The Adapted ADOS: A New Module Set for the Assessment of Minimally Verbal Adolescents and Adults.

Few measures are appropriate to assess autism symptoms in minimally verbal adolescents and adults. The Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2, Lord et al., in Autism diagnostic observation schedule-2nd edition (ADOS-2). Western Psychological Services, Los Angeles, 2012) Modules 1 and 2 were designed and validated with children whose spoken language ranges from few- to- no words to phrase speech. This study describes the development and initial validation of the Adapted-ADOS (A-ADOS), which includes tasks, materials and behavioral codes modified to be suitable for assessing older minimally verbal individuals. A-ADOS algorithms exhibit comparable sensitivity and improved specificity relative to ADOS-2 Modules 1 and 2. Although further validation is needed, the A-ADOS will facilitate research to further understanding of minimally verbal adults and symptom trajectories across the lifespan.

How interview questions are placed in time influences caregiver description of social communication symptoms on the ADI-R.

BACKGROUND: Caregiver report is crucial for the diagnosis of childhood onset psychiatric disorders, particularly autism. Three experiments were conducted to determine whether caregiver reports of past and current behaviors are affected by question timing and ordering. METHODS: Using the Autism Diagnostic Interview - Revised (ADI-R), two studies systematically varied the order in which caregivers were asked about behaviors. In a third study, descriptions of children's current behaviors at age 5 were compared to retrospective descriptions of behaviors at age 5 collected at age 10. RESULTS: Caregivers, who were first asked about a history of symptoms, described less severe past and present behavior than caregivers reporting current behaviors as well as caregivers reporting current and history of symptoms together. Caregivers retrospectively reported more severe behaviors for age 5 when their children were age 10 than they had when their children were age 5. CONCLUSIONS: Caregivers describe past behaviors differently depending on whether they are asked about current symptoms first. Methods of caregiver reporting can influence interpretations of symptom severity with effects on diagnoses and research findings.

Autism traits in the RASopathies.

BACKGROUND: Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs. METHODS: We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS). RESULTS: Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs. CONCLUSIONS: Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

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.

Neural activation to emotional faces in adolescents with autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) involve a core deficit in social functioning and impairments in the ability to recognize face emotions. In an emotional faces task designed to constrain group differences in attention, the present study used functional MRI to characterize activation in the amygdala, ventral prefrontal cortex (vPFC), and striatum, three structures involved in socio-emotional processing in adolescents with ASD. METHODS: Twenty-two adolescents with ASD and 20 healthy adolescents viewed facial expressions (happy, fearful, sad and neutral) that were briefly presented (250 ms) during functional MRI acquisition. To monitor attention, subjects pressed a button to identify the gender of each face. RESULTS: The ASD group showed greater activation to the faces relative to the control group in the amygdala, vPFC and striatum. Follow-up analyses indicated that the ASD relative to control group showed greater activation in the amygdala, vPFC and striatum (p < .05 small volume corrected), particularly to sad faces. Moreover, in the ASD group, there was a negative correlation between developmental variables (age and pubertal status) and mean activation from the whole bilateral amygdala; younger adolescents showed greater activation than older adolescents. There were no group differences in accuracy or reaction time in the gender identification task. CONCLUSIONS: When group differences in attention to facial expressions were limited, adolescents with ASD showed greater activation in structures involved in socio-emotional processing.

Neural circuitry of emotional face processing in autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) are associated with severe impairments in social functioning. Because faces provide nonverbal cues that support social interactions, many studies of ASD have examined neural structures that process faces, including the amygdala, ventromedial prefrontal cortex and superior and middle temporal gyri. However, increases or decreases in activation are often contingent on the cognitive task. Specifically, the cognitive domain of attention influences group differences in brain activation. We investigated brain function abnormalities in participants with ASD using a task that monitored attention bias to emotional faces. METHODS: Twenty-four participants (12 with ASD, 12 controls) completed a functional magnetic resonance imaging study while performing an attention cuing task with emotional (happy, sad, angry) and neutral faces. RESULTS: In response to emotional faces, those in the ASD group showed greater right amygdala activation than those in the control group. A preliminary psychophysiological connectivity analysis showed that ASD participants had stronger positive right amygdala and ventromedial prefrontal cortex coupling and weaker positive right amygdala and temporal lobe coupling than controls. There were no group differences in the behavioural measure of attention bias to the emotional faces. LIMITATIONS: The small sample size may have affected our ability to detect additional group differences. CONCLUSION: When attention bias to emotional faces was equivalent between ASD and control groups, ASD was associated with greater amygdala activation. Preliminary analyses showed that ASD participants had stronger connectivity between the amygdala ventromedial prefrontal cortex (a network implicated in emotional modulation) and weaker connectivity between the amygdala and temporal lobe (a pathway involved in the identification of facial expressions, although areas of group differences were generally in a more anterior region of the temporal lobe than what is typically reported for emotional face processing). These alterations in connectivity are consistent with emotion and face processing disturbances in ASD.

Alterations of resting state functional connectivity in the default network in adolescents with autism spectrum disorders.

Autism spectrum disorders (ASD) are associated with disturbances of neural connectivity. Functional connectivity between neural structures is typically examined within the context of a cognitive task, but also exists in the absence of a task (i.e., "rest"). Connectivity during rest is particularly active in a set of structures called the default network, which includes the posterior cingulate cortex (PCC), retrosplenial cortex, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus. We previously reported that adults with ASD relative to controls show areas of stronger and weaker connectivity within the default network. The objective of the present study was to examine the default network in adolescents with ASD. Sixteen adolescents with ASD and 15 controls participated in a functional MRI study. Functional connectivity was examined between a PCC seed and other areas of the default network. Both groups showed connectivity in the default network. Relative to controls, adolescents with ASD showed widespread weaker connectivity in nine of the eleven areas of the default network. Moreover, an analysis of symptom severity indicated that poorer social skills and increases in restricted and repetitive behaviors and interests correlated with weaker connectivity, whereas poorer verbal and non-verbal communication correlated with stronger connectivity in multiple areas of the default network. These findings indicate that adolescents with ASD show weaker connectivity in the default network than previously reported in adults with ASD. The findings also show that weaker connectivity within the default network is associated with specific impairments in ASD.

Abnormalities of intrinsic functional connectivity in autism spectrum disorders.

Autism spectrum disorders (ASD) impact social functioning and communication, and individuals with these disorders often have restrictive and repetitive behaviors. Accumulating data indicate that ASD is associated with alterations of neural circuitry. Functional MRI (FMRI) studies have focused on connectivity in the context of psychological tasks. However, even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic or resting connectivity. Notably, the default network, which includes the posterior cingulate cortex, retro-splenial, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus, is strongly active when there is no task. Altered intrinsic connectivity within the default network may underlie offline processing that may actuate ASD impairments. Using FMRI, we sought to evaluate intrinsic connectivity within the default network in ASD. Relative to controls, the ASD group showed weaker connectivity between the posterior cingulate cortex and superior frontal gyrus and stronger connectivity between the posterior cingulate cortex and both the right temporal lobe and right parahippocampal gyrus. Moreover, poorer social functioning in the ASD group was correlated with weaker connectivity between the posterior cingulate cortex and the superior frontal gyrus. In addition, more severe restricted and repetitive behaviors in ASD were correlated with stronger connectivity between the posterior cingulate cortex and right parahippocampal gyrus. These findings indicate that ASD subjects show altered intrinsic connectivity within the default network, and connectivity between these structures is associated with specific ASD symptoms.

The Autism Diagnostic Observation Schedule-toddler module: a new module of a standardized diagnostic measure for autism spectrum disorders.

The Autism Diagnostic Observation Schedule (ADOS; Lord et al., J Autism Dev Disord, 30(3):205-223, 2000) is widely accepted as a "gold standard" diagnostic instrument, but it is of restricted utility with very young children. The purpose of the current project was to modify the ADOS for use in children under 30 months of age. A modified ADOS, the ADOS Toddler Module (or Module T), was used in 360 evaluations. Participants included 182 children with best estimate diagnoses of ASD, non-spectrum developmental delay or typical development. A final set of protocol and algorithm items was selected based on their ability to discriminate the diagnostic groups. The traditional algorithm "cutoffs" approach yielded high sensitivity and specificity, and a new range of concern approach was proposed.

A replication of the Autism Diagnostic Observation Schedule (ADOS) revised algorithms.

OBJECTIVE: To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282). METHOD: Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment. RESULTS: Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified. CONCLUSIONS: Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.

Patterns of growth in verbal abilities among children with autism spectrum disorder.

Verbal skills were assessed at approximately ages 2, 3, 5, and 9 years for 206 children with a clinical diagnosis of autism (n = 98), pervasive developmental disorders-not otherwise specified (PDD-NOS; n = 58), or nonspectrum developmental disabilities (n = 50). Growth curve analyses were used to analyze verbal skills trajectories over time. Nonverbal IQ and joint attention emerged as strong positive predictors of verbal outcome. The gap between the autism and other 2 groups widened with time as the latter improved at a higher rate. However, there was considerable variability within diagnostic groups. Children with autism most at risk for more serious language impairments later in life can be identified with considerable accuracy at a very young age, while improvement can range from minimal to dramatic.

Between a ROC and a hard place: decision making and making decisions about using the SCQ.

BACKGROUND: The Social Communication Questionnaire (SCQ), formerly the Autism Screening Questionnaire (ASQ), is based on a well-validated parent interview, the Autism Diagnostic Interview (ADI). It has shown promise as a screening measure for autism spectrum disorders (ASDs) in a research-referred older sample, though recent studies with younger children reported lower sensitivities when using the suggested cutoff of > or = 15 to differentiate ASDs from children with nonspectrum disorders (NS). METHODS: Diagnostic discrimination of the SCQ was evaluated alone and in combination with the ADOS (Autism Diagnostic Observation Schedule) in a clinical and research-referred sample of 590 children and adolescents (2 to 16 years), with best estimate consensus diagnoses of autism, pervasive developmental disorder, not otherwise specified (PDD-NOS) and non-ASD disorders. The SCQ was completed before the evaluation in most cases. Performance of the SCQ was also compared with the Autism Diagnostic Interview - Revised (ADI-R). RESULTS: Absolute scores and sensitivity in the younger children and specificity for all groups were lower than reported in the original study. Using receiver operating curves (ROC) to examine the area under the curve (AUC), the SCQ was more similar to the ADI-R total score in differentiating ASD from NS disorders in the older (8-10, >11) than younger age groups (<5, 5-7). Lowering the cutoff score in the 2 younger groups improved sensitivity, with specificity remaining relatively low in all groups. Using the SCQ in combination with the ADOS resulted in improved specificity. Diagnostic discrimination was best using the ADI-R and ADOS in combination. CONCLUSIONS: Those interested in using the SCQ should consider adjusting cutoff scores according to age and purpose, and using it in combination with another measure. Sensitivity or specificity may be prioritized for research or screening depending on goals.

Using the autism diagnostic interview--revised to increase phenotypic homogeneity in genetic studies of autism.

BACKGROUND: Many chromosomal regions for susceptibility to autism spectrum disorders (ASDs) have been identified, but few have reached genomewide significance. In response, researchers have attempted to increase the power of their analyses by stratifying samples to increase phenotypic homogeneity. Although homogeneity has typically been defined by a single variable, resultant groups often differ in other dimensions that may be directly pertinent. Group differences in age, gender, IQ, and measures of autism severity are examined as related to Autism Diagnostic Interview-Revised (ADI-R) domains previously used for subsetting or Quantitative Trait Analysis (QTL). METHODS: Participants were research participants and clinic referrals for assessment of possible autism. Assessments included the ADI-R, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, and a developmental or cognitive test. Data were collected for 983 individuals, ages 4 to 52 years, with diagnoses of autism and ASDs. RESULTS: Findings suggest that, of several potential grouping variables, only restricted and repetitive behaviors associated with Insistence on Sameness were independent of age, IQ, and autism severity. CONCLUSIONS: Results emphasize the potential unintended effects of stratification and the importance of understanding such interrelationships between phenotypic characteristics when defining subgroups or performing QTL.

Effect of language and task demands on the diagnostic effectiveness of the autism diagnostic observation schedule: the impact of module choice.

The ADOS characterizes socio-communicative deficits in autism spectrum disorders (ASD). In this study the effect of module choice on ADOS classification was examined. For 74 participants (52 autism, 22 PDD-NOS), Module 1 and Module 2 were administered in a single session. Fifty-one participants maintained ADOS classification, with 17 more impaired on M2 and 6 more impaired on M1. For 64 participants (25 autism, 39 PDD-NOS), Module 2 and Module 3 were administered. Thirty-nine participants maintained classification, with 24 more impaired on M3 and 1 more impaired on M2. As expected, more impairment was indicated when a module with more language and task demands was administered. Clinical judgment of the most appropriate module for administration was found to be important.

The Autism Diagnostic Observation Schedule: revised algorithms for improved diagnostic validity.

Autism Diagnostic Observation Schedule (ADOS) Modules 1-3 item and domain total distributions were reviewed for 1,630 assessments of children aged 14 months to 16 years with an autism spectrum disorder (ASD) or with heterogeneous non-spectrum disorders. Children were divided by language level and age to yield more homogeneous cells. Items were chosen that best differentiated between diagnoses and were arranged into domains on the basis of multi-factor item-response analysis. Reflecting recent research, the revised algorithm now consists of two new domains, Social Affect and Restricted, Repetitive Behaviors (RRB), combined to one score to which thresholds are applied, resulting in generally improved predictive value.

Combining information from multiple sources in the diagnosis of autism spectrum disorders.

BACKGROUND: Standard case criteria are proposed for combined use of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule to diagnose autism and to define the broader category of autism spectrum disorders. METHOD: Single and combined Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule algorithms were compared to best estimate diagnoses in four samples: U.S. (n = 960) and Canadian (n = 232) participants 3 years and older, U.S. participants younger than 36 months (n = 270), and U.S. participants older than 36 months with profound mental retardation (n = 67). RESULTS: Sensitivities and specificities of 80% and higher were obtained when strict criteria for an autism diagnosis using both instruments were applied in the U.S. samples, and 75% or greater in the Canadian sample. Single-instrument criteria resulted in significant loss of specificity. Specificity was poor in the sample with profound mental retardation. Lower sensitivity and specificity were also obtained when proposed criteria for broader spectrum disorders were applied. CONCLUSIONS: The Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule make independent, additive contributions to the judgment of clinicians that result in a more consistent and rigorous application of diagnostic criteria.

Autism from 2 to 9 years of age.

CONTEXT: Autism represents an unusual pattern of development beginning in the infant and toddler years. OBJECTIVES: To examine the stability of autism spectrum diagnoses made at ages 2 through 9 years and identify features that predicted later diagnosis. DESIGN: Prospective study of diagnostic classifications from standardized instruments including a parent interview (Autism Diagnostic Interview-Revised [ADI-R]), an observational scale (Pre-Linguistic Autism Diagnostic Observation Schedule/Autism Diagnostic Observation Schedule [ADOS]), and independent clinical diagnoses made at ages 2 and 9 years compared with a clinical research team's criterion standard diagnoses. SETTING: Three inception cohorts: consecutive referrals for autism assessment to (1) state-funded community autism centers, (2) a private university autism clinic, and (3) case controls with developmental delay from community clinics. PARTICIPANTS: At 2 years of age, 192 autism referrals and 22 developmentally delayed case controls; 172 children seen at 9 years of age. MAIN OUTCOME MEASURES: Consensus best-estimate diagnoses at 9 years of age. RESULTS: Percentage agreement between best-estimate diagnoses at 2 and 9 years of age was 67, with a weighted kappa of 0.72. Diagnostic change was primarily accounted for by movement from pervasive developmental disorder not otherwise specified to autism. Each measure at age 2 years was strongly prognostic for autism at age 9 years, with odds ratios of 6.6 for parent interview, 6.8 for observation, and 12.8 for clinical judgment. Once verbal IQ (P = .001) was taken into account at age 2 years, the ADI-R repetitive domain (P = .02) and the ADOS social (P = .05) and repetitive domains (P = .005) significantly predicted autism at age 9 years. CONCLUSIONS: Diagnostic stability at age 9 years was very high for autism at age 2 years and less strong for pervasive developmental disorder not otherwise specified. Judgment of experienced clinicians, trained on standard instruments, consistently added to information available from parent interview and standardized observation.

Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study.

A multi-site study of 351 children with Autism Spectrum Disorders (ASD) and 31 typically developing children used caregiver interviews to describe the children's early acquisition and loss of social-communication milestones. For the majority of children with ASD who had experienced a regression, pre-loss development was clearly atypical. Children who had lost skills also showed slightly poorer outcomes in verbal IQ and social reciprocity, a later mean age of onset of autistic symptoms, and more gastrointestinal symptoms than children with ASD and no regression. There was no evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination. The implications of these findings for the existence of a 'regressive phenotype' of ASD are discussed.

Early regression in social communication in autism spectrum disorders: a CPEA Study.

In a multisite study of 351 children with autism spectrum disorders, 21 children with developmental delays, and 31 children with typical development, this study used caregiver interviews (i.e., the Autism Diagnostic Interview-Revised) at the time of entry into other research projects and follow-up telephone interviews designed for this project to describe the children's early acquisition and loss of social-communication milestones. Children who had used words spontaneously and meaningfully and then stopped talking were described by their caregivers as showing more gestures, greater participation in social games, and better receptive language before the loss and fewer of these skills after the loss than other children with autism spectrum disorders. A significant minority of children with autism without word loss showed a very similar pattern of loss of social-communication skills, a pattern not observed in the children with developmental delays or typical development.