Ami Klin, Ph.D. - US grants

family genetics; mental disorder diagnosis; autism; biomedical facility; neurobiology; neuropsychological tests;

The overarching goal of this project is to study social engagement in infants with autism spectrum disorders (ASD) by means of eye-tracking technology and innovative quantification of visual attention during viewing of naturalistic social situations. We will measure (1) visual fixation time during viewing of adults engaged in infant-directed approaches, and (2) temporally-sensitive visual scanning patterns during viewing of infants engaged in peer play. A cohort of 200 12- to 24-month-old infants will be shared with Projects 2 and 3, consisting of infants with ASD (N=70), non-autistic developmental delays (DD) (N=70) and typical development (TD) (N=60). The ASD and DD cohorts will be re-evaluated at age 36 to 48 months for confirmatory diagnosis and measures of developmental outcome;the TD group will be screened for false negatives at that time. This work builds on our findings of anomalous visual fixation patterns to dynamic social stimuli in adolescents (R01 HD04217) and in 24- to 36-month-olds (U54 MH66494, Yale STAART) with ASD. In both cases, summaries of visual fixation on regions of interest (eyes, mouth, body, object) were strong predictors of concurrent, standardized measures of social disability. In this project, we propose to downward extend this research to the second year of life, which is currently the period of earliest detectability of ASD. We also propose to employ novel group measures of moment-by-moment visual scanning behavior developed by our group, which are particularly sensitive to time-delimited social and physical cues occurring naturallly in infants'surrounding environment. The project builds thematically and methodologically on various core goals of the Yale ACE application: (1) the study of early-emerging mechanisms of socialization that are potential mediating phenotypes of social and communicative functioning;(2) the assessment of their predictive power relative to developmental and diagnostic outcome;and (3) the development of performance-based screening protocols for infants at risk for ASD. More broadly, we will explore the role of these mechanisms on heterogeneity of syndrome manifestation. This project addresses several key action items of the NIH Interagency Autism Coordinating Committee, emphasizing developmental markers and screening in infants, and neurodevelopmental processes.

[unreadable] DESCRIPTION (provided by applicant): This R01 focuses on the hypothesis that spontaneous visual fixation and visual scanning patterns are predictors of level of social competence in individuals with Autism Spectrum Disorders (ASD). This hypothesis originated from research using eye-tracking technology to measure visual fixation time while cognitively-able adolescents and adults with autism watched naturalistic social scenes. Time spent looking at mouth, body, and object regions was 2[unreadable] times greater in individuals with autism relative to age-, sex-, and verbal IQ-matched controls. Time spent looking at the eyes, however, was 2[unreadable] times less in individuals with autism. Fixation time on mouths and objects was a strong predictor of level of daily social adjustment and level of autistic social symptomatology, while fixation time on eyes showed little relation to these outcome measures of social competence. Increased fixation on mouths predicted more social competence, whereas increased fixation on objects predicted less. Work on visual scanning patterns seems to yield even greater differences between the individuals with autism and controls. We request 5 years of support to examine this hypothesis in the context of a wider spectrum of autism manifestations, age, and cognitive levels. We propose to complete eye-tracking procedures for 96 participants with ASD and 96 age- and verbal IQ-matched controls aged 5 to 12 years. In specific aim #1 we will study the relationship between visual fixation patterns and age, verbal IQ, and outcome measures of social competence, which include standardized measures of social impairment, social adjustment, and social cognition. In specific aim #2 we will examine the relationship between visual scanning patterns and the same outcome measures of social competence, as well as age and verbal IQ. Apart from providing a unique window into the ways in which individuals with autism search for meaning when confronted with social situations, our overarching goal is to develop the eye-tracking paradigm into a laboratory-based quantifier of social disability, which is an important need in current genetic research of the varying manifestations of autism. The proposed R01 works synergistically with other ongoing eye-tracking research including studies of toddlers at risk of having autism and studies of monkeys with mesiofrontal-limbic ablations.

Autism is a pervasive developmental disorder that is characterized by a severe set of social and communicative deficits. Autism is diagnosed behaviorally; there is no known blood test, genetic test, or functional imaging method that can diagnose autism. Existing diagnostic methods provide primarily qualitative descriptions of dysfunctional social skills. Given the need to capitalize on early brain plasticity and thus maximize the beneficial impacts of intervention, there is a great need for novel, sensitive and quantified performance-based measurements of social vulnerabilities in young children with autism.
The goal of this project is to enhance methods for diagnosing autism by providing technology that can produce quantitative, objective measurements of social response from both passive and interactive recognition techniques. Passive recognition systems characterize social responses without directly taking part in the social interaction (for example, from cameras and microphones in the walls and ceiling of a room). Interactive robots will engage in social presses with an individual in the interest of eliciting a social response that can be measured directly. Preliminary data shows that these interactive systems can provide measurements which are free of subjective bias, which can be tailored to the needs of an individual, and which generate interest and motivation in many children with autism.

PROJECT SUMMARY The Emory ACE Administrative Core is the repository of the administrative leadership?s track record and institutional resources, and of the structures and procedures to fulfill its objectives. It is justified on the basis of the challenges posed by complex research enterprises such this program project, which is at the intersection of clinical and translational science, and involves: 12 laboratories, bringing together six highly inter-connected research institutions; cross-species visual, audio and numerical data; novel and unique experimental technologies, methods and quantification approaches; and several infrastructure and core resources. Having the success of our current ACE as the starting point, this Core?s objectives are (1) To deploy Marcus Autism Center?s core principles in all stages of planning and execution of the Emory ACE; (2) To manage, oversee, lead and coordinate; to carry out the decision-making process, ensure productivity and quality control related to the Emory ACE projects and core resources; and to represent the Emory ACE and its community of scientists, administrators and staff to parent institutions, and local, regional, national and international organizations, including NIH; (3) To ensure effective communication among the Emory ACE community of scientists, administrators and staff through effective and efficient tools and structures, and through proven procedures; (4) To ensure compliance with IRB, IACUC, NDAR, and NIH requirements and directives in a timely, cost-effective, and successful manner; (5) To ensure compliance with NIH transparency, rigor & reproducibility guidelines and facilitate thoughtful considerations of, and solutions for, sex as a biological variable in our research despite sex ratio in ASD; (6) To organize, coordinate and report on the Emory ACE?s Advisory Committee?s activities and to implement its recommendations; (7) To manage, maintain and expand the physical and human resources available to, and generated by, the Emory ACE; and (8) To support dissemination/outreach efforts.

OVERVIEW OF PURPOSE, STAFFING, AND AIMS The overall purpose of the Yale ACE Assessment Core (AC) is to ensure that all projects have access to well-characterized patients, family members and control populations, from both a behavioral/phenotypic standpoint and from a medical/pediatric and genetics standpoint. By centralizing assessment procedures and ensuring consistency across projects, the efforts of this core also significantly contribute to the coherence of the Yale ACE and the mutually enriching synergy of the five component areas. In contrast to the assessment cores in the Yale CPEA and STAART, we address more extensively two critical issues inherent in complex research projects: (1) logistical and operational aspects of program implementation and (2) organizational, conceptual, and data management synergy within this program and collaboration with other scientific efforts within the Child Study Center and with those under the auspices of NIH networks of autism research. Our goal is to maximize scientific yield while responding to the critical need for centralized data bases through the National Database for Autism Research. The AC will be directed by Dr. Ami Klin, an experienced clinical researcher with expertise in behavioral characterization of individuals with autism spectrum disorders. The Core will be co-directed by Dr. Matthew State, a child psychiatrist and geneticist whose research focuses on gene discovery in developmental neuropsychiatric disorders. He will take responsibility for genetics lab work conducted within the scope of this. Dr. State is a longstanding collaborator of Drs. Klin, Volkmar, and Schultz. Other leading clinicians are Drs. Kasia Chawarska, Rhea Paul, and Celine Saulnier. Dr. Chawarska is an infancy specialist and seasoned clinical researcher who leads our clinics for infants and toddlers. Prior to completing her PhD, Dr. Chawarska had assessed many hundreds of infants in various research contexts (e.g., working with Dr. Linda Mayes at the Yale Child Study Center, Child Development Unit). For the past 6 years, Dr. Chawarska has led the evaluation of several hundred infants and toddlers with autism spectrum disorders (ASD) and other developmental disabilities. Dr. Rhea Paul is one of the leading speech-language pathologists in the country and a professor of Communication Disorders. Her experience in the field dates back to her work with Drs. Donald Cohen and Fred Volkmar in the early 1980's. She is the author of the main textbook in communication disorders and a contributor to the American Speech-Language-Hearing Association documents on best practice parameters in communication assessment of children with ASD. Dr. Saulnier is a neuropsychologist trained with Dr. Deborah Fein who was recruited through a NAAR mentorshipbased award (Dr. Klin, PI). She is now a leading clinician in our team and is a collaborator in research (e.g., Klin et al., In press;Saulnier &Klin, In press). All leading personnel in the AC work daily together in both clinical and research activities. The Core begins with several advantages: (1) the infrastructure for the AC, including clinical expertise, procedures, and management, has already been tested and proven in several past and ongoing program projects. Examples are: the Assessment Core for an NICHD-funded program project that ended in 2006 (Dr. Klin worked closely with Dr. Sara Sparrow, Core Director, for close to 15 years and, upon her retirement, replaced her as the Yale Child Study Center Chief of Psychology in 2002);the Assessment Core of the NICHD-funded program project that followed it (PO1 HD003008 38;Dr. Klin is Core Director, Dr. State is Core Co-Director);the Assessment Core of the NICHD-funded Collaborative Projects of Excellence in Autism (CPEA) (Dr. Klin was Co-Director of the Core, working closely with Dr. Catherine Lord, Core Director);and the Assessment Core of the NIMH-funded Yale STAART (Dr. Klin is Core Director, working closely with Drs. Paul and Chawarska, Core Associate Directors);(2) Dr. Klin, as reflected in longstanding collaborations with Drs. Volkmar, Sparrow, and Lord, has a longstanding interest in diagnostic issues, instrumentation and procedures, including development of new methods, training and education, and clinical assessment;(3) Drs. Klin, Paul, and Chawarska share a longstanding interest in assessment of infants and toddlers, have published novel research and didactic chapters pertaining to behavioral and experimental characterization of infants and toddlers with autism, and have evaluated several hundred children in this age bracket);and (4) The proposed functional expansion and refinement of the AC related to our information technology infrastructure has already been implemented in the context of one complex research program (a multivisit prospective study of siblings of children with autism from birth in PO1 HD003008 38). We prioritized that study because of its demanding and complex logistical challenges (primarily because of the multiple-visit nature of subject and family longitudinal participation in research and the need to minimize attrition and the loss of data points). Given that 4 of the 5 projects in this application involve infants in the second year of life, the similarities in measures and data formatting will allow for a quick expansion of the IT system to encompass most of the Yale ACE. The remaining project (Project IV) will follow. Its implementation will be relatively straightforward since subjects are already in the system (this is a cohort that has been followed-up since the age of 2 years) and the characterization protocol duplicates diagnostic and developmental measures used in other projects focused on school-aged children. We emphasize that this is not simply a proof of concept. Instead, this is a sophisticated information technology structure developed through the intimate collaboration with Prometheus Research for the past 1 Vz years. These various resources and connections are a reflection of the constant, intensive, and multifaceted web of collaborations bringing together the various leading investigators in the Yale ACE.

DESCRIPTION (provided by applicant): This application for an Autism Center of Excellence requests five years of support for an interdisciplinary program of research on behavioral, brain and molecular aspects of the autism spectrum disorders (ASD). It builds on longstanding programmatic research focused on early mechanisms of socialization and their disruption in ASD, on their neurodevelopmental implications for brain structure and function, and on genetic and cytogenetic etiologies associated with social disorders. This application consists of 5 projects and 3 cores. Projects I, II, and III focus on the same cohort of 12- to 24-month-old infants with ASD and their outcome at 36- to 48-months of age. Their objectives include quantification of visual scanning behavior in the context of naturalistic social situations, gaze processing, and auditory preferences associated with the acquisition of language and communicative skills. A byproduct of these studies is the development of performance-based screeners for ASD in the second year of life. Project 4 uses MRI to study indices of structural and functional connectivity in a cohort of 10-year-olds who have been followed-up longitudinally since the age of 24 months through our CPEA and STAART grants. Project 5 focuses on the identification of rare genetic variants contributing to ASDs as a means of discovering molecular pathways involved in these disorders. It leverages the exceedingly well characterized cohort of infants recruited under projects I to III, builds upon our groups'recent findings implicating both cytogenetic abnormalities and sequence mutations in Contactin and Contactin associated family of molecules in developmental disorders, and capitalizes on independent results by collaborators at UCLA suggesting increased risk for ASD resulting from a common haplotype in one of these molecules. The 5 projects are integrated and supported through proven governance and communication provided by an Administrative Core. An Assessment Core will ensure well- characterized subjects in our tradition of clinical excellence and methodological rigor. A Data Analytic and Methodology Core will provide ongoing consultation on study design and data analysis, and collaborate on Center-wide data mining and methodological innovations. The Yale ACE addresses several key action items of the NIH Interagency Autism Coordinating Committee, including neuro-developmental markers and screening in infants, function-specific neural circuitry, and genetic causes.

DESCRIPTION (provided by applicant): The goal of this project is to study prospectively the development of social visual engagement in infants with autism spectrum disorders (ASD) by means of eye-tracking technology and innovative quantification of visual attention during viewing of naturalistic social situations. We will measure (1) visual fixation time during viewing of adults engaged in infant-directed approaches, and (2) temporally-sensitive visual scanning patterns during viewing of infants engaged in play. Experimental data will be collected at 2, 4, 6, 9, 12, 18, and 24 months. A cohort of 235 infants will be enrolled in this project, consisting of infant siblings of children with autism who are at High Risk for developing an ASD (HR-ASD, N=135);infants at High Risk for Developmental Delays without familial history of ASD (HR-DD, N=50);and children at Low Risk of developmental problems with Typical Development expected (LR-TD expected, N=50). Confirmatory diagnostic assessment will take place at 36 months. The primary analyses will focus on comparisons between children who develop an ASD in comparison with DD and TD children. Given the familial nature of ASD and the potential for advancing research on mediating phenotypes, comparisons will also be made between all siblings of children with ASD (entire HR-ASD sample) in relation to the HR-DD and LR-TDexpected groups. This work builds on our findings of anomalous visual fixation patterns to dynamic social stimuli in adolescents (R01 HD04217) and in 24- to 36-month-olds (U54 MH66494, Yale STAART) with ASD. In both cases, summaries of visual fixation on regions of interest (eyes, mouth, body, &object) were strong predictors of concurrent, standardized measures of social disability. Here we extend this work in two ways: (1) we will employ novel group measures of moment-by-moment visual scanning behavior developed by our lab which are particularly sensitive to time-delimited social and physical cues occurring naturally in infants'surrounding environment;and (2) we will quantify the ontogeny of a key mechanism of socialization and its hypothesized derailment in the early pathogenesis of ASD by studying longitudinally a group of infants at greater risk for developing the disorder. We capitalize on a project focused on the detailed clinical characterization of the same cohort (Project 1, PO1 HD003008), and on the conceptual and technological advancements resulting from our continuing studies of young children with ASD (Project 1, P50 HD055726). Our programmatic goals are to (1) study early mechanisms of socialization and the role of these mechanisms in the heterogeneity of syndrome expression in ASD;and (2) to develop performance-based measures capable of predicting developmental and diagnostic outcome and able to serve as screening protocols for infants at risk for ASD. This project addresses several key action items of the NIH Interagency Autism Coordinating Committee, with emphasis on developmental markers and screening in infants, and neurodevelopmental processes. PUBLIC HEALTH RELEVANCE: In this project we will map and quantify the unfolding of social visual engagement from 2 to 24 months of age, using measures of visual fixation and visual scanning to study how infants with autism interact with the social world. Through a prospective study of the infant siblings of older children with autism, this project will measure the developmental course of altered social engagement in infants subsequently diagnosed with an autism spectrum disorder. The three goals of this project quantitative diagnostic markers, predictors of outcome, and endophenotypes capable of parsing the heterogeneity of the broader autism spectrum are also key objectives of the NIH Interagency Autism Committee. Like the Committee's action items, this project emphasizes developmental markers and screening in infants, as well as neurodevelopmental processes, and is, therefore, highly relevant to public health.

DESCRIPTION (provided by applicant): Our recent studies examining visual fixation patterns to both naturalistic and ambiguous social stimuli in toddlers with autism spectrum disorders (ASD) revealed that viewing patterns are driven by the physical contingencies of the stimuli rather than by their social context. In this project, we adopt a stepwise, experimental approach to determine how physical and social contingencies influence and can be used to induce changes in visual attention in 12- to 24-month-old infants with ASD (N=70) relative to well-matched non-autistic developmentally delayed (DD) (N=70) and typically developing (TD) (N=60) infants. To do this, we create audio and video stimuli that display physical contingencies, in the form of audiovisual synchrony, and social contingencies, in the form of social context afforded by faces and speech. Using eye-tracking technology to measure visual fixation, we determine how manipulating these contingencies affects viewing patterns. The first specific aim is to establish whether infants can track physical contingencies, independent of any potential influence from social contingencies. We will determine the extent to which children with autism can follow basic patterns of audiovisual synchrony in co-presented audio and video stimuli, when there are no implicit cues from social context that might affect visual attention. Our results will show whether infants with ASD are more or less sensitive than TD or DD peers to specific forms of audiovisual information. The second specific aim is to investigate how social contingencies influence infant perception of physical contingencies. We will determine the extent to which cues for social context presented in either auditory or visual modalities affect the ability of children with autism to track patterns of audiovisual synchrony. The results of our experiments will indicate whether audiovisual perception in infants with ASD is more or less susceptible to specific audiovisual cues for social context than in TD or DD controls. The third specific aim is to explore whether changes in visual scanning in infants can be induced by manipulating physical and social contingencies. By dynamically modifying patterns of audiovisual synchrony in otherwise naturalistic social scenes, we will test whether visual attention in children with autism can be altered experimentally. Our results will demonstrate whether manipulation of physical and social contingencies may provide a mechanism for therapeutic repurposing of visual attention in children with autism. This project will provide unique insights into the ways in which individuals with autism search for meaning in their immediate sensory environment when confronted with social situations, and will also suggest possible avenues for early diagnosis and treatment. The long-term objective of this research is to develop the eye-tracking paradigm into a laboratory-based quantifier of social disability, the results of which can be exploited for tailoring effective individual remedial therapies. This project addresses several key action items of the NIH Interagency Autism Coordinating Committee, emphasizing developmental markers and screening in infants.

DESCRIPTION (provided by applicant): / Abstract This project - 'Performance Indices of Social Disability in Toddlers with Autism'- addresses Challenge Area '(04) Clinical Research'and Specific Challenge Topic 'Autism: Addressing the Challenge (04-MH-101*)';and Challenge Area '(01) Behavior, Behavioral Change, and Prevention'and Specific Challenge Topic 'Individual- Based Model of Social Behavior (01-GM-101*)'. The overarching goal of this project is to develop performance indices of social engagement which can be used at the earliest point of diagnosis to parse out heterogeneity of syndrome expression and identify predictors of outcome. We will collect eye-tracking data to quantify visual fixation and scanning during viewing of naturalistic social situations in N=80 12- to 24-month-old infants with autism spectrum disorders (ASD), non-autistic developmental delays, and typical development. The children's extensive clinical characterization at the time of the experiments will be supported by the Yale ACE, which will also support diagnostic confirmation and developmental assessment procedures to be obtained at ages 36 to 48 months, which is beyond the scope of this RC1. Based on a single, 5-minute behavioral assay, we will derive measures of (1) eye-blink inhibition as an index of stimulus salience;(2) attention shifting as an index of adaptive, social visual pursuit;and (3) social visual monitoring as an index of active pursuit of communicative intentions. Work supporting the utility of these three methods has involved 2- to 3-year-olds, school-age children, and adolescents with ASD. In this application, we extend our methods to the study of social engagement in the second year of life. This application builds on 7 years of pioneering work capitalizing on eye-tracking technology to measure spontaneous visual fixations and visual scanning during viewing of naturalistic social situations in over 420 individuals with ASD, from infancy through adolescence (U54- MH66494, P50 MH081756, and R01 MH083727, PI A Klin). Our specific aims address directly three major themes in the National Institutes of Health Interagency Autism Coordinating Committee: 'Heterogeneity of Autism Spectrum Disorders', 'Predictors of Outcome'and 'Biomarkers'. The vast variability of abilities and symptoms displayed by individuals with autism is one of the greatest challenges for research on its causes and treatment. Using eye-tracking technology, this project employs three novel and converging performance measures of social engagement to quantify social disability in a group of 12- to 24-month old infants with autism spectrum disorders and to assess their clinical utility. These measures are derived from one brief, 5-minute viewing of a commercial video portraying toddlers at play. The goal of this work is to quantify a core and defining symptom of autism during the period of earliest detection.

DESCRIPTION: The Emory ACE joins 8 laboratories in 3 institutions, creating a center for clinical and translational science built-from its outset--on the expectation of transformative impact on the community. Laboratories from the Marcus Autism Center, Emory University School of Medicine, and Yerkes National Primate Research Center combine methodological and conceptual expertise in child development, behavioral neuroscience, speech science, molecular genetics, and treatment research; all against the backdrop of a city-wide initiative for autism research driven by the largest pediatric healthcare system in the country, Children's Healthcare of Atlanta. The thematic mission of the Emory ACE guides each of its 5 projects and 4 cores: to unravel the developmental complexities of risk and resilience in autism spectrum disorders, so that we may advance the most effective and successful treatments for children. Projects I and II quantify the developmental unfolding of social visual (PI) and social vocal (Pll) engagement, from birth until 24 months of age, to identify profiles for positive outcome as well as risk factors for disability. Project III advances rigorous, randomized-control trials for treatmnt of ASD into infancy and toddlerhood, testing the extent to which developmental trajectories of social engagement (Projects I and II) predict treatment response and outcome. Also starting in infancy. Projects IV and V establish-for normative social development (PV) and a genetic means to its disruption (PIV)-a nonhuman primate model for interrogating the underpinnings of social disability in genes, brain, and behavior. Together, these Projects advance our understanding of the developmental unfolding of autism, and set the stage for changing the course of ASD prior to the point when disability is even fully manifest. Four Cores provide the resources to support these goals, spanning Assessment, Informatics, Administration and Training. In its efforts to meet and exceed the aspirational goals for autism set forth by the NIH Interagency Autism Coordinating Committee (lACC), the Emory ACE creates in its wake a new scientific community, focused on the translational social neuroscience of autism spectrum disorders, in the service of children and families.

The overarching goal of the Emory ACE Research Training & Education Core (RT&EC) is to capitalize on ACE and associated resources, as well as web of relationships, to (a) promote education, training, and careers in autism and social neuroscience related areas of investigation, clinical practice and service, (b) disseminate best practices to and support primary care providers, and (c) disseminate relevant and empowering information to affected families and the community at large. The specific objectives of the RT&EC are 1: Translational Objective - To promote the integration of behavioral neuroscience and clinical science; 2: Clinical Science Objective - To promote the integration of clinical science and clinical practice, with a focus on pediatrics & allied professions as the locus of primary care, and as the gateway to early identification, early management and early intervention; 3: Community Objective - To promote tangible gains to the community at large, with focus on innovative and cost-effective practice tools and standards, under-served populations, and population-based considerations; 4: Bioethics Objective - To promote integration of bioethical considerations in research, clinical training and practice, and allocation of potential scientific/medical benefits, regarding both individuals (child/family) and community groups (different sectors ofthe population). These objectives will permeate our programmatic activities in 4 key domains of operation: (1) Training and advancement of scientists and practitioners; (2) Establishment of research goals and priorities, as well as allocation of resources; (3) Scientific study design and implementation; and (4) Dissemination of information and benefits yielded by this community of science. Core leadership reflects the desired integration of autism and social neuroscience focus and the 4 objectives, with key personnel representing longstanding interests and unique accomplishments, and unrivaled access to Emory-wide resources, in each of the Core's objectives. Tools and procedures for Core functioning and effectiveness are established, including quality control mechanisms for quantification of ACE-wide productivity in research training & education. Core co-leaders will also serve as an Internal Advisory Committee to the ACE, acting through procedures established in the Administrative Core.

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ ABSTRACT DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Autism Spectrum Disorder (ASD) is a common, often devastating neuropsychiatric condition with largely unknown pathophysiology. Although ASD has a multifactorial etiology, it encompasses a large genetic component. The investigators in this proposal aim to continue and enhance our collaborative effort that has produced significant advances in our understanding of ASD over the last four years and generated highly successful, open data and biomaterials resources for the research community, the NIMH Genetics Initiative and the Autism Genetic Resource Exchange (AGRE). Our Network has met or exceeded our original aims. We have built patient resources for research, identified rare and common ASD susceptibility alleles, defined models of ASD genetic susceptibility, provided evidence for convergent pathophysiology, and led development of animal and cell culture models. Here we propose to take a major new direction, filling a significant gap in ASD research, by recruiting underserved subjects of self-reported African ancestry (African-American; AA), an important population that has not previously been well-represented in ASD genetics research. Our Network involves six research sites and the AGRE DCC, collaborating in a systematic, comprehensive investigation of ASD genetics in order to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility in the AA population. Specifically, we will enrich existing resources by recruiting at least 600 AA probands and additional family members. Our recruitment plan includes an embedded health disparities project that will evaluate access to care for AAs with ASD and clarify factors influencing participation of AA individuals in genetic research. We will employ novel methods to define the ancestral origin of specific chromosomal segments and ascertain the background on which susceptibility alleles occur. We will perform follow up GWA on ASD-related endophenotypes or co-variates, such as language delay, sex and head circumference. In parallel, we will conduct whole exome sequencing (WES) and analysis of copy number variation (CNV) using 2.5M SNP arrays yielding high resolution molecular karyotypes and providing a resource on genome-wide CNV and coding sequence variation (SNV) in ASD. Gene expression profiling and network analysis will be used to prioritize variants. Genetic risk factors identified in the mostly European samples will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size providing power to replicate previous associations and to identify rare, recurrent CNV and SNV. The observation of new forms or different population frequencies of ASD-related variation in this sample as well as the sharing of most CNV and SNV with other cohorts are both outcomes that will have great significance for future studies and clinical care. As has been our practice, our Network will make all phenotypic and genotype data accessible via the internet on a rolling basis, further enhancing the value of this resource to the community.

DESCRIPTION (provided by applicant): The American Academy of Pediatrics recommends screening all children for autism spectrum disorder (ASD) at 18 and 24 months because research indicates that earlier intervention maximizes children's outcomes5. The earliest signs of ASD are delays in social communication milestones that appear in the first 2 years and yet most children are not diagnosed until 4-5 years of age. Underserved families are identified even later and significantly underrepresented in intervention research. It is vitally important to mobilize community service systems to impact family engagement throughout the process of screening, evaluation, and early intervention (EI) and to support linkages to public community-based EI in order to address health disparities. In response to RFA-MH-14-100, this collaborative investigation of 4 universities aims to document the effectiveness of an online automated universal screen for communication delay and autism initially at 18 months of age and decision rule for referral to an ASD evaluation, and to study an evidence-based intervention to increase family engagement and expedite receipt of screening, diagnosis, eligibility for EI, and EI services. The study will focus on the youngest age when ASD can be detected reliably, which is 18 months, and compare the effectiveness of screening and referral by 3 different community service systems: 1) primary care including private and public health care agencies and federally qualified health centers; 2) Women, Infants, and Children (WIC) Food and Nutrition Service; and 3) the National Black Church Initiative (NBCI). Using a web-based platform we will expand their capacity for universal ASD screening and referral for diagnosis and determining eligibility by EI providers through the public Individuals with Disabilities Education Act (IDEA) Part C system for children birth to 3 years of age. Innovative web-based technology will be integrated at multiple levels- as the basis for an interactive professional development course to enable these community service systems to efficiently learn about autism and implement a universal broadband and autism-specific screening with seamless automation that links to electronic health records and provides families with web-based tools about autism. This multidisciplinary research team will conduct a multisite pragmatic randomized clinical trial to tes the effectiveness of an evidence-based Family Engagement Intervention. We will also conduct an exploratory study to test strategies to improve uptake of evidence-based intervention by community-based EI providers throughout the Part C system. This protocol has the potential to lower the age of screening for ASD to 18 months, which will have important implications for earlier access to intervention and improving ASD service systems and be ready for immediate and rapid implementation in community settings across the US. Findings will advance science by providing researchers with a method for recruiting a population-based sample, allowing for research at younger ages, which could accelerate genetic, neuroscience, and intervention research, and lead to transformative changes to community healthcare delivery.

PROJECT SUMMARY The Emory ACE joins 12 laboratories in 6 institutions under the auspices of Emory University, creating a center for clinical and translational science built ? from its outset ? on the expectation of transformative impact on the community. These laboratories combine methodological and conceptual expertise in child development, speech science, behavioral neuroscience, and treatment research. The thematic mission of the Emory ACE guides each of its 5 projects and 4 cores: to execute science that leads directly to a future of optimized outcomes for the next generations of children with autism spectrum disorder (ASD). Projects I-III study reciprocal behavior, in the visual and vocal, brain and behavior domains, within the first six months of life, and in subsequent brain-behavior transitions until 30 months of age, in infants and toddlers at low and high risk for ASD. Project IV advances rigorous, randomized-controlled trials for treatment of ASD into infancy and toddlerhood, testing infant and infant- caregiver characteristics that predict treatment response and outcome; its goal is to optimize treatment effects, personalized to the developmental stage of the child, and within the structure of the child-caregiver dyad. Project V advances a nonhuman primate model of social development, interrogating the underpinnings of social disability in brain and behavior studies. Together, these Projects advance our understanding of the developmental unfolding of ASD, and sets the stage for changing its course prior to the point when disability is even fully manifest. Four Cores provide the resources to support these goals, spanning Clinical Assessment and Care, Informatics, Administration and Dissemination & Outreach. In its efforts to meet and exceed the aspirational goals for autism set forth by the US DHSS Interagency Autism Coordinating Committee and by NIMH Research Priorities, the Emory ACE expands a new scientific community, focused on the translational social neuroscience of ASD, in service of children and families. Its ultimate goal is to change the narrative of ASD from one of potentially devastating disability to one of positive diversity, in which individuals with autism are able to succeed despite their learning differences and because of their unique assets, unencumbered by the burdens of language, intellectual disabilities, and severe behavior challenges.

PROJECT ABSTRACT In response to RFA-MH-18-700, the goal of this collaborative R01 is to demonstrate the therapeutic value and community-wide implementability of an early intervention (EI) platform for toddlers with autism spectrum disorder (ASD) that is completely virtual, from recruitment through intervention. This platform?Early Social Interaction Mobile Coaching (ESI-MC) deploys individual telehealth sessions with coaching and feedback to help families embed intervention in everyday activities. Specifically, we will conduct an effectiveness trial of ESI-MC to address the important question of whether starting evidence-based intervention earlier leads to better outcomes than starting later. We will address this question by using a modified stepped wedge design and blended implementation research to analyze data obtained with ESI-MC start at 18, 24, or 30 months. We will diagnostically ascertain 240 children from a pool of 360 18-month-olds with early signs of autism, 60 in each of four US regions (Northeast, Southeast, Midwest, West Coast). They will be recruited using a new virtual platform?My Baby Navigator?linking a new surveillance and screening tool, an app to upload video-recorded home observations and telehealth intervention sessions, and a package of educational resources. The 240 children will be randomly assigned to one of three ESI-MC timing groups. We will measure child active engagement and social communication change every 6 months as the primary outcome variables. Outcome measures of developmental level, autism symptoms, and adaptive behavior will be examined to measure differential treatment effects. We will achieve these objectives through research AIMS: 1. Compare the effectiveness of ESI-MC implemented for 6 months on proximal outcome measures of child active engagement, child social communication change, parent transactional supports, and parent evidence-based strategy use (1A) with Treatment-as-Usual (TAU) at 24 and 30 months and (1B) across treatment timing groups initiated at 18, 24, or 30 months. 2. Examine (2A) change in parent transactional supports and evidence-based strategy use as the mechanism for change and (2B) individual child and family characteristics that moderate response to treatment. 3. Compare the effectiveness of intervention on secondary outcome measures of child developmental level, autism symptoms, and adaptive behavior (3A) with Treatment-as-Usual (TAU) at 24 and 30 months and (3B) across treatment timing groups initiated at 18, 24, or 30 months. 4. Explore outcomes at 36 months, individual patterns of change from 18-36 months, and predictors of change across treatment timing groups by estimating child growth trajectories. 5. Examine barriers and promotive factors impacting widespread dissemination, implementation and sustainability across racial, socioeconomic and geographic lines. Maximizing the use of mobile technology, ESI-MC offers the prospect of a community-viable, scalable and sustainable treatment to improve EI services for toddlers with ASD, particularly among minority and low-resource communities.