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1.  Frequency and Pattern of Documented Diagnostic Features and the Age of Autism Identification 
The DSM-IV-TR specifies 12 behavioral features that can occur in hundreds of possible combinations to meet diagnostic criteria for autism spectrum disorder (ASD). This paper describes the frequency and variability with which the 12 behavioral features are documented in a population-based cohort of 8-year-old children under surveillance for ASD, and examines whether documentation of certain features, alone or in combination with other features, is associated with earlier age of community identification of ASD.
Statistical analysis of behavioral features documented for a population-based sample of 2,757 children, 8 years old, with ASD in 11 geographically-defined areas in the US participating in the Autism and Developmental Disabilities Monitoring Network in 2006.
The median age at ASD identification was inversely associated with the number of documented behavioral features, decreasing from 8.2 years for children with only seven behavioral features to 3.8 years for children with all 12. Documented impairments in nonverbal communication, pretend play, inflexible routines, and repetitive motor behaviors were associated with earlier identification, whereas impairments in peer relations, conversational ability, and idiosyncratic speech were associated with later identification.
The age dependence of some of the behavioral features leading to an autism diagnosis, as well as the inverse association between age at identification and number of behavioral features documented, have implications for efforts to improve early identification. Progress in achieving early identification and provision of services for children with autism may be limited for those with fewer ASD behavioral features, as well as features likely to be detected at later ages.
PMCID: PMC4051284  PMID: 23582871
autism; autism spectrum disorder; identification; diagnosis; population-based
2.  Evaluation of An Activities of Daily Living Scale for Adolescents and Adults with Developmental Disabilities 
Activity limitations are an important and useful dimension of disability, but there are few validated measures of activity limitations for adolescents and adults with developmental disabilities.
To describe the development of the Waisman Activities of Daily Living (W-ADL) Scale for adolescents and adults with developmental disabilities, and systematically evaluate its measurement properties according to an established set of criteria.
The W-ADL was administered among four longitudinally-studied groups of adolescents and adults with developmental disabilities: 406 with autism; 147 with fragile-X syndrome; 169 with Down syndrome, and 292 with intellectual disability of other or unknown origin. The W-ADL contains 17 activities and each is rated on a 3-point scale (0=“does not do at all”, 1=“does with help”, 2=“independent”), and a standard set of criteria were used to evaluate its measurement properties.
Across the disability groups, Cronbach’s alphas ranged from 0.88 to 0.94, and a single-factor structure was most parsimonious. The W-ADL was reliable over time, with weighted kappas between 0.92 and 0.93. Criterion and construct validity were supported through substantial associations with the Vineland Screener, need for respite services, caregiving burden, and competitive employment. No floor or ceiling effects were present. There were significant group differences in W-ADL scores by maternally-reported level of intellectual disability (mild, moderate, severe, profound).
The W-ADL exceeded the recommended threshold for each quality criterion the authors evaluated. This freely-available tool is an efficient measure of activities of daily living for surveys and epidemiological research concerning adolescents and adults with developmental disabilities.
PMCID: PMC3531884  PMID: 23260606
Activities of Daily Living; Adolescent; Adult; Autistic Disorder; Developmental Disabilities; Down Syndrome; Fragile X Syndrome; Intellectual Disability
3.  Developmental Trajectories in Adolescents and Adults with Autism: The Case of Daily Living Skills 
This study aimed to investigate the longitudinal course of daily living skills in a large, community-based sample of adolescents and adults with autism spectrum disorders (ASD) over a 10-year period.
Adolescents and adults with ASD (n=397) were drawn from an ongoing, longitudinal study of individuals with ASD and their families. A comparison group of 167 individuals with Down syndrome (DS) were drawn from a linked longitudinal study. The Waisman Activities of Daily Living Scale was administered 4 times over a 10-year period.
We utilized latent growth curve modeling to examine change in daily living skills. Daily living skills improved for the individuals with ASD during adolescence and their early 20s, but plateaued during their late 20s. Having an intellectual disability was associated with lower initial levels of daily living skills and a slower change over time. Individuals with DS likewise gained daily living skills over time, but there was no significant curvature in the change.
Future research should explore what environmental factors and interventions may be associated with continued gains of daily living skills for adults with ASD.
PMCID: PMC3361701  PMID: 22632621
daily living skills; autism; adolescence; adulthood; trajectories
4.  Variability in the Labeling of Asthma among Pediatricians 
PLoS ONE  2013;8(4):e62398.
Few studies have examined variability among physicians in the perception and interpretation of asthma symptoms. We report the results of a pilot study to investigate the variability of symptom description and diagnostic labeling and nomenclature among a group of clinicians using standardized audiovisual presentations of asthma.
Practicing pediatricians in Wisconsin recruited from an electronic mailing list were shown the International Study of Asthma and Allergies in Childhood (ISAAC) video questionnaire online, and asked to describe the symptoms and signs they observed and suggest possible diagnostic labels for each presentation.
A total of 113 pediatricians (mean age = 43 years; 56% female) responded to ≥1 of the 5 video scenes. The number of practitioners who described the principal symptom(s) of asthma depicted in the 5 sequences ranged from 5.5% for Scene 5 (featuring both dyspnea and wheeze), to 100% for Scene 4 (featuring cough). The number who suggested label of ‘asthma’ as a possible cause of the presentations ranged from 69.7% for Scene 3 (featuring nocturnal wheeze), to 92.7% for Scene 2 (featuring exercise induced wheeze).
There is important unexplained variation in the perceptions and labeling of asthma symptoms among pediatricians. These differences may influence the likelihood of diagnosis and the apparent prevalence of asthma. Many participants suggested that the ISAAC video be used in the education and training of pediatricians.
PMCID: PMC3634749  PMID: 23638066
5.  Services for Adults With an Autism Spectrum Disorder 
The need for useful evidence about services is increasing as larger numbers of children identified with an autism spectrum disorder (ASD) age toward adulthood. The objective of this review was to characterize the topical and methodological aspects of research on services for supporting success in work, education, and social participation among adults with an ASD and to propose recommendations for moving this area of research forward. We reviewed the literature published in English from 2000 to 2010 and found that the evidence base about services for adults with an ASD is underdeveloped and can be considered a field of inquiry that is relatively unformed. Extant research does not reflect the demographic or impairment heterogeneity of the population, the range of services that adults with autism require to function with purposeful lives in the community, and the need for coordination across service systems and sectors. Future studies must examine issues related to cost and efficiency, given the broader sociopolitical and economic context of service provision. Further, future research needs to consider how demographic and impairment heterogeneity have implications for building an evidence base that will have greater external validity.
PMCID: PMC3538849  PMID: 22546060
autism; adulthood; services; review
7.  Maternal Smoking during Pregnancy and the Prevalence of Autism Spectrum Disorders, Using Data from the Autism and Developmental Disabilities Monitoring Network 
Environmental Health Perspectives  2012;120(7):1042-1048.
Background: Reported associations between gestational tobacco exposure and autism spectrum disorders (ASDs) have been inconsistent.
Objective: We estimated the association between maternal smoking during pregnancy and ASDs among children 8 years of age.
Methods: This population-based case–cohort study included 633,989 children, identified using publicly available birth certificate data, born in 1992, 1994, 1996, and 1998 from parts of 11 U.S. states subsequently under ASD surveillance. Of these children, 3,315 were identified as having an ASD by the active, records-based surveillance of the Autism and Developmental Disabilities Monitoring Network. We estimated prevalence ratios (PRs) of maternal smoking from birth certificate report and ASDs using logistic regression, adjusting for maternal education, race/ethnicity, marital status, and maternal age; separately examining higher- and lower-functioning case subgroups; and correcting for assumed under-ascertainment of autism by level of maternal education.
Results: About 13% of the source population and 11% of children with an ASD had a report of maternal smoking in pregnancy: adjusted PR (95% confidence interval) of 0.90 (0.80, 1.01). The association for the case subgroup autistic disorder (1,310 cases) was similar: 0.88 (0.72, 1.08), whereas that for ASD not otherwise specified (ASD-NOS) (375 cases) was positive, albeit including the null: 1.26 (0.91, 1.75). Unadjusted associations corrected for assumed under-ascertainment were 1.06 (0.98, 1.14) for all ASDs, 1.12 (0.97, 1.30) for autistic disorder, and 1.63 (1.30, 2.04) for ASD-NOS.
Conclusions: After accounting for the potential of under-ascertainment bias, we found a null association between maternal smoking in pregnancy and ASDs, generally. The possibility of an association with a higher-functioning ASD subgroup was suggested, and warrants further study.
PMCID: PMC3404663  PMID: 22534110
autism; epidemiology; intellectual disability; surveillance; tobacco
8.  Analysis of human mini-exome sequencing data from Genetic Analysis Workshop 17 using a Bayesian hierarchical mixture model 
BMC Proceedings  2011;5(Suppl 9):S93.
Next-generation sequencing technologies are rapidly changing the field of genetic epidemiology and enabling exploration of the full allele frequency spectrum underlying complex diseases. Although sequencing technologies have shifted our focus toward rare genetic variants, statistical methods traditionally used in genetic association studies are inadequate for estimating effects of low minor allele frequency variants. Four our study we use the Genetic Analysis Workshop 17 data from 697 unrelated individuals (genotypes for 24,487 autosomal variants from 3,205 genes). We apply a Bayesian hierarchical mixture model to identify genes associated with a simulated binary phenotype using a transformed genotype design matrix weighted by allele frequencies. A Metropolis Hasting algorithm is used to jointly sample each indicator variable and additive genetic effect pair from its conditional posterior distribution, and remaining parameters are sampled by Gibbs sampling. This method identified 58 genes with a posterior probability greater than 0.8 for being associated with the phenotype. One of these 58 genes, PIK3C2B was correctly identified as being associated with affected status based on the simulation process. This project demonstrates the utility of Bayesian hierarchical mixture models using a transformed genotype matrix to detect genes containing rare and common variants associated with a binary phenotype.
PMCID: PMC3287935  PMID: 22373180
9.  Evidence-based medicine training during residency: a randomized controlled trial of efficacy 
BMC Medical Education  2010;10:59.
Evidence-based medicine (EBM) has been widely integrated into residency curricula, although results of randomized controlled trials and long term outcomes of EBM educational interventions are lacking. We sought to determine if an EBM workshop improved internal medicine residents' EBM knowledge and skills and use of secondary evidence resources.
This randomized controlled trial included 48 internal medicine residents at an academic medical center. Twenty-three residents were randomized to attend a 4-hour interactive workshop in their PGY-2 year. All residents completed a 25-item EBM knowledge and skills test and a self-reported survey of literature searching and resource usage in their PGY-1, PGY-2, and PGY-3 years.
There was no difference in mean EBM test scores between the workshop and control groups at PGY-2 or PGY-3. However, mean EBM test scores significantly increased over time for both groups in PGY-2 and PGY-3. Literature searches, and resource usage also increased significantly in both groups after the PGY-1 year.
We were unable to detect a difference in EBM knowledge between residents who did and did not participate in our workshop. Significant improvement over time in EBM scores, however, suggests EBM skills were learned during residency. Future rigorous studies should determine the best methods for improving residents' EBM skills as well as their ability to apply evidence during clinical practice.
PMCID: PMC2940785  PMID: 20807453
10.  Detecting Gene-Environment Interactions in Genome-Wide Association Data 
Genetic epidemiology  2009;33(Suppl 1):S68-S73.
Despite the importance of gene-environment (G×E) interactions in the etiology of common diseases, little work has been done to develop methods for detecting these types of interactions in genome-wide association study data. This was the focus of Genetic Analysis Workshop 16 Group 10 contributions, which introduced a variety of new methods for the detection of G×E interactions in both case-control and family-based data using both cross-sectional and longitudinal study designs. Many of these contributions detected significant G×E interactions. Although these interactions have not yet been confirmed, the results suggest the importance of testing for interactions. Issues of sample size, quantifying the environmental exposure, longitudinal data analysis, family-based analysis, selection of the most powerful analysis method, population stratification, and computational expense with respect to testing G×E interactions are discussed.
PMCID: PMC2924567  PMID: 19924704
GAW; case-control; family-based; cross-sectional; longitudinal; rheumatoid arthritis; Framingham Heart Study
11.  Socioeconomic Inequality in the Prevalence of Autism Spectrum Disorder: Evidence from a U.S. Cross-Sectional Study 
PLoS ONE  2010;5(7):e11551.
This study was designed to evaluate the hypothesis that the prevalence of autism spectrum disorder (ASD) among children in the United States is positively associated with socioeconomic status (SES).
A cross-sectional study was implemented with data from the Autism and Developmental Disabilities Monitoring Network, a multiple source surveillance system that incorporates data from educational and health care sources to determine the number of 8-year-old children with ASD among defined populations. For the years 2002 and 2004, there were 3,680 children with ASD among a population of 557 689 8-year-old children. Area-level census SES indicators were used to compute ASD prevalence by SES tertiles of the population.
Prevalence increased with increasing SES in a dose-response manner, with prevalence ratios relative to medium SES of 0.70 (95% confidence interval [CI] 0.64, 0.76) for low SES, and of 1.25 (95% CI 1.16, 1.35) for high SES, (P<0.001). Significant SES gradients were observed for children with and without a pre-existing ASD diagnosis, and in analyses stratified by gender, race/ethnicity, and surveillance data source. The SES gradient was significantly stronger in children with a pre-existing diagnosis than in those meeting criteria for ASD but with no previous record of an ASD diagnosis (p<0.001), and was not present in children with co-occurring ASD and intellectual disability.
The stronger SES gradient in ASD prevalence in children with versus without a pre-existing ASD diagnosis points to potential ascertainment or diagnostic bias and to the possibility of SES disparity in access to services for children with autism. Further research is needed to confirm and understand the sources of this disparity so that policy implications can be drawn. Consideration should also be given to the possibility that there may be causal mechanisms or confounding factors associated with both high SES and vulnerability to ASD.
PMCID: PMC2902521  PMID: 20634960
12.  Detecting gene-by-smoking interactions in a genome-wide association study of early-onset coronary heart disease using random forests 
BMC Proceedings  2009;3(Suppl 7):S88.
Genome-wide association studies are often limited in their ability to attain their full potential due to the sheer volume of information created. We sought to use the random forest algorithm to identify single-nucleotide polymorphisms (SNPs) that may be involved in gene-by-smoking interactions related to the early-onset of coronary heart disease.
Using data from the Framingham Heart Study, our analysis used a case-only design in which the outcome of interest was age of onset of early coronary heart disease.
Smoking status was dichotomized as ever versus never. The single SNP with the highest importance score assigned by random forests was rs2011345. This SNP was not associated with age alone in the control subjects. Using generalized estimating equations to adjust for sex and account for familial correlation, there was evidence of an interaction between rs2011345 and smoking status.
The results of this analysis suggest that random forests may be a useful tool for identifying SNPs taking part in gene-by-environment interactions in genome-wide association studies.
PMCID: PMC2795991  PMID: 20018084
13.  Classification tree for detection of single-nucleotide polymorphism (SNP)-by-SNP interactions related to heart disease: Framingham Heart Study 
BMC Proceedings  2009;3(Suppl 7):S83.
The aim of this study was to detect the effect of interactions between single-nucleotide polymorphisms (SNPs) on incidence of heart diseases. For this purpose, 2912 subjects with 350,160 SNPs from the Framingham Heart Study (FHS) were analyzed. PLINK was used to control quality and to select the 10,000 most significant SNPs. A classification tree algorithm, Generalized, Unbiased, Interaction Detection and Estimation (GUIDE), was employed to build a classification tree to detect SNP-by-SNP interactions for the selected 10 k SNPs. The classes generated by GUIDE were reexamined by a generalized estimating equations (GEE) model with the empirical variance after accounting for potential familial correlation. Overall, 17 classes were generated based on the splitting criteria in GUIDE. The prevalence of coronary heart disease (CHD) in class 16 (determined by SNPs rs1894035, rs7955732, rs2212596, and rs1417507) was the lowest (0.23%). Compared to class 16, all other classes except for class 288 (prevalence of 1.2%) had a significantly greater risk when analyzed using GEE model. This suggests the interactions of SNPs on these node paths are significant.
PMCID: PMC2795986  PMID: 20018079
14.  Advanced Parental Age and the Risk of Autism Spectrum Disorder 
American Journal of Epidemiology  2008;168(11):1268-1276.
This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age ≥35 vs. 25–29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age ≥40 years vs. 25–29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20–34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.
PMCID: PMC2638544  PMID: 18945690
autistic disorder; birth order; maternal age; paternal age

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