Estimation with Interval Censored Data in Longitudinal Studies

In biostatistical applications interest often focuses on the estimation of the distribution of a time-until-event variable T. If one observes whether or not T exceeds an observed monitoring time at a random number of monitoring times, then the data structure is called interval censored data. We extend this data structure by allowing the presence of a possibly time-dependent covariate process that is observed until end of follow up. If one only assumes that the censoring mechanism satisfies coarsening at random, then, by the curve of dimensionality, typically no regular estimators will exist. To fight the curse of dimensionality we follow the approach of Robins and Rotnitzky (1992) by modeling parameters of the censoring mechanism. We model the right-censoring mechanism by modeling the hazard of the follow up time, conditional on T and the covariate process. For the monitoring mechanism we avoid modeling the joint distribution of the monitoring times by only modeling a univariate hazard of the pooled monitoring times, conditional on the follow up time, T, and the covariates process, which can be estimated by treating the pooled sample of monitoring times as i.i.d. In particular, it is assumed that the monitoring times and the right-censoring times only depend on T through the observed covariate process. We introduce inverse probability of censoring weighted (IPCW) estimator of the distribution of T and of smooth functionals thereof which are guaranteed to be consistent and asymptotically normal if we have available correctly specified semiparametric models for the two hazards of the censoring process. Furthermore, given such correctly specified models for these hazards of the censoring process, we propose a one-step estimator which will improve on the IPCW estimator if we correctly specify a lower-dimensional working model for the conditional distribution of T, given the covariate process, that remains consistent and asymptotically normal if this latter working model is misspecified. It is shown that the one-step estimator is efficient if each subject is at most monitored once and the working model contains the truth. In general, it is shown that the one-step estimator optimally uses the surrogate information if the working model contains the truth. It is not optimal in using the interval information provided by the current status indicators at the monitoring times, but simulations in Peterson, van der Laan (1997) show that the efficiency loss is small.

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

A disease model for wheezing disorders in preschool children based on clinicians' perceptions

BACKGROUND: Wheezing disorders in childhood vary widely in clinical presentation and disease course. During the last years, several ways to classify wheezing children into different disease phenotypes have been proposed and are increasingly used for clinical guidance, but validation of these hypothetical entities is difficult. METHODOLOGY/PRINCIPAL FINDINGS: The aim of this study was to develop a testable disease model which reflects the full spectrum of wheezing illness in preschool children. We performed a qualitative study among a panel of 7 experienced clinicians from 4 European countries working in primary, secondary and tertiary paediatric care. In a series of questionnaire surveys and structured discussions, we found a general consensus that preschool wheezing disorders consist of several phenotypes, with a great heterogeneity of specific disease concepts between clinicians. Initially, 24 disease entities were described among the 7 physicians. In structured discussions, these could be narrowed down to three entities which were linked to proposed mechanisms: a) allergic wheeze, b) non-allergic wheeze due to structural airway narrowing and c) non-allergic wheeze due to increased immune response to viral infections. This disease model will serve to create an artificial dataset that allows the validation of data-driven multidimensional methods, such as cluster analysis, which have been proposed for identification of wheezing phenotypes in children. CONCLUSIONS/SIGNIFICANCE: While there appears to be wide agreement among clinicians that wheezing disorders consist of several diseases, there is less agreement regarding their number and nature. A great diversity of disease concepts exist but a unified phenotype classification reflecting underlying disease mechanisms is lacking. We propose a disease model which may help guide future research so that proposed mechanisms are measured at the right time and their role in disease heterogeneity can be studied.

Growth curves for cardio-metabolic risk factors in children and adolescents

OBJECTIVE: This study developed percentile curves for anthropometric (waist circumference) and cardiovascular (lipid profile) risk factors for US children and adolescents. STUDY DESIGN: A representative sample of US children and adolescents from the National Health and Nutrition Examination Survey from 1988 to 1994 (NHANES III) and the current national series (NHANES 1999-2006) were combined. Percentile curves were constructed, nationally weighted, and smoothed using the Lambda, Mu, and Sigma method. The percentile curves included age- and sex-specific percentile values that correspond with and transition into the adult abnormal cut-off values for each of these anthropometric and cardiovascular components. To increase the sample size, a second series of percentile curves was also created from the combination of the 2 NHANES databases, along with cross-sectional data from the Bogalusa Heart Study, the Muscatine Study, the Fels Longitudinal Study and the Princeton Lipid Research Clinics Study. RESULTS: These analyses resulted in a series of growth curves for waist circumference, total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol from a combination of pediatric data sets. The cut-off for abnormal waist circumference in adult males (102 cm) was equivalent to the 94(th) percentile line in 18-year-olds, and the cut-off in adult females (88 cm) was equivalent to the 84(th) percentile line in 18-year-olds. Triglycerides were found to have a bimodal pattern among females, with an initial peak at age 11 and a second at age 20; the curve for males increased steadily with age. The HDL curve for females was relatively flat, but the male curve declined starting at age 9 years. Similar curves for total and LDL cholesterol were constructed for both males and females. When data from the additional child studies were added to the national data, there was little difference in their patterns or rates of change from year to year. CONCLUSIONS: These curves represent waist and lipid percentiles for US children and adolescents, with identification of values that transition to adult abnormalities. They could be used conditionally for both epidemiological and possibly clinical applications, although they need to be validated against longitudinal data.

Anterior Cruciate Ligament Injuries in Children and Adolescents: A Review of the Recent Literature

In contrast to the treatment of avulsion lesions of the anterior cruciate ligament (ACL) the management of intrasubstance ACL tears in the skeletally immature patient remains controversial. Prospective studies could show that conservative treatment results in severe instability with concomitant intraarticular damage and poor function of the knee. Reconstruction of a torn ACL always carries the risk of damaging the open growth plates; with consecutively affecting the longitudinal or axial growth of the lower extremity either on the femoral or the tibial side. Thus, several surgical procedures are available to prevent adverse events mentioned above. The purpose of this study is to review the recent literature regarding the treatment algorithm for ACL injuries in skeletally immature patients. This review will (1) investigate the indications for ACL surgery in children; (2) determine if a surgical procedure is clinically superior in skeletally immature patients; and (3) correlate the adverse events with the surgical technique.

When to start antiretroviral therapy in children aged 2-5 years: a collaborative causal modelling analysis of cohort studies from southern Africa

BACKGROUND There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4 percentage (CD4%) <25%. METHODS AND FINDINGS ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping. The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm(3) (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1-6.5) (no ART) to 2.1% (95% CI: 1.3%-3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%-3.5%) and 2.2% (95% CI: 1.4%-3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data. CONCLUSIONS The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm(3) or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values. Please see later in the article for the Editors' Summary.

Atopic conditions and brain tumor risk in children and adolescents--an international case-control study (CEFALO)

BACKGROUND A number of epidemiological studies indicate an inverse association between atopy and brain tumors in adults, particularly gliomas. We investigated the association between atopic disorders and intracranial brain tumors in children and adolescents, using international collaborative CEFALO data. PATIENTS AND METHODS CEFALO is a population-based case-control study conducted in Denmark, Norway, Sweden, and Switzerland, including all children and adolescents in the age range 7-19 years diagnosed with a primary brain tumor between 2004 and 2008. Two controls per case were randomly selected from population registers matched on age, sex, and geographic region. Information about atopic conditions and potential confounders was collected through personal interviews. RESULTS In total, 352 cases (83%) and 646 controls (71%) participated in the study. For all brain tumors combined, there was no association between ever having had an atopic disorder and brain tumor risk [odds ratio 1.03; 95% confidence interval (CI) 0.70-1.34]. The OR was 0.76 (95% CI 0.53-1.11) for a current atopic condition (in the year before diagnosis) and 1.22 (95% CI 0.86-1.74) for an atopic condition in the past. Similar results were observed for glioma. CONCLUSIONS There was no association between atopic conditions and risk of all brain tumors combined or of glioma in particular. Stratification on current or past atopic conditions suggested the possibility of reverse causality, but may also the result of random variation because of small numbers in subgroups. In addition, an ongoing tumor treatment may affect the manifestation of atopic conditions, which could possibly affect recall when reporting about a history of atopic diseases. Only a few studies on atopic conditions and pediatric brain tumors are currently available, and the evidence is conflicting.

Impact of medications prescribed for treatment of attention-deficit hyperactivity disorder on physical growth in children and adolescents with HIV.

OBJECTIVE: To examine the relationships between physical growth and medications prescribed for symptoms of attention-deficit hyperactivity disorder in children with HIV. METHODS: Analysis of data from children with perinatally acquired HIV (N = 2251; age 3-19 years), with and without prescriptions for stimulant and nonstimulant medications used to treat attention-deficit hyperactivity disorder, in a long-term observational study. Height and weight measurements were transformed to z scores and compared across medication groups. Changes in z scores during a 2-year interval were compared using multiple linear regression models adjusting for selected covariates. RESULTS: Participants with (n = 215) and without (n = 2036) prescriptions were shorter than expected based on US age and gender norms (p < .001). Children without prescriptions weighed less at baseline than children in the general population (p < .001) but gained height and weight at a faster rate (p < .001). Children prescribed stimulants were similar to population norms in baseline weight; their height and weight growth velocities were comparable with the general population and children without prescriptions (for weight, p = .511 and .100, respectively). Children prescribed nonstimulants had the lowest baseline height but were similar to population norms in baseline weight. Their height and weight growth velocities were comparable with the general population but significantly slower than children without prescriptions (p = .01 and .02, respectively). CONCLUSION: The use of stimulants to treat symptoms of attention-deficit hyperactivity disorder does not significantly exacerbate the potential for growth delay in children with HIV and may afford opportunities for interventions that promote physical growth. Prospective studies are needed to confirm these findings.

Restrained and external-emotional eating patterns in young overweight children-results of the ulm birth cohort study

Childhood obesity is one of the greatest public health challenges in Western countries. Abnormal eating behavior is thought to be a developmental trajectory to obesity. The Eating Pattern Inventory for Children (EPI-C) has not been used for children as young as eight years, and possible associations with body weight have not yet been established. Five hundred and twenty-one children of the Ulm Birth Cohort Study (UBCS; age eight) filled out the EPI-C and BMI was assessed. Adequacy of the scales was tested with confirmatory factor analysis and a MANOVA and cluster analysis established associations between eating patterns and BMI. The factor structure of the EPI-C was confirmed (GFI = .968) and abnormal eating behavior was associated with overweight (χ2(8) = 79.29, p<.001). The EPI-C is a valid assessment tool in this young age group. Overweight children consciously restrain their eating.

Development of self-esteem and relationship satisfaction in couples: Two longitudinal studies

We examined the effects of self-esteem development on the development of relationship satisfaction in 2 samples of couples. Study 1 used data from both partners of 885 couples assessed 5 times over 12 years, and Study 2 used data from both partners of 6,116 couples assessed 3 times over 15 years. The pattern of results was similar across the 2 studies. First, development of relationship satisfaction could be modeled as a couple-level process. Second, initial level of self-esteem of each partner predicted the initial level of the partners’ common relationship satisfaction, and change in self-esteem of each partner predicted change in the partners’ common relationship satisfaction. Third, these effects did not differ by gender and held when controlling for participants’ age, length of relationship, health, and employment status. Fourth, self-esteem similarity among partners did not influence the development of their relationship satisfaction. The findings suggest that the development of self-esteem in both partners of a couple contributes in a meaningful way to the development of the partners’ common satisfaction with their relationship.

Erosive tooth wear in children.

Erosive tooth wear in children is a common condition. Besides the anatomical differences between deciduous and permanent teeth, additional histological differences may influence their susceptibility to dissolution. Considering laboratory studies alone, it is not clear whether deciduous teeth are more liable to erosive wear than permanent teeth. However, results from epidemiological studies imply that the primary dentition is less wear resistant than permanent teeth, possibly due to the overlapping of erosion with mechanical forces (like attrition or abrasion). Although low severity of tooth wear in children does not cause a significant impact on their quality of life, early erosive damage to their permanent teeth may compromise their dentition for their entire lifetime and require extensive restorative procedures. Therefore, early diagnosis of erosive wear and adequate preventive measures are important. Knowledge on the aetiological factors of erosive wear is a prerequisite for preventive strategies. Like in adults, extrinsic and intrinsic factors, or a combination of them, are possible reasons for erosive tooth wear in children and adolescents. Several factors directly related to erosive tooth wear in children are presently discussed, such as socio-economic aspects, gastroesophageal reflux or vomiting, and intake of some medicaments, as well as behavioural factors such as unusual eating and drinking habits. Additionally, frequent and excessive consumption of erosive foodstuffs and drinks are of importance.