Modeling the underlying biological processes in Alzheimer's disease using a multivariate competing risk joint model.

Many clinical trials repeatedly measure several longitudinal outcomes on patients. Patient follow-up can discontinue due to an outcome-dependent event, such as clinical diagnosis, death, or dropout. Joint modeling is a popular choice for the analysis of this type of data. Using example data from a prodromal Alzheimer's disease trial, we propose a new type of multivariate joint model in which longitudinal brain imaging outcomes and memory impairment ratings are allowed to be associated both with time to open-label medication and dropout, and where the brain imaging outcomes may also directly affect the memory impairment ratings. Existing joint models for multivariate longitudinal outcomes account for the correlation between the longitudinal outcomes through the random effects, often by assuming a multivariate normal distribution. However, for these models, it is difficult to interpret how the longitudinal outcomes affect each other. We model the dependence between the longitudinal outcomes differently so that a first longitudinal outcome affects a second one. Specifically, for each longitudinal outcome, we use a linear mixed-effects model to estimate its trajectory, where, for the second longitudinal outcome, we include the linear predictor of the first outcome as a time-varying covariate. This facilitates an easy and direct interpretation of the association between the longitudinal outcomes and provides a framework for latent mediation analysis to understand the underlying biological processes. For the trial considered here, we found that part of the intervention effect is mediated through hippocampal brain atrophy. The proposed joint models are fitted using a Bayesian framework via MCMC simulation.

A marginal estimate for the overall treatment effect on a survival outcome within the joint modeling framework.

Joint models for longitudinal and survival data are increasingly used and enjoy a wide range of application areas. In this article, we focus on the application of joint models on clinical trial data with special interest in the treatment effect on the survival outcome. Within a joint model, the estimated treatment effect on the survival outcome is an aggregate comprising the indirect treatment effect through the longitudinal outcome and the direct treatment effect on the survival outcome. This overall treatment effect is, however, conditional on random effects, and therefore has a subject-specific interpretation. The conditional interpretation arises from the shared random effects between the longitudinal and survival process in combination with the nonlinear link function of the survival model. The overall treatment effect is, therefore, not valid for population-based inference, which is the goal for most clinical trials. We propose a method to obtain a marginal estimate of the overall treatment effect on the survival outcome in a joint model. Additionally, we extend our proposal to allow for different parameterizations for the association between the longitudinal and survival outcome. The proposed method is demonstrated on data of a clinical study on the effect of synbiotic on the gut microbiota of cesarean delivered infants, where we estimate the marginal overall treatment effect on the risk of eczema or atopic dermatitis using longitudinal information on fecal bifidobacteria.

Using joint models to disentangle intervention effect types and baseline confounding: an application within an intervention study in prodromal Alzheimer's disease with Fortasyn Connect.

BACKGROUND: Many prodromal Alzheimer's disease trials collect two types of data: the time until clinical diagnosis of dementia and longitudinal patient information. These data are often analysed separately, although they are strongly associated. By combining the longitudinal and survival data into a single statistical model, joint models can account for the dependencies between the two types of data. METHODS: We illustrate the major steps in a joint modelling approach, motivated by data from a prodromal Alzheimer's disease study: the LipiDiDiet trial. RESULTS: By using joint models we are able to disentangle baseline confounding from the intervention effect and moreover, to investigate the association between longitudinal patient information and the time until clinical dementia diagnosis. CONCLUSIONS: Joint models provide a valuable tool in the statistical analysis of clinical studies with longitudinal and survival data, such as in prodromal Alzheimer's disease trials, and have several added values compared to separate analyses.

Latent class analysis reveals five homogeneous behavioural and developmental profiles in a large Dutch population sample of infants aged 14-15 months.

Precursors of child psychiatric disorders are often present in infancy, but little is known about the prevalence and course of general psychopathology in population-based samples of children 0-3 years. We examined whether homogeneous behavioural and developmental profiles could be identified in children aged 14-15 months (M = 14.84; SD = 2.19), and we explored whether or not these profiles corresponded with existing classifications of DSM-IV-TR, ICD-10, and DC 0-3R. Parents of 6,330 children answered 74 items about externalizing, internalizing, and social-communicative behaviour. Exploratory factor analysis revealed nine factors: deviant communication, negative emotionality, deviant reactive behaviour, deviant play behaviour, demanding behaviour, social anxiety/inhibition, advanced social interaction problems, basic social interaction problems, and sleep problems. Latent class analysis yielded five profiles, of which three were associated with increased behavioural and developmental problems. Some infants (5.7 %) had communication and social interaction problems corresponding to multisystem developmental disorders (DC 0-3R) and suggestive of anxiety, mood, or pervasive developmental disorders (DSM-IV-TR, ICD-10). Other infants (16.4 %) had communication problems, possibly precursors of communication, language, or speech disorders (DSM-IV-TR, ICD-10). Yet other infants (10.8 %) showed negative and demanding behaviour suggestive of regulation disorders (DC 0-3R), attention-deficit and disruptive behaviour disorders (DSM-IV-TR), or hyperkinetic and conduct disorders (ICD-10). Thus, even in infancy certain distinct behavioural and developmental profiles can be recognized. This combined approach will enable follow-up research into the stability of factors, classes, and profiles over time, and will facilitate early detection, diagnosis, and treatment of behavioural and developmental problems.

Pairwise ratio-based differential abundance analysis of infant microbiome 16S sequencing data.

Differential abundance analysis of infant 16S microbial sequencing data is complicated by challenging data properties, including high sparsity, extreme dispersion and the relative nature of the information contained within the data. In this study, we propose a pairwise ratio analysis that uses the compositional data analysis principle of subcompositional coherence and merges it with a beta-binomial regression model. The resulting method provides a flexible and easily interpretable approach to infant 16S sequencing data differential abundance analysis that does not require zero imputation. We evaluate the proposed method using infant 16S data from clinical trials and demonstrate that the proposed method has the power to detect differences, and demonstrate how its results can be used to gain insights. We further evaluate the method using data-inspired simulations and compare its power against related methods. Our results indicate that power is high for pairwise differential abundance analysis of taxon pairs that have a large abundance. In contrast, results for sparse taxon pairs show a decrease in power and substantial variability in method performance. While our method shows promising performance on well-measured subcompositions, we advise strong filtering steps in order to avoid excessive numbers of underpowered comparisons in practical applications.

Effects of attentional/ hyperactive and oppositional/ aggressive problem behaviour at 14 months and 21 months on parenting stress.

BACKGROUND: To evaluate effects of attentional/ hyperactive (Att/Hi) and oppositional/ aggressive (Opp/Agg) behaviours of children at 14 and 21 months of age on parenting stress at 21 months. METHOD: 107 children from the general population with low, intermediate, and high levels of disruptive behaviours at 14 months, as evaluated by parents on a 55-item checklist, participated. Parents completed the Child Behaviour Checklist 1.5-5 and the Dutch version of Parenting Stress Index (NOSI) at 21 months. Effects of problem behaviours were examined in a 2 (Att/Hi and Opp/Agg) by 2 (not high versus high) by 2 (14 and 21 months) multivariate design with parental stress as dependent variable. RESULTS: Oppositional/ aggressive behaviour at 14 months had a strong main effect on parenting stress, but not at 21 months. There was a significant interaction between parenting stress and Att/Hi behaviour at 14 and 21 months, indicating that increase in these behaviours over time was associated with parenting stress. Both Opp/Agg behaviour and an interaction between Att/Hi behaviour and parenting stress contributed to maternal role restriction and social isolation. Oppositional/ aggressive behaviour led to higher scores for parental competence and depression, whereas Att/Hi behaviour led to lower scores for attachment. CONCLUSIONS: Early Opp/Agg and Att/Hi behaviour had differential effects on parenting stress at 21 months. The increase in parenting stress associated with early Opp/Agg behaviour may be linked to overall feelings of parental competence, whereas the course of Att/Hi behaviour may be associated with increased demands on parent-child interactions and attachment. Our results have implications for development of early intervention programmes.

A competing risk joint model for dealing with different types of missing data in an intervention trial in prodromal Alzheimer's disease.

BACKGROUND: Missing data can complicate the interpretability of a clinical trial, especially if the proportion is substantial and if there are different, potentially outcome-dependent causes. METHODS: We aimed to obtain unbiased estimates, in the presence of a high level of missing data, for the intervention effects in a prodromal Alzheimer's disease trial: the LipiDiDiet study. We used a competing risk joint model that can simultaneously model each patient's longitudinal outcome trajectory in combination with the timing and type of missingness. RESULTS: Using the competing risk joint model, we were able to provide unbiased estimates of the intervention effects in the presence of the different types of missingness. For the LipiDiDiet study, the intervention effects remained statistically significant after this correction for the timing and type of missingness. CONCLUSION: Missing data is a common problem in (Alzheimer) clinical trials. It is important to realize that statistical techniques make specific assumptions about the missing data mechanisms. When there are different missing data sources, a competing risk joint model is a powerful method because it can explicitly model the association between the longitudinal data and each type of missingness. TRIAL REGISTRATION: Dutch Trial Register, NTR1705 . Registered on 9 March 2009.

Predictive value of subclinical autistic traits at age 14-15 months for behavioural and cognitive problems at age 3-5 years.

It is unclear whether subclinical autistic traits at very young age are transient or stable, and have clinical relevance. This study investigated the relationship between early subclinical autistic traits and the occurrence of later developmental and behavioural problems as well as problems in cognitive and language functioning. Parents of infants aged 14-15 months from the general population completed the Early Screening of Autistic Traits Questionnaire (ESAT). Three groups of children with high, moderate, and low ESAT-scores (total n = 103) were selected. Follow-up assessments included the CBCL 1(1/2)-5 at age 3 years, and the SCQ, the ADI-R, the ADOS-G, an on-verbal intelligence test, and language tests for comprehension and production at age 4-5 years. None of the children met criteria for autism spectrum disorder at follow-up. Children with high ESAT-scores at 14-15 months showed significantly more internalizing and externalizing problems at age 3 years and scored significantly lower on language tests at age 4-5 years than children with moderate or low ESAT-scores. Further, significantly more children with high ESAT-scores (14/26, 53.8%) than with moderate and low ESAT-scores (5/36, 13.9% and 1/41, 2.4%, respectively) were in the high-risk/clinical range on one or more outcome domains (autistic symptoms, behavioural problems, cognitive and language abilities). Subclinical autistic traits at 14-15 months predict later behavioural problems and delays in cognitive and language functioning rather than later ASD-diagnoses. The theoretical implications of the findings lie in the pivotal role of early social and communication skills for the development of self-regulation of emotions and impulses. The practical implications bear on the early recognition of children at risk for behavioural problems and for language and cognitive problems.

Externalizing behaviors in preadolescents: familial risk to externalizing behaviors and perceived parenting styles.

The aim was to investigate the contribution of familial risk to externalizing behaviors (FR-EXT), perceived parenting styles, and their interactions to the prediction of externalizing behaviors in preadolescents. Participants were preadolescents aged 10-12 years who participated in TRAILS, a large prospective population-based cohort study in the Netherlands (N = 2,230). Regression analyses were used to determine the relative contribution of FR-EXT and perceived parenting styles to parent and teacher ratings of externalizing behaviors. FR-EXT was based on lifetime parental externalizing psychopathology and the different parenting styles (emotional warmth, rejection, and overprotection) were based on the child's perspective. We also investigated whether different dimensions of perceived parenting styles had different effects on subdomains of externalizing behavior. We found main effects for FR-EXT (vs. no FR-EXT), emotional warmth, rejection, and overprotection that were fairly consistent across rater and outcome measures. More specific, emotional warmth was the most consistent predictor of all outcome measures, and rejection was a stronger predictor of aggression and delinquency than of inattention. Interaction effects were found for FR-EXT and perceived parental rejection and overprotection; other interactions between FR-EXT and parenting styles were not significant. Correlations between FR-EXT and perceived parenting styles were absent or very low and were without clinical significance. Predominantly main effects of FR-EXT and perceived parenting styles independently contribute to externalizing behaviors in preadolescents, suggesting FR-EXT and parenting styles to be two separate areas of causality. The relative lack of gene-environment interactions may be due to the epidemiological nature of the study, the preadolescent age of the subjects, the measurement level of parenting and the measurement level of FR-EXT, which might be a consequence of both genetic and environmental factors.

Inter-rater reliability and stability of diagnoses of autism spectrum disorder in children identified through screening at a very young age.

To examine the inter-rater reliability and stability of autism spectrum disorder (ASD) diagnoses made at a very early age in children identified through a screening procedure around 14 months of age. In a prospective design, preschoolers were recruited from a screening study for ASD. The inter-rater reliability of the diagnosis of ASD was measured through an independent assessment of a randomly selected subsample of 38 patients by two other psychiatrists. The diagnoses at 23 months and 42 months of 131 patients, based on the clinical assessment and the diagnostic classifications of standardised instruments, were compared to evaluate stability of the diagnosis of ASD. Inter-rater reliability on a diagnosis of ASD versus non-ASD at 23 months was 87% with a weighted kappa of 0.74 (SE 0.11). The stability of the different diagnoses in the autism spectrum was 63% for autistic disorder, 54% for pervasive developmental disorder, not otherwise specified (PDD-NOS), and 91% for the whole category of ASD. Most diagnostic changes at 42 months were within the autism spectrum from autistic disorder to PDD-NOS and were mainly due to diminished symptom severity. Children who moved outside the ASD category at 42 months made significantly larger gains in cognitive and language skills than children with a stable ASD diagnosis. In conclusion, the inter-rater reliability and stability of the diagnoses of ASD established at 23 months in this population-based sample of very young children are good.

Externalizing behaviors in preadolescents: familial risk to externalizing behaviors, prenatal and perinatal risks, and their interactions.

BACKGROUND: Accumulating evidence indicates that there is a rich and varied interplay between persons and their environments, which strongly suggests that this involves gene-environment correlations and interactions. We investigated whether familial risk (FR) to externalizing behaviors and prenatal and perinatal risk factors, separately or in interaction with each other, predicted externalizing behaviors. METHODS: The subjects were 10- to 12-year-old preadolescents who were taking part in TRAILS, a large prospective population-based cohort study (N = 2,230). Regression analyses were used to determine the relative contribution of FR and prenatal and perinatal risks to parent and teacher ratings of inattention, hyperactivity/impulsivity aggression, and delinquency. RESULTS: Regression models explained between 6 and 11% of the variance of externalizing behaviors. We found main effects of FR (vs. no FR), macrosomia (birth weight > 4,500 g), maternal prenatal smoking (MPS), pregnancy and delivery complications (PDCs), and gender that were rather consistent across rater and outcome measures. For some outcome measures, the effect of MPS and PDCs depended on the presence of FR. These included both positive and negative interaction effects. Correlations between FR and prenatal and perinatal risks were significant but rather low. CONCLUSIONS: Both main effects and interaction effects of FR and prenatal and perinatal risks contributed to externalizing behaviors in preadolescents, but all effects were of small size. Further research including use of candidate gene polymorphisms is necessary to identify the underlying neurobiological mechanisms of these main and interaction effects.

HPA-axis activity and externalizing behavior problems in early adolescents from the general population: the role of comorbidity and gender The TRAILS study.

Contradictory findings on the relationship between hypothalamus-pituitary-adrenal (HPA)-axis activity and externalizing behavior problems could be due to studies not accounting for issues of comorbidity and gender. In a population-based cohort of 1768 (10- to 12-year-old) early adolescents, we used a person-oriented approach and a variable-oriented approach to investigate whether comorbidity with internalizing behavior problems and gender moderate the relationship between HPA-axis activity (cortisol awakening response and evening cortisol levels) and externalizing behavior problems. We found that: (1) in early adolescents with pure externalizing behavior problems, there was a particularly strong effect of gender, in that girls showed significantly higher total cortisol levels after awakening (AUC(G) levels) and a significantly higher cortisol awakening response (AUC(I) levels) than boys. (2) Girls with pure externalizing behavior problems showed a significantly higher cortisol awakening response (AUC(I) levels) than girls without behavior problems or girls with comorbid internalizing behavior problems. This effect was absent in boys. (3) Externalizing behavior problems, in contrast to internalizing behavior problems, were associated with higher evening cortisol levels. This effect might, however, result from girls with externalizing behavior problems showing the highest evening cortisol levels. Overall, we were unable to find the expected relationships between comorbidity and HPA-axis activity, and found girls with pure externalizing behavior problems to form a distinct group with regard to their HPA-axis activity. There is need for prospective longitudinal studies of externalizing behavior problems in boys and girls in relation to their HPA-axis activity. It would be useful to consider how other risk factors such as life events and family and parenting factors as well as genetic risks affect the complex relationship between externalizing behavior problems and HPA-axis activity.

Play behavior and attachment in toddlers with autism.

Play helps to develop social skills. Children with autism show deviances in their play behavior that may be associated with delays in their social development. In this study, we investigated manipulative, functional and symbolic play behavior of toddlers with and without autism (mean age: 26.45, SD 5.63). The results showed that the quality of interaction between the child and the caregiver was related to the development of play behavior. In particular, security of attachment was related to better play behavior. When the developmental level of the child is taken into account, the attachment relationship of the child with the caregiver at this young age is a better predictor of the level of play behavior than the child's disorder.

Parental compliance after screening social development in toddlers.

OBJECTIVES: To examine the prevalence of parents' compliance with follow-up measurements after their child tested positive at a screening to assess problems in social development, as well as to find demographic, screening-related, and child-specific factors associated with parental compliance. DESIGN: Two-stage screening design. SETTING: Utrecht, the Netherlands. PARTICIPANTS: A random population of 31,724 children were screened at well-baby clinics at age 14 to 15 months (screen 1). Three hundred sixty-four children underwent screen 2 (255 children who scored positive at screen 1 [population screening] and 109 children younger than 36 months who were identified by surveillance because of suspected problems in their social development). Main Exposure A 2-stage screening was applied. MAIN OUTCOME MEASURES: Compliance with recommendations of having either a second screening (after screen 1) or clinical evaluation (after screen 2). RESULTS: Of 370 children who tested positive at screen 1, parents of 255 children (69%) complied with screen 2. Three groups were distinguished after screen 2 (n = 173): early compliance (clinical evaluation within 6 months) (68%), late compliance (clinical evaluation after 6 months) (14%), and noncompliance (no clinical evaluation) (18%). Late compliance and noncompliance were more common in parents of younger children and children who were identified via population screening. Parents of children with either relatively high cognitive skills and/or low scores on screening measures were less inclined to comply. CONCLUSIONS: Study results suggest higher effectiveness of surveillance over population screening. Screening may well be applied as a second step after surveillance to identify children who need further clinical evaluation.

Attachment in toddlers with autism and other developmental disorders.

Attachment was assessed in toddlers with Autistic Disorder (n=20), Pervasive Developmental Disorder (n=14), Mental Retardation (n=12), Language Development Disorder (n=16), and a non-clinical comparison group (n=18), using the Strange Situation Procedure (SSP). Children in the clinical groups were more often disorganized and less often securely attached. Severity of autism was associated with more attachment insecurity, and lower developmental level increased the chance for disorganized attachment. Attachment disorganization was related to increased heart rate during the SSP. Controlling for basal cortisol and developmental level, more autistic symptoms predicted lower cortisol responses to the SSP. The findings support the importance of disorganized attachment for children with autism.

Body length and head growth in the first year of life in autism.

Data on the growth of the head in the first year of life in children with autism spectrum disorders are inconsistent. We measured head circumference and body length during the first year of life, and determined whether the head grew in proportion to body length. This is a case-control study nested in a population-based screening study of autism spectrum disorders. Longitudinal data for head circumference and body length of 53 children with autism spectrum disorders were compared with those of a control group and population norms, using univariate and multilevel statistical modeling. Growth of body length was accelerated, but growth of head circumference was normal in children with autism spectrum disorders compared with controls in the first year of life. The rate of macrocephaly we detected in the first year of life in our sample, 11.3%, fits within the 95% confidence intervals of macrocephaly rates in previous studies. Our findings suggest that autism spectrum disorder is due to a dysregulation of growth in general, rather than to a dysregulation of neuronal growth in the brain. It is unclear whether this early, disproportionate growth of children with autism spectrum disorders is specific to the disorder, and whether this growth could serve as a biomarker to delineate more homogeneous subtypes of autism spectrum disorders.

Joint attention and attachment in toddlers with autism.

Joint attention is often referred to as a triadic relation between self, other and object. Young children with autism show deficiencies in the use of joint attention behaviors. Individual differences may be expected, and they may be determined by the children's cognitive development or the characteristics of the relationship of the child with the caregiver. Although most joint attention skills develop under the age of three, most studies of joint attention in children with autism involved children older than 3 years of age, due to difficulties in diagnosing autism under this age. In this study we investigated joint attention behaviors of 78 young children (mean age 25.7 months, SD 6.1) with autism spectrum disorders (n = 20), other developmental delays (n = 18), and typically developing children (n = 40). Following the pertinent literature and confirmed by factor analysis, two types of joint attention behaviors were distinguished, Basic Joint Attention (BJA) and Associated Joint Attention (AJA). We found that cognitive delays and autistic symptoms-but not attachment insecurity or disorganization-were related to less joint attention. Already at the age of 2 years, children with more autistic symptoms show less joint attention, even after controlling for developmental level.

Autism, attachment and parenting: a comparison of children with autism spectrum disorder, mental retardation, language disorder, and non-clinical children.

Children with Autism Spectrum Disorder (ASD) have severe and pervasive impairments in the development of social interaction, which may affect the attachment relationship with their parents and may have an impact on parenting. In the current investigation 89 families with young children (mean age 26.5 months) were involved, who were diagnosed as ASD, mentally retarded (MR), or language delayed (LD), or part of a non-clinical comparison group. Attachment security was observed with the Brief Attachment Screening Questionnaire, and several parental self-report questionnaires assessed the parenting style, parental efficacy, parental experiences of daily hassles, social support, and psychological problems. Children with ASD were rated as less secure compared to the other clinical and normal comparison groups. Parents of non-clinical children reported higher levels of authoritative parenting than parents in the ASD group and in the total clinical group, and they also received less social support. Parents of children with ASD coped remarkably well with the challenges of raising a child with ASD.

Autism and attachment: the Attachment Q-Sort.

Children with autism are able to show secure attachment behaviours to their parents/caregivers. Most studies on attachment in children with autism used a (modified) Strange Situation Procedure (SSP) to examine attachment security. An advantage of the Attachment Q-Sort (AQS) over the SSP is that it can be attuned to the secure-base behaviour of children from special populations. In this study experts in the field of autism (both clinicians and researchers: N = 59) defined an AQS criterion sort for children with autism and tested its content validity. Separate criterion sorts were defined for the social subtypes aloof and active-but-odd, but the two criterion sorts could be combined into one AQS criterion sort for children with autism. It is concluded that with minor amendments the original Attachment Q-Sort is applicable in observing the attachment behaviour of children with autism.