1. Al-Ayadhi LY, Halepoto DM, Al-Dress AM, Mitwali Y, Zainah R. {{Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder}}. {J Coll Physicians Surg Pak};2015 (Nov);25(11):819-823.
OBJECTIVE: To investigate the possible therapeutic effects of camel milk on behavioral characteristics as an interventional strategy in autistic children. STUDY DESIGN: Double-blind, Randomized Clinical Trial (RCT). PLACE AND DURATION OF STUDY: Autism Research and Treatment Center, Al-Amodi Autism Research Chair, Department of Physiology, Faculty of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, from October 2012 to May 2013. METHODOLOGY: Changes in behavioral characteristics in 65 (boys=60, girls=5) children with autism (aged from 2 to 12 years) were assessed. The behavioral symptoms were evaluated by Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Autism Treatment Evaluation Checklist (ATEC) before and after the 2 weeks of camel milk therapy. RESULTS: Significant differences were detected on Autism Spectrum Disorder (ASD) by CARS, SRS and ATEC scales, following 2 weeks of camel milk consumption, but not in the placebo group. CONCLUSION: The present study demonstrates that camel milk could be very promising therapeutic intervention in ASD. Further wide scale studies are strongly recommended.
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2. Antezana L, Mosner MG, Troiani V, Yerys BE. {{Social-Emotional Inhibition of Return in Children with Autism Spectrum Disorder Versus Typical Development}}. {J Autism Dev Disord};2015 (Nov 19)
In typical development there is a bias to orient visual attention to social information. Children with ASD do not reliably demonstrate this bias, and the role of attention orienting has not been well studied. We examined attention orienting via the inhibition of return (IOR) mechanism in a spatial cueing task using social-emotional cues; we studied 8- to 17-year-old children with ASD (n = 41) and typically developing controls (TDC) (n = 25). The ASD group exhibited a significantly stronger IOR effect than the TDC group, and the IOR effect correlated positively with social impairments but was unrelated to co-occurring ADHD or anxiety symptoms. The results provide evidence of an early altered attention mechanism that is associated with to core social deficits in ASD.
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3. Bahrami F, Movahedi A, Marandi SM, Sorensen C. {{The Effect of Karate Techniques Training on Communication Deficit of Children with Autism Spectrum Disorders}}. {J Autism Dev Disord};2015 (Nov 17)
This investigation examined the long term effect of Karate techniques training on communication of children with autism spectrum disorders (ASD). Thirty school aged children with ASD were randomly assigned to an exercise (n = 15) or a control group (n = 15). Participants in the exercise group were engaged in 14 weeks of Karate techniques training. Communication deficit at baseline, post-intervention (week 14), and at 1 month follow up were evaluated. Exercise group showed significant reduction in communication deficit compared to control group. Moreover, reduction in communication deficit in the exercise group at one month follow up remained unchanged compared to post-intervention time. We concluded that teaching Karate techniques to children with ASD leads to significant reduction in their communication deficit.
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4. Besterman AD, Hendren RL. {{A Review of: Life, Animated: A Story of Sidekicks, Heroes, and Autism, by Ron Suskind}}. {J Child Adolesc Psychopharmacol};2015 (Nov);25(9):734-735.
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5. Geurts HM, Stek M, Comijs H. {{Autism Characteristics in Older Adults with Depressive Disorders}}. {Am J Geriatr Psychiatry};2015 (Sep 3)
OBJECTIVE: To study the prevalence of autism spectrum disorder (ASD) characteristics in older adults with and without depressive disorders and the social network and past negative life events in those with a high number of ASD characteristics and those without a large number of these characteristics. METHODS: This large, multisite, naturalistic, prospective cohort study used data from the Netherlands Study of Depression in Older persons (aged 60-90 years) with (N = 259) and without (N = 114) a depressive disorder according to DSM-IV criteria. ASD characteristics were measured with the abbreviated Autism Spectrum Quotient with a cutoff score of 70. Additional measures were the Composite International Diagnostic Interview, the Inventory of Depressive Symptomatology, the Becks Anxiety Inventory, the Close Person Inventory, and the life events questionnaire. RESULTS: Of the older adults with a depressive disorder, 31% showed elevated ASD characteristics, which is much higher than the observed 6% in the comparison group. High ASD characteristics were associated with elevated depression and anxiety symptoms and more comorbid anxiety disorders. Those with a high number of ASD characteristics did not differ in the size of their social network or the number of negative life events as compared with those with less ASD characteristics. CONCLUSION: ASD might be overlooked in older adults, especially within geriatric psychiatry. When diagnosing and treating depression and anxiety in older patients, one should be attentive to ASD.
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6. Hanson EM, Sideridis G, Jackson FI, Porche K, Campe KL, Huntington N. {{Behavior and Sensory Interests Questionnaire: Validation in a sample of children with autism spectrum disorder and other developmental disability}}. {Res Dev Disabil};2015 (Nov 12);48:160-175.
Repetitive behaviors, restricted interests and other unusual sensory behaviors often significantly impact the lives of many individuals with developmental disabilities, including Autism Spectrum Disorder (ASD). Identifying specific patterns of atypical behaviors across different disorders allows for improved specificity of diagnoses, monitoring response to treatment and elucidating the genetic and neurobiological underpinnings of these disorders. The Behavior and Sensory Interests Questionnaire (BSIQ) is a newly designed, continuous dimensional instrument that comprehensively assesses the type, frequency, intensity, age of onset, and duration of these behaviors. The BSIQ takes 15-40min to administer to a caregiver in an interview format. Using a large sample of children with either ASD, intellectual disabilities or who were typically developing, the construct validity of the BSIQ was confirmed using a series of multi-group confirmatory factor analysis models. Configural and metric invariance were satisfied, but not scalar invariance, as expected. The BSIQ showed acceptable internal consistency, excellent inter-rater reliability and excellent test-retest reliability.
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7. Hashimoto R, Nakazawa T, Tsurusaki Y, Yasuda Y, Nagayasu K, Matsumura K, Kawashima H, Yamamori H, Fujimoto M, Ohi K, Umeda-Yano S, Fukunaga M, Fujino H, Kasai A, Hayata-Takano A, Shintani N, Takeda M, Matsumoto N, Hashimoto H. {{Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder}}. {J Hum Genet};2015 (Nov 19)
Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P<0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P=0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes.Journal of Human Genetics advance online publication, 19 November 2015; doi:10.1038/jhg.2015.141.
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8. He X, Thacker S, Romigh T, Yu Q, Frazier TW, Jr., Eng C. {{Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits}}. {Mol Autism};2015;6:63.
BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. METHODS: We developed a Pten knock-in murine model to study the effects of Pten germline mutations, specifically altering subcellular localization, in ASD. Proteins were isolated from the hemispheres of the male littermates, and Western blots were performed to determine protein expression levels of tyrosine hydroxylase (TH). Immunohistochemical stains were carried out to validate the localization of TH and dopamine D2 receptors (D2R). PC12 cells ectopically expressing either wild-type or missense mutant PTEN were then compared for the differences in TH expression. RESULTS: Mice carrying Pten mutations have high TH and D2R in the striatum and prefrontal cortex. They also have increased phosphorylation of cAMP response element-binding protein (CREB) and TH. Mechanistically, PTEN downregulates TH production in PC12 cells via inhibiting the phosphoinositide 3-kinase (PI3K)/CREB signaling pathway, while PTEN reduces TH phosphorylation via suppressing MAPK pathway. Unlike wild-type PTEN but similar to the mouse knock-in mutant Pten, three naturally occurring missense mutations of PTEN that we previously identified in ASD patients, H93R, F241S, and D252G, were not able to suppress TH when overexpressed in PC12 cells. In addition, two other PTEN missense mutations, C124S (pan phosphatase dead) and G129E (lipid phosphatase dead), failed to suppress TH when ectopically expressed in PC12 cells. CONCLUSIONS: Our data reveal a non-canonical PTEN-TH pathway in the brain that may work as a core regulator of dopamine signaling, which when dysfunctional is pathogenic in ASD.
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9. Huang TN, Hsueh YP. {{Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders}}. {Front Neurosci};2015;9:406.
T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1 — mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, Tbr1 +- mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in Tbr1 — mice, these features are not found in Tbr1 +- mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to Tbr1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections) and excitation/inhibition imbalance (NMDAR hypoactivity), two prominent models for ASD etiology, are present in Tbr1 +- mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK) was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in Tbr1 +- mice. In addition to Grin2b, cell adhesion molecules-including Ntng1, Cdh8, and Cntn2-are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of Tbr1 provide an integrated picture of ASD etiology at the cellular and circuit levels.
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10. Irvine CA, Eigsti IM, Fein DA. {{Uh, Um, and Autism: Filler Disfluencies as Pragmatic Markers in Adolescents with Optimal Outcomes from Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Nov 19)
Filler disfluencies-uh and um-are thought to serve distinct discourse functions. We examined fillers in spontaneous speech by youth with autism spectrum disorder (ASD), who struggle with pragmatic language, and by youth with ASD who have achieved an ‘optimal outcome’ (OO), as well as in peers with typical development (TD). While uh rates did not differ, participants with ASD produced um less frequently than OO or TD groups. Um rate was associated with autism symptom severity, but not executive function or language abilities, suggesting that um serves a pragmatic, listener-oriented function. Moreover, in contrast to minimal production in ASD, the typical OO um production substantiates the normalization of subtle social communication in this population.
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11. Kratsman N, Getselter D, Elliott E. {{Sodium Butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model}}. {Neuropharmacology};2015 (Nov 11)
The core behavioral symptoms of Autism Spectrum Disorders (ASD) include dysregulation of social communication and the presence of repetitive behaviors. However, there is no pharmacological agent that is currently used to target these core symptoms. Epigenetic dysregulation has been implicated in the etiology of ASD, and may present a pharmacological target. The effect of Sodium Butyrate, a histone deacetylase inhibitor, on social behavior and repetitive behavior, and the frontal cortex transcriptome, was examined in the BTBR autism mouse model. A 100mg/kg dose, but not a 1200mg/kg dose, of sodium butyrate attenuated social deficits in the BTBR mouse model. In addition, both doses decreased marble burying, an indication of repetitive behavior, but had no significant effect on self-grooming. Using RNA-seq, we determined that the 100mg/kg dose of Sodium Butyrate induced changes in many behavior-related genes in the prefrontal cortex, and particularly affected genes involved in neuronal excitation or inhibition. The decrease in several excitatory neurotransmitter and neuronal activation marker genes, including cFos Grin2b, and Adra1, together with the increase in inhibitory neurotransmitter genes Drd2 and Gabrg1, suggests that sodium butyrate promotes the transcription of inhibitory pathway transcripts. Finally, DMCM, a GABA reverse agonist, decreased social behaviors in sodium-butyrate treated BTBR mice, suggesting that sodium butyrate increases social behaviors through modulation of the excitatory/inhibitory balance. Therefore, transcriptional modulation by sodium butyrate may have beneficial effects on autism related behaviors.
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12. Muller CL, Anacker AM, Veenstra-VanderWeele J. {{The serotonin system in autism spectrum disorder: From biomarker to animal models}}. {Neuroscience};2015 (Nov 11)
Elevated whole-blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole-blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole-blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin (OT), may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker.
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13. Paul A, Sharda M, Menon S, Arora I, Kansal N, Arora K, Singh NC. {{The effect of sung speech on socio-communicative responsiveness in children with autism spectrum disorders}}. {Front Hum Neurosci};2015;9:555.
There is emerging evidence to demonstrate the efficacy of music-based interventions for improving social functioning in children with Autism Spectrum Disorders (ASD). While this evidence lends some support in favor of using song over spoken directives in facilitating engagement and receptive intervention in ASD, there has been little research that has investigated the efficacy of such stimuli on socio-communicative responsiveness measures. Here, we present preliminary results from a pilot study which tested whether sung instruction, as compared to spoken directives, could elicit greater number of socio-communicative behaviors in young children with ASD. Using an adapted single-subject design, three children between the ages of 3 and 4 years, participated in a programme consisting of 18 sessions, of which 9 were delivered with spoken directives and 9 with sung. Sessions were counterbalanced and randomized for three play activities-block matching, picture matching and clay play. All sessions were video-recorded for post-hoc observational coding of three behavioral metrics which included performance, frequency of social gesture and eye contact. Analysis of the videos by two independent raters indicated increased socio-communicative responsiveness in terms of frequency of social gesture as well as eye contact during sung compared to spoken conditions, across all participants. Our findings suggest that sung directives may play a useful role in engaging children with ASD and also serve as an effective interventional medium to enhance socio-communicative responsiveness.
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14. Rosenblau G, Kliemann D, Lemme B, Walter H, Heekeren HR, Dziobek I. {{The role of the amygdala in naturalistic mentalising in typical development and in autism spectrum disorder}}. {Br J Psychiatry};2015 (Nov 19)
BackgroundThe substantial discrepancy between mentalising in experimental settings v. real-life social interactions hinders the understanding of the neural basis of real-life social cognition and of social impairments in psychiatric disorders.AimsTo determine the neural mechanisms underlying naturalistic mentalising in individuals with and without autism spectrum disorder.MethodWe investigated mentalising with a new video-based functional magnetic resonance imaging task in 20 individuals with autism spectrum disorder and 22 matched healthy controls.ResultsNaturalistic mentalising implicated regions of the traditional mentalising network (medial prefrontal cortex, temporoparietal junction), and additionally the insula and amygdala. Moreover, amygdala activity predicted implicit mentalising performance on an independent behavioural task. Compared with controls, the autism spectrum disorder group did not show differences in neural activity within classical mentalising regions. They did, however, show reduced amygdala activity and a reduced correlation between amygdala activity and mentalising accuracy on the behavioural task, compared with controls.ConclusionsThese findings highlight the crucial role of the amygdala in making accurate implicit mental state inferences in typical development and in the social cognitive impairments of individuals with autism spectrum disorder.
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15. Scott M, Falkmer M, Girdler S, Falkmer T. {{Correction: Viewpoints on Factors for Successful Employment for Adults with Autism Spectrum Disorder}}. {PLoS One};2015;10(11):e0143674.
[This corrects the article DOI: 10.1371/journal.pone.0139281.].
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16. Shang L, Henderson LB, Cho MT, Petrey DS, Fong CT, Haude KM, Shur N, Lundberg J, Hauser N, Carmichael J, Innis J, Schuette J, Wu YW, Asaikar S, Pearson M, Folk L, Retterer K, Monaghan KG, Chung WK. {{De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism}}. {Neurogenetics};2015 (Nov 17)
Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3beta)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.
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17. Watkins L, Kuhn M, Ledbetter-Cho K, Gevarter C, O’Reilly M. {{Evidence-Based Social Communication Interventions for Children with Autism Spectrum Disorder}}. {Indian J Pediatr};2015 (Nov 19)
Impairments in social communication skills are a core feature of autism spectrum disorder (ASD) and include deficits in social-emotional reciprocity, non-verbal communicative behaviors used for social interaction, and developing, maintaining, and understanding relationships. In order to improve outcomes for children with ASD, much research has been focused on developing effective interventions to treat these social communication deficits. The purpose of this paper is to highlight the evidence-based practices found within the intervention literature that specifically targets social communication impairments and provide an overview of these strategies. Four relevant themes regarding evidence-based social communication interventions are considered and discussed: (a) social communication outcomes and practices relevant to different stages of development, (b) practices that both reduce interfering behaviors and improve social communication skills
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18. Zander E, Willfors C, Berggren S, Choque-Olsson N, Coco C, Elmund A, Moretti AH, Holm A, Jifalt I, Kosieradzki R, Linder J, Nordin V, Olafsdottir K, Poltrago L, Bolte S. {{The objectivity of the Autism Diagnostic Observation Schedule (ADOS) in naturalistic clinical settings}}. {Eur Child Adolesc Psychiatry};2015 (Nov 19)
The Autism Diagnostic Observation Schedule (ADOS) is a first-choice diagnostic tool in autism spectrum disorder (ASD). Excellent interpersonal objectivity (interrater reliability) has been demonstrated for the ADOS under optimal conditions, i.e., within groups of highly trained « research reliable » examiners in research setting. We investigated the spontaneous interrater reliability among clinically trained ADOS users across multiple sites in clinical routine. Forty videotaped administrations of the ADOS modules 1-4 were rated by five different raters each from a pool of in total 15 raters affiliated to 13 different clinical sites. G(q,k) coefficients (analogous to intraclass correlations), kappas (k) and percent agreement (PA) were calculated. The median interrater reliability for items across the four modules was G(q,k) = .74-.83, with the single ADOS items ranging from .23 to .94. G(q,k) for total scores was .85-.92. For diagnostic classification (ASD/non-spectrum), PA was 64-82 % and Fleiss’ k .19-.55. Objectivity was lower for pervasive developmental disorder not otherwise specified and non-spectrum diagnoses as compared to autism. Interrater reliabilities of the ADOS items and domain totals among clinical users across multiple sites were in the same range as previously reported for research reliable users, while the one for diagnostic classification was lower. Differences in sample characteristics, rater skills and statistics compared with previous studies are discussed. Findings endorse the objectivity of the ADOS in naturalistic clinical settings, but also pinpoint its limitations and the need and value of adequate and continuous rater training.
