Opal Ousley

A Multisite Study of the Clinical Diagnosis of Different Autism Spectrum Disorders

CONTEXT Best-estimate clinical diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder-not otherwise specified, and Asperger syndrome) have been used as the diagnostic gold standard, even when information from standardized instruments is available. OBJECTIVE To determine whether the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites. DESIGN Multisite observational study collecting clinical phenotype data (diagnostic, developmental, and demographic) for genetic research. Classification trees were used to identify characteristics that predicted diagnosis across and within sites. SETTING Participants were recruited through 12 university-based autism service providers into a genetic study of autism. PARTICIPANTS A total of 2102 probands (1814 male probands) between 4 and 18 years of age (mean [SD] age, 8.93 [3.5] years) who met autism spectrum criteria on the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule and who had a clinical diagnosis of an autism spectrum disorder. MAIN OUTCOME MEASURE Best-estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures. RESULTS Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs. CONCLUSIONS Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.

Patterns of Adaptive Behavior in Very Young Children with Autism.

The Vineland Adaptive Behavior Scales were used to investigate patterns of adaptive behavior in children with autism who were under 36 months of age. Subjects were 30 children with autism and 30 children with developmental delay matched on CA and MA. Relative to controls, the autistic group demonstrated weaker socialization and communication skills and greater discrepancies between adaptive behavior and MA. Different patterns of relations between adaptive behavior domains and cognitive and language skills were obtained for the two groups. Preliminary support for the utility of adaptive behavior profiles in identifying subgroups of children with autism is provided. Results are discussed in terms of their implications for early diagnosis of autism.

Decoding Children's Social Behavior

We introduce a new problem domain for activity recognition: the analysis of childrens social and communicative behaviors based on video and audio data. We specifically target interactions between children aged 1-2 years and an adult. Such interactions arise naturally in the diagnosis and treatment of developmental disorders such as autism. We introduce a new publicly-available dataset containing over 160 sessions of a 3-5 minute child-adult interaction. In each session, the adult examiner followed a semi-structured play interaction protocol which was designed to elicit a broad range of social behaviors. We identify the key technical challenges in analyzing these behaviors, and describe methods for decoding the interactions. We present experimental results that demonstrate the potential of the dataset to drive interesting research questions, and show preliminary results for multi-modal activity recognition.

Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

IMPORTANCE Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

Autism Spectrum Disorder: Defining Dimensions and Subgroups

Autism spectrum disorder (ASD) is a behaviorally defined neurodevelopmental disorder associated with the presence of social-communication deficits and restricted and repetitive behaviors. In the latest conceptualization of ASD, these two behavioral dimensions represent the core defining features of ASD, whereas associated dimensions, such as intellectual and language ability, provide a means for describing the ASD heterogeneity. In addition, the characterization of ASD subgroups, defined by the presence of known medical, genetic, or other psychiatric disorders, furthers our understanding of ASD heterogeneity. This paper reviews the history of autism, describes its core defining features, and provides an overview of the clinically and etiologically relevant subgroups that add to the complexity of this condition.

Performance on the Modified Card Sorting Test and Its Relation to Psychopathology in Adolescents and Young Adults with 22Q11.2 Deletion Syndrome.

BACKGROUND Approximately one-third of individuals with 22q11.2 deletion syndrome (22q11DS), a common genetic disorder highly associated with intellectual disabilities, may develop schizophrenia, likely preceded by a mild to moderate cognitive decline. METHODS We examined adolescents and young adults with 22q11DS for the presence of executive function deficits using a modified version of the Wisconsin Card Sorting Test (MCST) and assessed whether specific performances were associated with concurrent schizophrenia-prodrome symptoms. We also examined possible relationships between MCST performance and broader indices of psychopathology, including self-reported internalising and externalising behavioural symptoms. RESULTS Participants with 22q11DS scored significantly below age-matched controls on seven out of nine MCST measures, and poorer MCST performance was associated with increased positive prodromal and internalising behavioural symptoms. CONCLUSIONS The schizophrenia-prodrome in 22q11DS involves executive dysfunction, and longitudinal investigation is necessary to examine if specific executive function impairments precedes or co-occurs with the emergence of behavioural psychopathology.

Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report.

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1β, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r=0.851, p=0.004; r=0.580, p=0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r=0.795, p=0.033; r=0.774, p=0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry.

Prodromal and autistic symptoms in schizotypal personality disorder and 22q11.2 deletion syndrome.

Despite clear diagnostic distinctions, schizophrenia and autism share symptoms on several dimensions. Recent research has suggested the two disorders overlap in etiology, particularly with respect to inherited and noninherited genetic factors. Studying the relationship between psychotic-like and autistic-like symptoms in risk groups such as 22q11 deletion syndrome (22q11DS) and schizotypal personality disorder (SPD) has the potential to shed light on such etiologic factors; thus, the current study examined prodromal symptoms and autistic features in samples of 22q11DS and SPD subjects using standardized diagnostic measures, including the Structured Interview for Prodromal Symptoms (SIPS) and the Autism Diagnostic Inventory-Revised (ADI-R). Results showed that SPD subjects manifested significantly more severe childhood and current social as well as stereotypic autistic features, as well as more severe positive prodromal symptoms. The two groups did not differ on negative, disorganized, or general prodromal symptoms, but were distinguishable based on correlations between prodromal and autistic features; the relationships between childhood autistic features and current prodromal symptoms were stronger for the SPD group. The results suggest that childhood autistic features are less continuous with subsequent prodromal signs in 22q11DS patients relative to those with SPD, and the findings highlight the importance of studying the overlap in diagnostic phenomenology in groups at risk for developing psychosis and/or autism.

Axis I psychiatric diagnoses in adolescents and young adults with 22q11 deletion syndrome

BACKGROUND 22q11.2 deletion syndrome (22q11DS) associates with schizophrenia spectrum disorders (SSDs), autism spectrum disorders (ASDs), and other psychiatric disorders, but co-occurrence of diagnoses are not well described. METHODS We evaluated the co-occurrence of SSDs, ASDs and other axis I psychiatric diagnoses in 31 adolescents and adults with 22q11DS, assessing ASDs using either stringent Collaborative Program for Excellence in Autism (ASD-CPEA) criteria, or less stringent DSM-IV criteria alone (ASD-DSM-IV). RESULTS Ten (32%) individuals met criteria for an SSD, five (16%) for ASD-CPEA, and five others (16%) for ASD-DSM-IV. Of those with ASD-CPEA, one (20%) met SSD criteria. Of those with ASD-DSM-IV, four (80%) met SSD criteria. Depressive disorders (8 individuals; 26%) and anxiety disorders (7; 23%) sometimes co-occurred with SSDs and ASDs. SSDs, ASDs, and anxiety occurred predominantly among males and depression predominantly among females. CONCLUSIONS Individuals with 22q11DS can manifest SSDs in the presence or absence of ASDs and other axis I diagnoses. The results suggest that standard clinical care should include childhood screening for ASDs, and later periodic screening for all axis I diagnoses.

Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15–50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA), which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observational Schedule (ADOS), and a clinician’s best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults (n = 56) with 22q11.2DS, who were ascertained irrespective of parents’ behavioral or developmental concerns, and found that 17.9% (n = 10) of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood.