Bennett L. Leventhal

The Autism Diagnostic Observation Schedule-Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism

The Autism Diagnostic Observation Schedule—Generic (ADOS-G) is a semistructured, standardized assessment of social interaction, communication, play, and imaginative use of materials for individuals suspected of having autism spectrum disorders. The observational schedule consists of four 30-minute modules, each designed to be administered to different individuals according to their level of expressive language. Psychometric data are presented for 223 children and adults with Autistic Disorder (autism), Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) or nonspectrum diagnoses. Within each module, diagnostic groups were equivalent on expressive language level. Results indicate substantial interrater and test—retest reliability for individual items, excellent interrater reliability within domains and excellent internal consistency. Comparisons of means indicated consistent differentiation of autism and PDDNOS from nonspectrum individuals, with some, but less consistent, differentiation of autism from PDDNOS. A priori operationalization of DSM-IV/ICD-10 criteria, factor analyses, and ROC curves were used to generate diagnostic algorithms with thresholds set for autism and broader autism spectrum/PDD. Algorithm sensitivities and specificities for autism and PDDNOS relative to nonspectrum disorders were excellent, with moderate differentiation of autism from PDDNOS.

Prevalence of Autism Spectrum Disorders in a Total Population Sample

OBJECTIVE Experts disagree about the causes and significance of the recent increases in the prevalence of autism spectrum disorders (ASDs). Limited data on population base rates contribute to this uncertainty. Using a population-based sample, the authors sought to estimate the prevalence and describe the clinical characteristics of ASDs in school-age children. METHOD The target population was all 7- to 12-year-old children (N=55,266) in a South Korean community; the study used a high-probability group from special education schools and a disability registry and a low-probability, general-population sample from regular schools. To identify cases, the authors used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of children who screened positive were offered comprehensive assessments using standardized diagnostic procedures. RESULTS The prevalence of ASDs was estimated to be 2.64% (95% CI=1.91-3.37), with 1.89% (95% CI=1.43-2.36) in the general-population sample and 0.75% (95% CI=0.58-0.93) in the high-probability group. ASD characteristics differed between the two groups: the male-to-female ratios were 2.5:1 and 5.1:1 in the general population sample and high-probability group, respectively, and the ratios of autistic disorders to other ASD subtypes were 1:2.6 and 2.6:1, respectively; 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group. CONCLUSIONS Two-thirds of ASD cases in the overall sample were in the mainstream school population, undiagnosed and untreated. These findings suggest that rigorous screening and comprehensive population coverage are necessary to produce more accurate ASD prevalence estimates and underscore the need for better detection, assessment, and services.

A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p

Autism is characterized by impairments in reciprocal communication and social interaction and by repetitive and stereotyped patterns of activities and interests. Evidence for a strong underlying genetic predisposition comes from twin and family studies, although susceptibility genes have not yet been identified. A whole-genome screen for linkage, using 83 sib pairs with autism, has been completed, and 119 markers have been genotyped in 13 candidate regions in a further 69 sib pairs. The addition of new families and markers provides further support for previous reports of linkages on chromosomes 7q and 16p. Two new regions of linkage have also been identified on chromosomes 2q and 17q. The most significant finding was a multipoint maximum LOD score (MLS) of 3.74 at marker D2S2188 on chromosome 2; this MLS increased to 4.80 when only sib pairs fulfilling strict diagnostic criteria were included. The susceptibility region on chromosome 7 was the next most significant, generating a multipoint MLS of 3.20 at marker D7S477. Chromosome 16 generated a multipoint MLS of 2.93 at D16S3102, whereas chromosome 17 generated a multipoint MLS of 2.34 at HTTINT2. With the addition of new families, there was no increased allele sharing at a number of other loci originally showing some evidence of linkage. These results support the continuing collection of multiplex sib-pair families to identify autism-susceptibility genes.

Evidence of linkage between the serotonin transporter and autistic disorder

The serotonin transporter gene (HTT) is a primary candidate in autistic disorder based on efficacy of potent serotonin transporter inhibitors in reducing rituals and routines. We initiated a candidate gene study of HTT in trios consisting of probands with autistic disorder and both parents. Preliminary transmission/disequilibrium test (TDT) analysis with 86 families revealed no evidence for linkage or linkage disequilibrium between autistic disorder and a polymorphism in the second intron of HTT. However, preferential transmission of a short variant of the HTT promoter was found in the same 86 trios (TDT χ2 = 4.69, 1 d.f., P = 0.030). In further analyses, we considered haplotypes of the HTT promoter variant and second intron locus as alleles in a multiallelic TDT. Results confirmed the significance of the effect of this region (TDT χ2 = 11.85, 4 d.f., P = 0.018). This provides preliminary evidence of linkage and association between HTT and autistic disorder.

The serotonin system in autism.

The serotonin system has been implicated as a factor in some cases of autism since the finding in 1961 of elevated serotonin (5-hydroxytryptamine) levels in the blood of patients with autism. This has been clarified as elevation in the platelet content of serotonin. Subjects with elevated whole blood serotonin levels have been shown to have elevated platelet serotonin transport into platelets and decreased serotonin 5-HT2 receptor binding. Most individuals with autism who are treated with potent serotonin transporter inhibitors have a reduction in ritualistic behavior and aggression. Reduction of central nervous system serotonin, induced by acute tryptophan depletion, causes a worsening of stereotyped behavior. Recent developments in the molecular biology of serotonin receptors are reviewed.

Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism.

The oxytocin receptor gene (OXTR) has been studied in autism because of the role of oxytocin (OT) in social cognition. Linkage has also been demonstrated to the region of OXTR in a large sample. Two single nucleotide polymorphisms (SNPs) and a haplotype constructed from them in OXTR have been associated with autism in the Chinese Han population. We tested whether these associations replicated in a Caucasian sample with strictly defined autistic disorder. We genotyped the two previously associated SNPs (rs2254298, rs53576) in 57 Caucasian autism trios. Probands met clinical, ADI-R, and ADOS criteria for autistic disorder. Significant association was detected at rs2254298 (p=0.03) but not rs53576. For rs2254298, overtransmission of the G allele to probands with autistic disorder was found which contrasts with the overtransmission of A previously reported in the Chinese Han sample. In both samples, G was more frequent than A. However, in our Caucasian autism trios and the CEU Caucasian HapMap samples the frequency of A was less than that reported in the Chinese Han and Chinese in Bejing HapMap samples. The haplotype test of association did not reveal excess transmission from parents to affected offspring. These findings provide support for association of OXTR with autism in a Caucasian population. Overtransmission of different alleles in different populations may be due to a different pattern of linkage disequilibrium between the marker rs2254298 and an as yet undetermined susceptibility variant in OXTR.

Linkage-Disequilibrium Mapping of Autistic Disorder, with 15q11-13 Markers

Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.

Maternal Smoking During Pregnancy and Severe Antisocial Behavior in Offspring: A Review

OBJECTIVES Recent research suggests that in utero exposure to maternal smoking is a risk factor for conduct disorder and delinquency. We review evidence of causality, a controversial but important public health question. METHODS We analyzed studies of maternal prenatal smoking and offspring antisocial behavior within a causal framework. RESULTS The association is (1) independent of confounders, (2) present across diverse contexts, and (3) consistent with basic science. Methodological limitations of existing studies preclude causal conclusions. CONCLUSIONS Existing evidence provides consistent support for, but not proof of, an etiologic role for prenatal smoking in the onset of antisocial behavior. The possibility of identifying a preventable prenatal risk factor for a serious mental disorder makes further research on this topic important for public health.

School Bullying and Suicidal Risk in Korean Middle School Students

Objective. Being a victim or a perpetrator of school bullying, the most common type of school violence, has been frequently associated with a broad spectrum of behavioral, emotional, and social problems. In a Korean middle school community sample, this study specifically investigated the prevalence of suicidal ideations and behaviors in victims, perpetrators, and victim-perpetrators of school bullying and compared them with a group of students who were in the same schools and were not involved with bullying. Methods. In a cross-sectional study, 1718 seventh- and eighth-grade students in 2 middle schools participated in the study in October 2000. Students completed demographic information, Korean Peer Nomination Inventory, and Korean Youth Self-Report. Results. Compared with the students who were not involved with school bullying, victim-perpetrators reported more suicidal/self-injurious behaviors and suicidal ideation in the previous 6 months (odds ratio [OR]: 1.9 and 1.9, respectively). In female students, all 3 school bullying groups had increased suicidal ideation for the previous 2 weeks (OR: 2.8, 2.0, and 2.8, respectively) but not in male students (OR: 0.9, 1.1, and 1.3, respectively). Conclusions. Students who were involved in school bullying, especially victim-perpetrators and female students, had significantly higher risks for suicide ideation and suicidal behavior when compared with individuals who were not involved in school bullying. In addition to attempting to decrease bullying in a community, students who are involved in school bullying should be the targets for suicide monitoring and prevention programs.

Bullying and suicide: A review

Being a victim or perpetrator of school bullying, the most common type of school violence, has been frequently associated with a broad spectrum of behavioral, emotional, and social problems. Suicide is third leading cause of mortality in children and adolescent in the United States of America and around the world. This paper provides a systematic review of the previous 37 studies conducted in children and adolescents from communities, as well as in special populations that examined the association between bullying experiences and suicide, with an emphasis on the strengths and limitations of the study designs. Despite methodological and other differences and limitations, it is increasingly clear that any participation in bullying increases the risk of suicidal ideations and/or behaviors in a broad spectrum of youth.