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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.

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.

Contains fulltext : 136250.pdf (publisher's version ) (Open Access), BACKGROUND: Little is known about the stability of behavioural and developmental problems as children develop from infants to toddlers in the general population. Therefore, we investigated behavioural profiles at two time points and determined whether behaviours are stable during early development. METHODS: Parents of 4,237 children completed questionnaires with 62 items about externalizing, internalizing, and social-communicative behaviour when the children were 14-15 and 36-37 months old. Factor mixture modelling identified five homogeneous profiles at both time points: three with relatively normal behaviour or with mild/moderate problems, one with clear communication and interaction problems, and another with pronounced negative and demanding behaviour. RESULTS: More than 85% of infants with normal behaviour or mild problems at 14-15 months were reported to behave relatively typically as toddlers at 36-37 months. A similar percentage of infants with moderate communication problems outgrew their problems by the time they were toddlers. However, infants with severe problems had mild to severe problems as toddlers, and did not show completely normal behaviour. Improvement over time occurred more often in children with negative and demanding behaviour than in children with communication and interaction problems. The former showed less homotypic continuity than the latter. CONCLUSIONS: Negative and demanding behaviour is more often transient and a less specific predictor of problems in toddlerhood than communication and interaction problems.

Contains fulltext : 125607.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 115433.pdf (publisher's version ) (Open Access), It is unclear whether symptoms of autism spectrum disorder (ASD) in young children in the population fit the three-factor structure of ASD as described in the DSM-IV, and cluster together in individual subjects. This study analysed questionnaire data on ASD symptoms filled in by mothers of 11,332 18-month-old children that was collected in the context of the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Confirmatory Factor Analyses showed that the three-factor model had a significantly better fit then the two- and one-factor model of ASD symptoms. Latent class analysis revealed four homogeneous groups of children (classes) with different scores for Social Interaction and Communication at one hand and Stereotypies/Rigidity at the other hand.

Contains fulltext : 95857.pdf (publisher's version ) (Closed access), OBJECTIVE: To investigate the extent that baseline cognitive impairment and intake adherence affected the 13-item Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) intervention response of a medical food in Alzheimer's Disease (AD) patients. DESIGN/SETTING/PARTICIPANTS /INTERVENTION/MEASUREMENTS: This analysis was performed on data from a proof-of-concept study, consisting of a 12-week, double-blind, randomized, controlled, multicenter trial, followed by a similarly designed 12-week extension study. Patients with mild AD (Mini-Mental State Examination [MMSE] score of 20-26) were randomized to receive active or control product as a 125 ml daily drink. One of the co-primary outcome measures was the 13-item ADAS-cog. In this analysis, the study population was divided into two subgroups: patients with 'low' baseline ADAS-cog scores (<25.0) and patients with 'high' baseline ADAS-cog scores (>/=25.0). Repeated Measures Models (RMM) were used to determine the relationship between ADAS-cog score and intervention. RESULTS: A significant treatment effect (F[1,319]=4.0, p=0.046) was shown in patients with 'high' baseline ADAS-cog, but not in patients with 'low' baseline ADAS-cog (F[1,250]=1.25, p=0.265). Overall, intake adherence was significantly correlated with ADAS-cog improvement in the active product group (correlation coefficient=-0.260; p=0.019), but not the control group. CONCLUSION: These data indicate that baseline ADAS-cog significantly influenced the effect of Souvenaid intervention on ADAS-cog outcome. A higher intake of active study product was also associated with greater cognitive benefit. These findings highlight the potential benefits of Souvenaid in AD patients and warrant confirmation in larger, controlled studies.

Contains fulltext : 97852.pdf (publisher's version ) (Closed access), OBJECTIVES: To investigate the effect of a medical food (Souvenaid) on body mass index (BMI) and functional abilities in patients with mild Alzheimer's disease (AD). DESIGN/SETTING/PARTICIPANTS/INTERVENTION /MEASUREMENTS: These analyses were performed on data from a 12-week, double-blind, randomized, controlled, multicenter, proof-of-concept study with a similarly designed and exploratory 12-week extension period. Patients with mild AD (Mini-Mental State Examination score of 20-26) were randomized to receive either the active product or an iso-caloric control product. While primary outcomes included measures of cognition, the 23-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale was included as a secondary outcome. Both ADCS-ADL and BMI were assessed at baseline and Weeks 6, 12 and 24. Data were analyzed using a repeated-measures mixed model. RESULTS: Overall, data suggested an increased BMI in the active versus the control group at Week 24 (ITT: p = 0.07; PP: p = 0.03), but no treatment effect on ADCS-ADL was observed. However, baseline BMI was found to be a significant treatment effect modifier (ITT: p = 0.04; PP: p = 0.05), and an increase in ADCS-ADL was observed at Week 12 in patients with a 'low' baseline BMI (ITT: p = 0.02; PP: p = 0.04). CONCLUSIONS: These data indicate that baseline BMI significantly impacts the effect of Souvenaid on functional abilities. In addition, there was a suggestion that Souvenaid increased BMI.

1 november 2010, Contains fulltext : 88293.pdf (publisher's version ) (Closed access), BACKGROUND: The Social Communication Questionnaire (SCQ) is a screening instrument with established validity against the Autism Diagnostic Interview-Revised (ADI-R) in children aged 4 years and older. Indices of diagnostic accuracy have been shown to be strong in school-aged samples; however, relatively little is known about the performance of the SCQ in toddlers at risk of autism spectrum disorder (ASD). METHODS: This study replicates and extends previous research by Corsello et al. (2007) in a comparatively large (N = 208), substantially younger (20-40 months) sample of children at high risk of ASD. The usefulness of the SCQ as a second-level screening instrument with different cut-off scores was evaluated in relation to IQ, age, and type of ASD diagnosis. The use of the SCQ as compared to the ADI-R was evaluated against clinical diagnosis, both alone and in combination with the ADOS. RESULTS: The SCQ with different cut-offs consistently showed an unsatisfactory balance between sensitivity and specificity in screening for ASD in high-risk toddlers, with only a few exceptions for specific age, IQ, or diagnostic groups. Even though the SCQ and ADI-R were highly correlated, diagnostic agreement with the best evidence clinical diagnosis was poor for both measures. The ADOS used alone consistently had the highest predictive value. For autism versus not-autism, the combined SCQ and ADOS performed as well as the ADOS alone and notably better than the combination ADI-R and ADOS. CONCLUSIONS: The SCQ is likely to result in a number of false-positive findings, particularly in children with autism symptomatology, and the balance between sensitivity and specificity is poor. The ADOS should be considered the most valid and reliable diagnostic instrument in these very young at-risk children.

1 maart 2010, Contains fulltext : 87982.pdf (publisher's version ) (Closed access), BACKGROUND: Few field trials exist on the impact of implementing guidelines for the early detection of autism spectrum disorders (ASD). The aims of the present study were to develop and evaluate a clinically relevant integrated early detection programme based on the two-stage screening approach of Filipek et al. (1999), and to expand the evidence base for this approach. METHODS: The integrated early detection programme encompassed: 1) training relevant professionals to recognise early signs of autism and to use the Early Screening of Autistic Traits Questionnaire (ESAT; Dietz, Swinkels et al., 2006; Swinkels, van Daalen, van Engeland, & Buitelaar, 2006), 2) using a specific referral protocol, and 3) building a multidisciplinary diagnostic team. The programme was evaluated in a controlled study involving children in two regions (N = 2793, range 0-11 years). The main outcome variables were a difference in mean age at ASD diagnosis and a difference in the proportion of children diagnosed before 36 months. RESULTS: ASD was diagnosed 21 months (95% CI 9.6, 32.4) earlier in the experimental region than in the control region during the follow-up period, with the mean age at ASD diagnosis decreasing by 19.5 months (95% CI 10.5, 28.5) from baseline in the experimental region. Children from the experimental region were 9.4 times (95% CI 2.1, 41.3) more likely than children from the control region to be diagnosed before age 36 months after correction for baseline measurements. Most of these early diagnosed children had narrowly defined autism with mental retardation. CONCLUSIONS: The integrated early detection programme appears to be clinically relevant and led to the earlier detection of ASD, mainly in children with a low IQ.

1 juli 2010, Contains fulltext : 88620.pdf (publisher's version ) (Closed access), 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 envi

01 december 2010, Contains fulltext : 89501.pdf (publisher's version ) (Closed access), This randomized controlled trial compared results obtained after 12 months of nonintensive parent training plus care-as-usual and care-as-usual alone. The training focused on stimulating joint attention and language skills and was based on the intervention described by Drew et al. (Eur Child Adolesc Psychiatr 11:266-272, 2002). Seventy-five toddlers with autism spectrum disorder (65 autism, 10 PDD-NOS, mean age = 34.4 months, SD = 6.2) were enrolled. Analyses were conducted on a final sample of 67 children (lost to follow-up = 8). No significant intervention effects were found for any of the primary (language), secondary (global clinical improvement), or mediating (child engagement, early precursors of social communication, or parental skills) outcome variables, suggesting that the 'Focus parent training' was not of additional value to the more general care-as-usual.

1 augustus 2010, Contains fulltext : 89698.pdf (publisher's version ) (Closed access), 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.

1 juni 2010, Contains fulltext : 88133.pdf (publisher's version ) (Closed access), Recently, Gotham et al. (2007) proposed revised algorithms for the Autism Diagnostic Observation Schedule (ADOS) with improved diagnostic validity. The aim of the current study was to replicate predictive validity, factor structure, and correlations with age and verbal and nonverbal IQ of the ADOS revised algorithms for Modules 1 and 2 in a large independent Dutch sample (N = 532). Results showed that the improvement of diagnostic validity was most apparent for autism, except in very young or low functioning children. Results for other autism spectrum disorders were less consistent. Overall, these findings support the use of the more homogeneous revised algorithms, with the use of similar items across developmental cells making it easier to compare ADOS scores within and between individuals.

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 populationbased 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. FREXT 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 FREXT 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 FREXT, which might be a consequence of both genetic and environm

Contains fulltext : 80710.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 81679.pdf (publisher's version ) (Closed access), Several instruments have been developed to screen for autism spectrum disorders (ASD) in high-risk populations. However, few studies compare different instruments in one sample. Data were gathered from the Early Screening of Autistic Traits Questionnaire, Social Communication Questionnaire, Communication and Symbolic Behavior Scales-Developmental Profile, Infant-Toddler Checklist and key items of the Checklist for Autism in Toddlers in 238 children (mean age = 29.6 months, SD = 6.4) at risk for ASD. Discriminative properties are compared in the whole sample and in two age groups separately (8-24 months and 25-44 months). No instrument or individual item shows satisfying power in discriminating ASD from non-ASD, but pros and cons of instruments and items are discussed and directions for future research are proposed.

Contains fulltext : 80152.pdf (publisher's version ) (Closed access), The perceptual pattern in autism has been related to either a specific localized processing deficit or a pathway-independent, complexity-specific anomaly. We examined auditory perception in autism using an auditory disembedding task that required spectral and temporal integration. 23 children with high-functioning-autism and 23 matched controls participated. Participants were presented with two-syllable words embedded in various auditory backgrounds (pink noise, moving ripple, amplitude-modulated pink noise, amplitude-modulated moving ripple) to assess speech-in-noise-reception thresholds. The gain in signal perception of pink noise with temporal dips relative to pink noise without temporal dips was smaller in children with autism (p = 0.008). Thus, the autism group was less able to integrate auditory information present in temporal dips in background sound, supporting the complexity-specific perceptual account.

Contains fulltext : 80144.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 73473.pdf (publisher's version ) (Open Access), Study Objectives: To study the prevalence of and symptoms of eating disorders in patients with narcolepsy. Design: We performed a case-control study comparing symptoms of eating disorders in patients with narcolepsy versus healthy population controls, using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN 2.1). To study whether an increased body mass index (BMI) could be responsible for symptoms of an eating disorder, we also compared patients with BMI-matched controls, using the SCAN as well as the Eating Disorder Examination-Questionnaire. Setting: University hospital. Patients and participants: Patients with narcolepsy/cataplexy (n = 60) were recruited from specialized sleep centers. Healthy controls (n = 120) were drawn from a population study previously performed in the Netherlands. Separately, 32 BMI-matched controls were recruited. Interventions: N/A. Measurements and Results: In total, 23.3% of the patients fulfilled the criteria for a clinical eating disorder, as opposed to none of the control subjects. Most of these were classified as Eating Disorder–Not Otherwise Specified, with an incomplete form of binge eating disorder. On the symptom level, half of the patients reported a persistent craving for food, as well as binge eating. Twenty-five percent of patients even reported binging twice a week or more often. When compared with BMI matched controls, the significant increases persisted in symptoms of eating disorders among patients with narcolepsy. Except for a higher level of interference in daily activities due to eating problems in patients using antidepressants, medication use did not influence our findings. Conclusions: The majority of patients with narcolepsy experience a number of symptoms of eating disorders, with an irresistible craving for food and binge eating as the most prominent features. Eating disorder symptomatology interfered with daily activities. These findings justify more attention for eating disorders in the treatment o

Contains fulltext : 70165.pdf (publisher's version ) (Closed access), Deficits in the perception of social stimuli may contribute to the characteristic impairments in social interaction in high functioning autism (HFA). Although the cortical processing of voice is abnormal in HFA, it is unclear whether this gives rise to impairments in the perception of voice gender. About 20 children with HFA and 20 matched controls were presented with voice fragments that were parametrically morphed in gender. No differences were found in the perception of gender between the two groups of participants, but response times differed significantly. The results suggest that the perception of voice gender is not impaired in HFA, which is consistent with behavioral findings of an unimpaired voice-based identification of age and identity by individuals with autism. The differences in response times suggest that individuals with HFA use different perceptual approaches from those used by typically developing individuals.

Contains fulltext : 71472.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 69584.pdf (publisher's version ) (Closed access), Deficits in Joint Attention (JA) may be one of the earliest signs of Autism Spectrum Disorders (ASD). In this longitudinal study we investigated several types of JA behaviors at the age of 24 and 42 months, and their development over time. Eleven children with ASD, 10 children with other developmental disorders, and eight children without a developmental disorder participated. It was found that children with ASD showed significantly less JA at the age of 24 months. At this age, the various types of JA (Basic Joint Attention, Associated Joint Attention, Joint Visual Attention) were correlated with developmental level and number of autistic characteristics. However, at the age of 42 months, these associations were absent. Although children with ASD may show less JA at the age of 24 months compared to other groups of children, by the age of 42 months they reach about the same level of JA, except for joint visual attention. In fact, at both ages, children with ASD differed consistently only on JVA from the other groups. JVA may be a core component of an early screening device for ASD.

Contains fulltext : 70260.pdf (publisher's version ) (Closed access), Behavioral genetic studies imply that salient environmental influences operate within families, making siblings in a family different rather than similar. This study is the first one to examine differential sibling experiences (as measured with the Sibling Inventory of Differential Experience) and its effect on behavioral outcomes within ADHD families. Subjects were 45 Dutch ADHD probands and their unaffected siblings (n = 45) aged 10-18 years. ADHD probands and their unaffected siblings reported differences in sibling interaction, parental treatment, and peer characteristics. These nonshared environmental influences were related to both the severity of ADHD symptoms as well as to comorbid problem behaviors. These findings suggest that environmental influences that operate within ADHD families appear relevant to the severity of problem behaviors of ADHD children and their siblings.

Contains fulltext : 70110.pdf (publisher's version ) (Closed access), 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-a

Contains fulltext : 71211.pdf (publisher's version ) (Closed access), OBJECTIVE: To study the correlation between symptoms of ADHD in adults, obtained with different methods and from different sources. METHOD: Information was obtained from 120 adults with ADHD, their partners, and their parents, using the ADHD Rating Scale, the Conners' Adult ADHD Rating Scales (CAARS), the Brown Attention-Deficit Disorder Scale (BADDS), and the structured interview Diagnostic Interview Schedule-IV, section L (DIS-L). RESULTS: All self-report rating scales can be used to assess ADHD symptoms in clinical samples of adults. The BADDS and the ADHD Rating Scale proved best in predicting the clinical diagnosis. The DSM-IV factors, originally developed for children, achieve lower patient-informant agreement than the other factors. CONCLUSION: Adults with ADHD appear to be the best informants with regard to their symptoms but tend to underreport the severity of their symptoms. Informant report may be used to get additional information on symptoms and impairment.

Contains fulltext : 53303.pdf (publisher's version ) (Closed access), AIM: To investigate cognitive development in preschool-age children diagnosed with Autistic Spectrum Disorder (ASD; N = 39) compared with that of children diagnosed with mental retardation (MR; N = 14) and normally developing children (NC; N = 36). METHOD: In a prospective longitudinal study, cognitive development was tested at age 24 months (T1; SD = 6 months) and 43 months (T2; SD = 5). RESULTS: Group IQ scores were stable between T1 and T2 as evidenced by high correlations (r = .81, P < .01) and consistency of average group scores. At the same time however, about a third of children with ASD showed an increase of cognitive scores of 15 points or more. This increase of IQ was correlated with lower scores at the early screening of autistic traits (ESAT) at T1, higher IQ level at T2 and higher expressive language skills at T2. Intensity of treatment was not related to IQ increase. CONCLUSIONS: High correlations between cognitive scores in preschool children with ASD suggest that measurements of cognitive function are valid at this age. We found indications of both stability and change of IQ scores. Findings suggest that some children with ASD show catch-up intellectual development. To the best of our knowledge, this increase in IQ scores cannot be attributed to treatment effects.

Contains fulltext : 53261.pdf (publisher's version ) (Closed access), Few studies have examined the presence, structure, and stability of behavior problems in a community sample of 14- and 19-month-old infants. A questionnaire with items on emotional, attentional, and impulsive behavior and social communication was completed by the parents of 6,491 infants aged 14 months and 1,803 infants aged 19 months. Particularly externalizing behavior problems were reported to present sometimes or often for 50% of more of the sample and could be considered as common. In contrast, social communication problems were reported to be present in less than 10% of the sample. Overall, boys showed more problem behaviors than girls. Principal component analysis at the 14 months data revealed seven factors, which could all be replicated in the 19 months data. Pearson correlations between scores at 14 months and 19 months were highest for oppositional and attention factors (0.68 and 0.63) and lowest for the inhibiton factor (0.38). More than 50% of those scoring in the top 10% for total problem score at 14 months were in the top 10% at 19 months. These results will facilitate the recognition of psychopathology at very early age and the study of its development over time.

Contains fulltext : 52066.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 52867.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 51957.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 52011.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 52172.pdf (publisher's version ) (Closed access)

Contains fulltext : 53466.pdf (publisher's version ) (Open Access)

Contains fulltext : 53399.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 51958.pdf (publisher's version ) (Closed access), This study on sensitivity and attachment included 55 toddlers and their parents. Samples included children with autism spectrum disorder (ASD), mental retardation, language delay, and typical development. Children were diagnosed at 4 years of age. Two years before diagnosis, attachment was assessed with the Strange Situation procedure, and parental sensitivity and child involvement during free play were assessed with the Emotional Availability Scale. Parents of children with ASD were equally sensitive as parents of children without ASD, but their children showed more attachment disorganization and less child involvement. More sensitive parents had more secure children, but only in the group without ASD. Less severe autistic symptoms in the social domain predicted more attachment security. Autism challenges the validity of attachment theory.

Contains fulltext : 50179.pdf (publisher's version ) (Closed access), This article describes the development of a screening instrument for young children. Screening items were tested first in a non-selected population of children aged 8-20 months (n = 478). Then, parents of children with clinically diagnosed ASD (n = 153, average age 87 months) or ADHD (n = 76, average age 112 months) were asked to score the items retrospectively for when their child was 14 months old. A 14-item screening instrument, Early Screening of Autistic Traits (ESAT) which had maximal sensitivity and specificity for ASD was developed. The sensitivity of the ESAT was checked in an independent sample of 34 children aged 16-48 months clinically diagnosed with ASD. A 4-item version appears to be a promising prescreening instrument.

Contains fulltext : 50178.pdf (publisher's version ) (Closed access), A two-stage protocol for screening for autistic spectrum disorders (ASD) was evaluated in a random population of 31,724 children aged 14-15 months. Children were first pre-screened by physicians at well-baby clinics using a 4-item screening instrument. Infants that screened positive were then evaluated during a 1.5-h home visit by a trained psychologist using a recently developed screening instrument, the 14-item Early Screening of Autistic Traits Questionnaire (ESAT). Children with 3 or more negative scores were considered to be at high-risk of developing ASD and were invited for further systematic psychiatric examination. Eighteen children with ASD were identified. The group of children with false positive results had related disorders, such as Language Disorder (N = 18) and Mental Retardation (N = 13).

Contains fulltext : 54613.pdf (publisher's version ) (Closed access), Aim - To examine, in a prospective study, the influence of prenatal stress on infant temperament and problem behavior. Method - Self-report data on stress and anxiety, and levels of cortisol in saliva were collected from nulli-parous women during pregnancy. Temperament of the child was measured at 27 months by parent report on the Infant Characteristics Questionnaire. Behavior of the child was assessed by direct observation during the administration of the Bayley Scales of Development 2–30, and by parent report on the Child Behavior Checklist 2–3. Results - Complete data were available for 103 healthy toddlers. Logistic regression analyses were performed and results were adjusted for possible prenatal, perinatal and postnatal confounders. Perceived stress during pregnancy was a predictor of lower levels of restless/disruptive temperament (OR=0.77), more total behavioral problems (OR=1.17), and more externalizing behavioral problems (OR=1.12) in 2-year-olds. Fear of bearing a handicapped child was a predictor of higher levels of restless/disruptive temperament (OR=1.39) and more attention regulation problems in toddlers (OR=1.46). Conclusions - Increased levels of maternal prenatal stress appear to be associated with temperamental and behavioral problems in toddlers.

Contains fulltext : 57832.pdf (publisher's version ) (Closed access)

IERA-conference `Regulation, deregulation and re-regulation: the scope of employment relations in the 21st century¿., 9 juli 2003, Greenwich University, London : [S.n.], Item does not contain fulltext

Item does not contain fulltext, There is consensus about the disorders that comprise the autistic spectrum, with autistic disorder, Asperger's disorder, and PDD-NOS as the most typical examples and Rett's disorder and disintegrative disorder as the other components. Important controversies regarding the precise definitions of autistic spectrum disorders and the boundaries between the milder manifestations of those disorders, particularly PDD-NOS, and non-autistic conditions have not been and cannot be resolved fully as long as there is no known biologic cause or consistent biologic or psychological marker. This includes issues as basic as whether the autistic spectrum is a predominantly unitary entity or a collection of more or less similar phenotypes with multiple, varying etiologies. This is why the highest long-term priority in the area of definite diagnosis is the search for biologic marker(s) for autism and related autism spectrum disorders [91]. In the absence of a medical test to unequivocally diagnose autism, definitions of autism and related conditions are based only on manifestations in overt behavior, with all the unreliability this entails. In the future, the discovery of biologic correlates, causes, and pathogenetic pathways will undoubtedly change the way in which autism is diagnosed and lead to a new nosology [95]. Until that time the definitions in the current versions of the classification systems should be considered in a state of evolution. The key problem of the current classification systems is the fact that the boundaries between the various disorders are fuzzy. Instead of a categorical approach, a more useful description might be that of "autistic spectrum disorder," which reflects the range of severity of symptoms. Such a dimensional understanding of PDD is useful to clinicians, who may otherwise use nonspecific terms to avoid the categorical diagnosis of autism [31]. Rutter and Schopler [96] argued for separate clinical and research schemes because clinical and research ne

Item does not contain fulltext, The effects of olanzapine on the symptomatology of children with pervasive developmental disorder with emphasis on problems of communication and the safety of the drug were investigated in a 3-month open-label, open-dosage study. Participating in the study were 25 children age 6 to 16 years with a diagnosis of either autistic disorder or pervasive developmental disorder not otherwise specified. Psychometric measures included the Clinical Global Impression of Severity/Improvement, the Aberrant Behavior Checklist, and the TARGET (a checklist of five target symptoms). Communication skills were assessed during behavioral analysis of a playroom session. Safety measures included clinical chemistry variables, electrocardiography, the SimpsonAngus Neurological Rating Scale, the Barnes Akathisia Scale, and vital signs. Twenty-three children completed the study and showed significant improvement on three subscales of the Aberrant Behavior Checklist (Irritability, Hyperactivity, and Excessive Speech) and the TARGET. The final mean dose was 10.7 mg/day. Several aspects of communication were also improved after olanzapine treatment. However, only three children were considered responders in terms of the Clinical Global Impression of Severity/Improvement scores. The most important adverse events were weight gain, increased appetite, and loss of strength. Three children showed extrapyramidal symptoms that disappeared after the dose was lowered. Thus, while olanzapine was a relatively safe medication in children, its clinical relevance in children with pervasive developmental disorder may be limited.

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