Although autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) continue to rise in prevalence, together affecting >10% of today’s pediatric population, the methods of diagnosis remain subjective, cumbersome and time intensive. With gaps upward of a year between initial suspicion and diagnosis, valuable time where treatments and behavioral interventions could be applied is lost as these disorders remain undetected. Methods to quickly and accurately assess risk for these, and other, developmental disorders are necessary to streamline the process of diagnosis and provide families access to much-needed therapies sooner. Using forward feature selection, as well as undersampling and 10-fold cross-validation, we trained and tested six machine learning models on complete 65-item Social Responsiveness Scale score sheets from 2925 individuals with either ASD (n=2775) or ADHD (n=150). We found that five of the 65 behaviors measured by this screening tool were sufficient to distinguish ASD from ADHD with high accuracy (area under the curve=0.965). These results support the hypotheses that (1) machine learning can be used to discern between autism and ADHD with high accuracy and (2) this distinction can be made using a small number of commonly measured behaviors. Our findings show promise for use as an electronically administered, caregiver-directed resource for preliminary risk evaluation and/or pre-clinical screening and triage that could help to speed the diagnosis of these disorders.

The Autism Diagnostic Observation Schedule-Generic (ADOS) is one of the most widely used instruments for behavioral evaluation of autism spectrum disorders. It is composed of four modules, each tailored for a specific group of individuals based on their language and developmental level. On average, a module takes between 30 and 60 min to deliver. We used a series of machine-learning algorithms to study the complete set of scores from Module 1 of the ADOS available at the Autism Genetic Resource Exchange (AGRE) for 612 individuals with a classification of autism and 15 non-spectrum individuals from both AGRE and the Boston Autism Consortium (AC). Our analysis indicated that 8 of the 29 items contained in Module 1 of the ADOS were sufficient to classify autism with 100% accuracy. We further validated the accuracy of this eight-item classifier against complete sets of scores from two independent sources, a collection of 110 individuals with autism from AC and a collection of 336 individuals with autism from the Simons Foundation. In both cases, our classifier performed with nearly 100% sensitivity, correctly classifying all but two of the individuals from these two resources with a diagnosis of autism, and with 94% specificity on a collection of observed and simulated non-spectrum controls. The classifier contained several elements found in the ADOS algorithm, demonstrating high test validity, and also resulted in a quantitative score that measures classification confidence and extremeness of the phenotype. With incidence rates rising, the ability to classify autism effectively and quickly requires careful design of assessment and diagnostic tools. Given the brevity, accuracy and quantitative nature of the classifier, results from this study may prove valuable in the development of mobile tools for preliminary evaluation and clinical prioritization—in particular those focused on assessment of short home videos of children—that speed the pace of initial evaluation and broaden the reach to a significantly larger percentage of the population at risk.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut–brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.

Although the prevalence of autism spectrum disorder (ASD) has risen sharply in the last few years reaching 1 in 68, the average age of diagnosis in the United States remains close to 4—well past the developmental window when early intervention has the largest gains. This emphasizes the importance of developing accurate methods to detect risk faster than the current standards of care. In the present study, we used machine learning to evaluate one of the best and most widely used instruments for clinical assessment of ASD, the Autism Diagnostic Observation Schedule (ADOS) to test whether only a subset of behaviors can differentiate between children on and off the autism spectrum. ADOS relies on behavioral observation in a clinical setting and consists of four modules, with module 2 reserved for individuals with some vocabulary and module 3 for higher levels of cognitive functioning. We ran eight machine learning algorithms using stepwise backward feature selection on score sheets from modules 2 and 3 from 4540 individuals. We found that 9 of the 28 behaviors captured by items from module 2, and 12 of the 28 behaviors captured by module 3 are sufficient to detect ASD risk with 98.27% and 97.66% accuracy, respectively. A greater than 55% reduction in the number of behaviorals with negligible loss of accuracy across both modules suggests a role for computational and statistical methods to streamline ASD risk detection and screening. These results may help enable development of mobile and parent-directed methods for preliminary risk evaluation and/or clinical triage that reach a larger percentage of the population and help to lower the average age of detection and diagnosis.

Summary: We developed an algorithm that improves upon the common procedure of taking reciprocal best blast hits (rbh) in the identification of orthologs. The method—reciprocal smallest distance algorithm (rsd)—relies on global sequence alignment and maximum likelihood estimation of evolutionary distances to detect orthologs between two genomes. rsd finds many putative orthologs missed by rbh because it is less likely than rbh to be misled by the presence of a close paralog. Availability: A Python program and ReadMe file are freely available from: http://charles.stanford.edu/~dennis/research.html