) colonization during pregnancy. Our aim was to investigate the association between maternal GBS colonization, intrapartum antibiotics, antenatal pet exposure and infant aortic intima-media thickness (aIMT), an intermediate vascular phenotype, and whether this association varied by mode of delivery., Methods: The Barwon Infant Study is a population-derived pre-birth cohort. Perinatal data were collected on participants. Women were tested for vagino-enteric group B streptococcus (GBS) colonization during third trimester. Six-week infant aIMT was measured by trans-abdominal ultrasound. Adjustment for confounders included maternal age, pre-pregnancy body mass index (BMI), smoking, socioeconomic status, gestational diabetes, length of gestation, infant sex, birthweight and aortic internal diameter., Results: Data were available on 835 mother-infant pairs. Of these, 574 (69%) women delivered vaginally; of those, 129 (22%) were GBS-colonized; and of these women, 111 (86%) received prophylactic intrapartum antibiotics. An association between maternal GBS colonization and infant aIMT was observed among those delivered vaginally (β = 19.5 µm, 95% CI 9.5, 29.4; P  < 0.0001) but not by Caesarean section ( P for interaction = 0.02). A similar pattern was seen for intrapartum antibiotics. There was a negative association between antenatal pet exposure and aIMT observed in those delivered vaginally., Conclusion: Maternal GBS colonization and intrapartum antibiotics were associated with increased infant aIMT in those delivered vaginally, whereas antenatal pet exposure was associated with decreased aIMT. These data suggest that differences in early life microbial experience may contribute to an increased cardiovascular risk., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Background: The Australian Longitudinal Study on Male Health (Ten to Men) used a complex sampling scheme to identify potential participants for the baseline survey. This raises important questions about when and how to adjust for the sampling design when analyzing data from the baseline survey., Methods: We describe the sampling scheme used in Ten to Men focusing on four important elements: stratification, multi-stage sampling, clustering and sample weights. We discuss how these elements fit together when using baseline data to estimate a population parameter (e.g., population mean or prevalence) or to estimate the association between an exposure and an outcome (e.g., an odds ratio). We illustrate this with examples using a continuous outcome (weight in kilograms) and a binary outcome (smoking status)., Results: Estimates of a population mean or disease prevalence using Ten to Men baseline data are influenced by the extent to which the sampling design is addressed in an analysis. Estimates of mean weight and smoking prevalence are larger in unweighted analyses than weighted analyses (e.g., mean = 83.9 kg vs. 81.4 kg; prevalence = 18.0 % vs. 16.7 %, for unweighted and weighted analyses respectively) and the standard error of the mean is 1.03 times larger in an analysis that acknowledges the hierarchical (clustered) structure of the data compared with one that does not. For smoking prevalence, the corresponding standard error is 1.07 times larger. Measures of association (mean group differences, odds ratios) are generally similar in unweighted or weighted analyses and whether or not adjustment is made for clustering., Conclusions: The extent to which the Ten to Men sampling design is accounted for in any analysis of the baseline data will depend on the research question. When the goals of the analysis are to estimate the prevalence of a disease or risk factor in the population or the magnitude of a population-level exposure-outcome association, our advice is to adopt an analysis that respects the sampling design.

Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so-and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting.

Infant body composition and postnatal weight gain have been implicated in the development of adult obesity and cardiovascular disease, but there are limited prospective data regarding the association between infant adiposity, postnatal growth and early cardiovascular parameters. Increased aortic intima-media thickness (aortic IMT) is an intermediate phenotype of early atherosclerosis. The aim of the present study was to investigate the relationship between weight and adiposity at birth, postnatal growth and aortic IMT. The Barwon Infant Study (n=1074 mother-infant pairs) is a population-derived birth cohort. Infant weight and other anthropometry were measured at birth and 6 weeks of age. Aortic IMT was measured by trans-abdominal ultrasound at 6 weeks of age (n=835). After adjustment for aortic size and other factors, markers of adiposity including increased birth weight (β=19.9 μm/kg, 95%CI 11.1, 28.6; P<0.001) and birth skinfold thickness (β=6.9 μm/mm, 95%CI 3.3, 10.5; P<0.001) were associated with aortic IMT at 6 weeks. The association between birth skinfold thickness and aortic IMT was independent of birth weight. In addition, greater postnatal weight gain was associated with increased aortic IMT, independent of birth weight and age at time of scan (β=11.3 μm/kg increase, 95%CI 2.2, 20.3; P=0.01). Increased infant weight and adiposity at birth, as well as increased early weight gain, were positively associated with aortic IMT. Excessive accumulation of adiposity during gestation and early infancy may have adverse effects on cardiovascular risk., (© 2016 Authors; published by Portland Press Limited.)

Background: Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth., Methods: This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943., Findings: 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55-0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44-0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo., Interpretation: RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines., Funding: Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Mental and behavioral disorders increase in prevalence with the passage through puberty. Yet the first symptoms for many children emerge between seven and 11 years, before the pubertal rise in gonadal hormones. A possibility that symptom onset may be linked to the adrenarchal rise in androgens has been little explored., Methods: The Childhood to Adolescence Transition Study recruited a stratified random sample of 1,239 eight-nine year olds from primary schools in Melbourne, Australia. Saliva samples were assayed for dehydroepiandrosterone, dehydroepiandrosterone-sulphate (DHEA-S), and testosterone. Emotional and behavioral problems were assessed through parental report on the Strengths and Difficulties Questionnaire., Results: In males, high levels of all androgens were associated with greater total difficulties and peer problems. Higher dehydroepiandrosterone and testosterone were associated with emotional symptoms and DHEA-S with conduct problems. In females, DHEA-S was associated with peer problems., Conclusions: In late childhood, androgens are associated with emotional and behavioral problems in males, raising a possibility that the adrenarchal transition plays a contributing role. If so, the late primary school years may prove to be an important phase for preventing the onset of mental health and behavioral problems in boys., (Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: There are limited longitudinal data on the associations between different social contexts of alcohol use and risky adolescent drinking., Methods: Australian prospective longitudinal cohort of 1943 adolescents with 6 assessment waves at ages 14-17 years. Drinkers were asked where and how frequently they drank. Contexts were: at home with family, at home alone, at a party with friends, in a park/car, or at a bar/nightclub. The outcomes were prevalence and incidence of risky drinking (≥5 standard drinks (10g alcohol) on a day, past week) and very risky drinking (>20 standard drinks for males and >11 for females) in early (waves 1-2) and late (waves 3-6) adolescence., Results: Forty-four percent (95 % CI: 41-46 %) reported past-week risky drinking on at least one wave during adolescence (waves 1-6). Drinking at a party was the most common repeated drinking context in early adolescence (28 %, 95 % CI 26-30 %); 15 % reported drinking repeatedly (3+ times) with their family in early adolescence (95 % CI: 14-17 %). For all contexts (including drinking with family), drinking 3+ times in a given context was associated with increased the risk of risky drinking in later adolescence. These effects remained apparent after adjustment for potential confounders (e.g. for drinking with family, adjusted RR 1.9; 95 % CI: 1.5-2.4). Similar patterns were observed for very risky drinking., Conclusions: Our results suggest that consumption with family does not protect against risky drinking. Furthermore, parents who wish to minimise high risk drinking by their adolescent children might also limit their children's opportunities to consume alcohol in unsupervised settings.

Background: Multiple imputation (MI) is a well-recognised statistical technique for handling missing data. As usually implemented in standard statistical software, MI assumes that data are 'Missing at random' (MAR); an assumption that in many settings is implausible. It is not possible to distinguish whether data are MAR or 'Missing not at random' (MNAR) using the observed data, so it is desirable to discover the impact of departures from the MAR assumption on the MI results by conducting sensitivity analyses. A weighting approach based on a selection model has been proposed for performing MNAR analyses to assess the robustness of results obtained under standard MI to departures from MAR., Methods: In this article, we use simulation to evaluate the weighting approach as a method for exploring possible departures from MAR, with missingness in a single variable, where the parameters of interest are the marginal mean (and probability) of a partially observed outcome variable and a measure of association between the outcome and a fully observed exposure. The simulation studies compare the weighting-based MNAR estimates for various numbers of imputations in small and large samples, for moderate to large magnitudes of departure from MAR, where the degree of departure from MAR was assumed known. Further, we evaluated a proposed graphical method, which uses the dataset with missing data, for obtaining a plausible range of values for the parameter that quantifies the magnitude of departure from MAR., Results: Our simulation studies confirm that the weighting approach outperformed the MAR approach, but it still suffered from bias. In particular, our findings demonstrate that the weighting approach provides biased parameter estimates, even when a large number of imputations is performed. In the examples presented, the graphical approach for selecting a range of values for the possible departures from MAR did not capture the true parameter value of departure used in generating the data., Conclusions: Overall, the weighting approach is not recommended for sensitivity analyses following MI, and further research is required to develop more appropriate methods to perform such sensitivity analyses.

In cost-effectiveness analyses of drugs or health technologies, estimates of life years saved or quality-adjusted life years saved are required. Randomised controlled trials can provide an estimate of the average treatment effect; for survival data, the treatment effect is the difference in mean survival. However, typically not all patients will have reached the endpoint of interest at the close-out of a trial, making it difficult to estimate the difference in mean survival. In this situation, it is common to report the more readily estimable difference in median survival. Alternative approaches to estimating the mean have also been proposed. We conducted a simulation study to investigate the bias and precision of the three most commonly used sample measures of absolute survival gain--difference in median, restricted mean and extended mean survival--when used as estimates of the true mean difference, under different censoring proportions, while assuming a range of survival patterns, represented by Weibull survival distributions with constant, increasing and decreasing hazards. Our study showed that the three commonly used methods tended to underestimate the true treatment effect; consequently, the incremental cost-effectiveness ratio (ICER) would be overestimated. Of the three methods, the least biased is the extended mean survival, which perhaps should be used as the point estimate of the treatment effect to be inputted into the ICER, while the other two approaches could be used in sensitivity analyses. More work on the trade-offs between simple extrapolation using the exponential distribution and more complicated extrapolation using other methods would be valuable., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Perinatal depression is a neglected global health priority, affecting 10-15% of women in high-income countries and a greater proportion in low-income countries. Outcomes for children include cognitive, behavioural, and emotional difficulties and, in low-income settings, perinatal depression is associated with stunting and physical illness. In the Victorian Intergenerational Health Cohort Study (VIHCS), we aimed to assess the extent to which women with perinatal depressive symptoms had a history of mental health problems before conception., Methods: VIHCS is a follow-up study of participants in the Victorian Adolescent Health Cohort Study (VAHCS), which was initiated in August, 1992, in the state of Victoria, Australia. In VAHCS, participants were assessed for health outcomes at nine timepoints (waves) from age 14 years to age 29 years. Depressive symptoms were measured with the Revised Clinical Interview Schedule and the General Health Questionnaire. Enrolment to VIHCS began in September, 2006, during the ninth wave of VAHCS; depressive symptoms at this timepoint were measured with the Composite International Diagnostic Interview. We contacted women every 6 months (from age 29 years to age 35 years) to identify any pregnancies. We assessed perinatal depressive symptoms with the Edinburgh Postnatal Depression Scale (EPDS) by computer-assisted telephone interview at 32 weeks of gestation, 8 weeks after birth, and 12 months after birth. We defined perinatal depression as an EPDS score of 10 or more., Findings: From a stratified random sample of 1000 female participants in VAHCS, we enrolled 384 women with 564 pregnancies. 253 (66%) of these women had a previous history of mental health problems at some point in adolescence or young adulthood. 117 women with a history of mental health problems in both adolescence and young adulthood had 168 pregnancies, and perinatal depressive symptoms were reported for 57 (34%) of these pregnancies, compared with 16 (8%) of 201 pregnancies in 131 women with no preconception history of mental health problems (adjusted odds ratio 8·36, 95% CI 3·34-20·87). Perinatal depressive symptoms were reported at one or more assessment points in 109 pregnancies; a preconception history of mental health problems was reported in 93 (85%) of these pregnancies., Interpretation: Perinatal depressive symptoms are mostly preceded by mental health problems that begin before pregnancy, in adolescence or young adulthood. Women with a history of persisting common mental disorders before pregnancy are an identifiable high-risk group, deserving of clinical support throughout the childbearing years. Furthermore, the window for considering preventive intervention for perinatal depression should extend to the time before conception., Funding: National Health and Medical Research Council (Australia), Victorian Health Promotion Foundation, Colonial Foundation, Australian Rotary Health Research and Perpetual Trustees., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The modern environment is associated with an increasing burden of non-communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n = 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early-life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2- and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [peter.vuillermin@deakin.edu.au]., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Multiple imputation is gaining popularity as a strategy for handling missing data, but there is a scarcity of tools for checking imputation models, a critical step in model fitting. Posterior predictive checking (PPC) has been recommended as an imputation diagnostic. PPC involves simulating "replicated" data from the posterior predictive distribution of the model under scrutiny. Model fit is assessed by examining whether the analysis from the observed data appears typical of results obtained from the replicates produced by the model. A proposed diagnostic measure is the posterior predictive "p-value", an extreme value of which (i.e., a value close to 0 or 1) suggests a misfit between the model and the data. The aim of this study was to evaluate the performance of the posterior predictive p-value as an imputation diagnostic. Using simulation methods, we deliberately misspecified imputation models to determine whether posterior predictive p-values were effective in identifying these problems. When estimating the regression parameter of interest, we found that more extreme p-values were associated with poorer imputation model performance, although the results highlighted that traditional thresholds for classical p-values do not apply in this context. A shortcoming of the PPC method was its reduced ability to detect misspecified models with increasing amounts of missing data. Despite the limitations of posterior predictive p-values, they appear to have a valuable place in the imputer's toolkit. In addition to automated checking using p-values, we recommend imputers perform graphical checks and examine other summaries of the test quantity distribution., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Children with cardiomyopathy (CM) are at risk of sudden cardiac death (SCD), but the incidence and risk factors for this outcome are not clear., Objectives: This study sought to determine the incidence and risk factors for SCD in children with varying CM phenotypes from a long-term population-based study of childhood CM., Methods: The NACCS (National Australian Childhood Cardiomyopathy Study) is an ongoing longitudinal cohort study including all children in Australia with primary CM who were diagnosed between January 1, 1987, and December 31, 1996, and were <10 years of age. The cumulative incidence and risk factors for SCD within individual CM phenotypes were explored using survival analysis., Results: Of 289 eligible patients, 16 (5.5%) experienced SCD over a median follow-up of 11.9 years (interquartile range: 1.7 to 15.4). The risk of SCD varied according to CM phenotype (p=0.007). The cumulative incidence of SCD at 15 years was 5% for dilated cardiomyopathy (DCM), 6% for hypertrophic cardiomyopathy (HCM), 12% for restrictive cardiomyopathy, and 23% for left ventricular (LV) noncompaction. Older age at diagnosis, positive family history of CM, and severity of LV dysfunction were related to increased risk of SCD in patients with DCM, and a higher posterior wall thickness Z-score was the sole risk factor identified for patients with HCM., Conclusions: Predictors of SCD include CM phenotype, family history of CM (DCM), severity of systolic dysfunction (DCM), and extent of LV hypertrophy (HCM). Continuing follow-up of this cohort into adulthood is likely to reveal an ongoing risk of SCD., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: We describe Pseudomonas aeruginosa acquisitions in children with cystic fibrosis (CF) aged ≤5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources., Methods: Of 168 CF children aged ≤5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy., Results: Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) reacquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably., Conclusions: CF children acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

There is substantial interest in studying lung function in infants, to better understand the early life origins of chronic lung diseases such as asthma. Multiple breath washout (MBW) is a technique for measuring lung function that has been adapted for use in infants. Respiratory sighs occur frequently in young infants during natural sleep, and in accordance with current MBW guidelines, result in exclusion of data from a substantial proportion of testing cycles. We assessed how sighs during MBW influenced the measurements obtained using data from 767 tests conducted on 246 infants (50% male; mean age 43 days) as part of a large cohort study. Sighs occurred in 119 (15%) tests. Sighs during the main part of the wash-in phase (before the last 5 breaths) were not associated with differences in standard MBW measurements compared with tests without sighs. In contrast, sighs that occurred during the washout were associated with a small but discernible increase in magnitude and variability. For example, the mean lung clearance index increased by 0.36 (95% CI: 0.11-0.62) and variance increased by a multiplicative factor of 2 (95% CI: 1.6-2.5). The results suggest it is reasonable to include MBW data from testing cycles where a sigh occurs during the wash-in phase, but not during washout, of MBW. By recovering data that would otherwise have been excluded, we estimate a boost of about 10% to the final number of acceptable tests and 6% to the number of individuals successfully tested., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Objectives: To describe the incidence rate and clinical outcomes of intussusception in Australia in children aged <24 months prior to the use of rotavirus vaccines in Australia, and to explore associations between patient characteristics and outcomes in children with intussusception., Methods: This study used Australian national hospital discharge data on intussusception from July 2000 to June 2006 for children aged <24 months and data from the Australian Bureau of Statistics (ABS) as a proxy for population numbers to estimate incidence. Logistic regression was used to examine associations between patient characteristics (age, sex, ethnicity) and outcomes (length of hospital stay >2 days and the need for surgical intervention)., Results: The overall incidence rate of intussusception was 5.4 per 10,000 child-years in children under 24 months (95%CI 5.17-5.70). There was a declining rate over the study period (p<0.001). Age at time of intussusception was strongly associated with length of hospital stay and surgery., Conclusions: This study provides an estimate of the pre-rotavirus vaccine incidence of intussusception across Australia, which is important for monitoring the occurrence of intussusceptions post the introduction of rotavirus vaccine., (© 2014 Public Health Association of Australia.)

Background: Neonatal illness is a leading cause of death worldwide; sepsis is one of the main contributors. The etiologies of community-acquired neonatal bacteremia in developing countries have not been well characterized., Methods: Infants <2 months of age brought with illness to selected health facilities in Bangladesh, Bolivia, Ghana, India, Pakistan and South Africa were evaluated, and blood cultures taken if they were considered ill enough to be admitted to hospital. Organisms were isolated using standard culture techniques., Results: Eight thousand eight hundred and eighty-nine infants were recruited, including 3177 0-6 days of age and 5712 7-59 days of age; 10.7% (947/8889) had a blood culture performed. Of those requiring hospital management, 782 (54%) had blood cultures performed. Probable or definite pathogens were identified in 10.6% including 10.4% of newborns 0-6 days of age (44/424) and 10.9% of infants 7-59 days of age (39/358). Staphylococcus aureus was the most commonly isolated species (36/83, 43.4%) followed by various species of Gram-negative bacilli (39/83, 46.9%; Acinetobacter spp., Escherichia coli and Klebsiella spp. were the most common organisms). Resistance to second and third generation cephalosporins was present in more than half of isolates and 44% of the Gram-negative isolates were gentamicin-resistant. Mortality rates were similar in hospitalized infants with positive (5/71, 7.0%) and negative blood cultures (42/557, 7.5%)., Conclusions: This large study of young infants aged 0-59 days demonstrated a broad array of Gram-positive and Gram-negative pathogens responsible for community-acquired bacteremia and substantial levels of antimicrobial resistance. The role of S. aureus as a pathogen is unclear and merits further investigation.

Objective: Cardiorespiratory fitness and adiposity may influence cardiovascular risk through their effects on inflammation. The long-term effects of these modifiable factors on adult inflammation remain uncertain. The associations of childhood and adulthood cardiorespiratory fitness and adiposity with adult inflammation [C-reactive protein (CRP), fibrinogen] were examined., Methods: 1,976 children examined in 1985 and re-examined as young adults in 2004-2006 were included. Cardiorespiratory fitness and adiposity were assessed at both waves. CRP and fibrinogen were measured at follow-up., Results: Higher childhood fitness was associated with lower adult inflammation in both sexes. After adjusting for childhood adiposity, the association with CRP attenuated in males, but remained in females (average reduction of CRP 18.1% (95% CI 11.3-24.4%) per 1-SD increase in childhood fitness). Higher adult fitness, adjusting for childhood fitness (an increase in fitness from childhood to adulthood), was associated with lower adult CRP in females and lower fibrinogen in males. Higher childhood and adulthood adiposity (an increase in adiposity from childhood to adulthood) were associated with higher adult inflammation in both sexes., Conclusions: Prevention programs to increase fitness and reduce adiposity in childhood, and maintain a favorable fitness and weight into adulthood, may lead to reduction in adult systemic inflammation., (© 2014 The Obesity Society.)

Multiple imputation has entered mainstream practice for the analysis of incomplete data. We have used it extensively in a large Australian longitudinal cohort study, the Victorian Adolescent Health Cohort Study (1992-2008). Although we have endeavored to follow best practices, there is little published advice on this, and we have not previously examined the extent to which variations in our approach might lead to different results. Here, we examined sensitivity of analytical results to imputation decisions, investigating choice of imputation method, inclusion of auxiliary variables, omission of cases with excessive missing data, and approaches for imputing highly skewed continuous distributions that are analyzed as dichotomous variables. Overall, we found that decisions made about imputation approach had a discernible but rarely dramatic impact for some types of estimates. For model-based estimates of association, the choice of imputation method and decisions made to build the imputation model had little effect on results, whereas estimates of overall prevalence and prevalence stratified by subgroup were more sensitive to imputation method and settings. Multiple imputation by chained equations gave more plausible results than multivariate normal imputation for prevalence estimates but appeared to be more susceptible to numerical instability related to a highly skewed variable., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: 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., Study Design: Costs were assessed in a randomized controlled trial conducted in Australia and New Zealand on infants diagnosed with CF after newborn screening and assigned to receive either BAL-directed or standard therapy until they reached 5 years of age. A health care funder perspective was adopted. Resource use measurement was based on standardized data collection forms administered for patients across all sites. Unit costs were obtained primarily from government schedules., Results: Mean costs per child during the study period were Australian dollars (AUD)92 860 in BAL-directed therapy group and AUD90 958 in standard therapy group (mean difference AUD1902, 95% CI AUD-27 782 to 31 586, P = .90). Mean hospital costs per child during the study period were AUD57 302 in the BAL-directed therapy group and AUD66 590 in the standard therapy group (mean difference AUD-9288; 95% CI AUD-35 252 to 16 676, P = .48)., Conclusions: BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a standard protocol based upon clinical features and oropharyngeal culture results alone. Following on our previous findings that BAL-directed treatment offers no clinical advantage over standard therapy at age 5 years, flexible bronchoscopy with BAL cannot be recommended for the routine management of preschool children with CF on the basis of overall cost savings., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: 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., Discussion: Minimally-invasive surfactant therapy has the potential to ease the burden of respiratory morbidity in preterm infants. The trial will provide definitive evidence on the effectiveness of this approach in the care of preterm infants born at 25-28 weeks gestation., Trial Registration: Australia and New Zealand Clinical Trial Registry: ACTRN12611000916943; ClinicalTrials.gov: NCT02140580.

Background: 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., Methods: Participants were term infants recruited to a population-derived birth cohort study. Transabdominal ultrasound was performed at six weeks of age by one of two trained operators. Thirty participants had ultrasounds performed by both operators on the same day. Data were collected on environmental (infant sleeping, presence of a sibling, use of sucrose, timing during study visit) and individual (post-conception age, weight, gender) variables. Two readers assessed image quality and measured aIMT by edge-detection software and a subset by manual sonographic calipers. Measurements were repeated by the same reader and between readers to obtain intra-observer and inter-observer reliability., Results: Aortic IMT was measured successfully using edge-detection in 814 infants, and 290 of these infants also had aIMT measured using manual sonographic calipers. The intra-reader intra-class correlation (ICC) (n = 20) was 0.90 (95% CI 0.76, 0.96), mean difference 1.5 μm (95% LOA -39, 59). The between reader ICC using edge-detection (n = 20) was 0.92 (95% CI 0.82, 0.97) mean difference 2 μm (95% LOA -45.0, 49.0) and with manual caliper measurement (n = 290) the ICC was 0.84 (95% CI 0.80, 0.87) mean difference 5 μm (95% LOA -51.8, 61.8). Edge-detection measurements were greater than those from manual sonographic calipers (mean aIMT 618 μm (50) versus mean aIMT 563 μm (49) respectively; p < 0.001, mean difference 44 μm, 95% LOA -54, 142). With the exception of infant crying (p = 0.001), no associations were observed between individual and environmental variables and image quality., Conclusion: In a population-derived cohort of term infants, aIMT measurement has a high level of intra and inter-reader reproducibility. Measurement of aIMT using edge-detection software gives higher inter-reader ICC than manual sonographic calipers. Image quality is not substantially affected by individual and environmental factors.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Australia's National Health and Medical Research Council., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: 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., Method: 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., Results: 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%)., Interpretation: 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., (© 2013 Mac Keith Press.)

Aim: 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., Method: 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., Results: 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., Interpretation: 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., (© 2013 Mac Keith Press.)

The self-controlled case series method is a statistical approach to investigating associations between acute outcomes and transient exposures. The method uses cases only and compares time at risk after the transient exposure with time at risk outside the exposure period within an individual, using conditional Poisson regression. The risk of outcome and exposure often varies over time, for example, with age, and it is important to allow for such time dependence within the analysis. The standard approach for modelling time-varying covariates is to split observation periods into blocks according to categories of the covariate and then to model the relationship using indicators for each category. However, this can be inefficient and can lead to problems with collinearity if the exposure occurs at approximately the same time in all individuals. As an alternative, we propose using fractional polynomials to model the relationship between the time-varying covariate and incidence of the outcome. We present the results from an analysis exploring the association between rotavirus vaccination and intussusception risk as well as a simulation study. We conclude that fractional polynomials provide a useful approach to adjusting for time-varying covariates but that it is important to explore the sensitivity of the results to the number of categories and the method of adjustment., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

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 aged 1 to <12 months were identified from national hospitalization databases, supplemented by active hospital-based surveillance, from July 2007 through 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 the risk of IS associated with both vaccines in prespecified periods after vaccination. The estimated burden of vaccine-attributable IS was compared with estimated reductions in gastroenteritis hospitalizations., Results: Based on 306 confirmed cases of IS, the relative incidence of IS in the 1-7-day period after the first vaccine dose, was 6.8 (95% confidence interval, 2.4-19.0; P < .001) for RV1, and 9.9 (95% confidence interval, 3.7-26.4; P < .001) for RV5. There was a smaller increased risk 1-7 days after the second dose of each vaccine. The case-control analysis gave similar results. We estimate an excess of 14 IS cases and >6500 fewer gastroenteritis hospitalizations in young children annually in Australia after vaccine introduction., Conclusions: We found a similarly increased risk of IS after both vaccines, but the balance of benefits and risks at population level was highly favorable, a finding likely to extend to other settings despite varying incidence of IS and potentially higher morbidity and mortality from both gastroenteritis and IS.

Unlabelled: 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., (© 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.)

Background: 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)., Methods: 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., Results: 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., Conclusions: 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.

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., (Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

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.

Objective: To evaluate the applicability and potential effectiveness of a technique of minimally-invasive surfactant therapy (MIST) in preterm infants on continuous positive airway pressure (CPAP)., Methods: An open feasibility study of MIST was conducted at two sites. Infants were eligible for MIST if needing CPAP pressure ≥7 cm H(2)O and FiO(2) ≥0.3 (25-28 weeks gestation, n=38) or ≥0.35 (29-32 weeks, n=23). Without premedication, a narrow-bore catheter was inserted through the vocal cords under direct vision. Surfactant (100 or 200 mg/kg Curosurf) was then instilled, followed by reinstitution of CPAP. Outcomes were compared between surfactant-treated infants and historical controls achieving the same CPAP and FiO(2) thresholds., Results: Surfactant was successfully administered via MIST in all cases, with a rapid and sustained reduction in FiO(2) thereafter. For infants at 25-28 weeks gestation, need for intubation <72 h was diminished after MIST compared with controls (32% vs 68%; OR 0.21, 95% CI 0.083 to 0.55), with a similar trend at 29-32 weeks (22% vs 45%; OR 0.34, 95% CI 0.11 to 1.1). Duration of ventilation and incidence of bronchopulmonary dysplasia were similar, but infants receiving MIST had a shorter duration of oxygen therapy., Conclusion: Surfactant delivery via a narrow-bore tracheal catheter is feasible and potentially effective, and deserves further investigation in clinical trials.

Unlabelled: Lung lavage using two aliquots of 15 mL/kg of dilute surfactant was performed in 30 ventilated infants with severe meconium aspiration syndrome (MAS). Mean recovery of instilled lavage fluid was 46%, with greater fluid return associated with lower mean airway pressure at 24 h and a shorter duration of respiratory support., Conclusion: Recovery of instilled lavage fluid is paramount in effective lung lavage in MAS and must be afforded priority in the lavage technique., (©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.)

Context: No study has documented how symptomatic morbidity varies across the body mass index (BMI) spectrum (underweight, normal weight, overweight and obese) or across the entire child and adolescent age range., Objective: To (1) quantify physical and psychosocial morbidities experienced by 2-18-year-olds according to BMI status and (2) explore morbidity patterns by age., Design, Setting and Participants: Cross-sectional data from two Australian population studies (the Longitudinal Study of Australian Children and the Health of Young Victorians Study) were collected during 2000-2006. Participants were grouped into five age bands: 2-3 (n=4606), 4-5 (n=4983), 6-7 (n=4464), 8-12 (n=1541) and 13-18 (n=928) years., Main Measures: Outcomes-Parent- and self-reported global health; physical, psychosocial and mental health; special health-care needs; wheeze; asthma and sleep problems. Exposure-measured BMI (kg m(-2)) categorised using standard international cutpoints., Analyses: The variation in comorbidities across BMI categories within and between age bands was examined using linear and logistic regression models., Results: Comorbidities varied with BMI category for all except sleep problems, generally showing the highest levels for the obese category. However, patterns differed markedly between age groups. In particular, poorer global health and special health-care needs were associated with underweight in young children, but obesity in older children. Prevalence of poorer physical health varied little by BMI in 2-5-year-olds, but from 6 to 7 years was increasingly associated with obesity. Normal-weight children tended to experience the best psychosocial and mental health, with little evidence that the U-shaped associations of these variables with BMI status varied by age. Wheeze and asthma increased slightly with BMI at all ages., Conclusions: Deviation from normal weight is associated with health differences in children and adolescents that vary by morbidity and age. As well as lowering risks for later disease, promoting normal body weight appears central to improving the health and well-being of the young.

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., (Copyright © 2013 S. Karger AG, Basel.)