Andy Shih

Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

Approaches to Enhancing the Early Detection of Autism Spectrum Disorders: A Systematic Review of the Literature

BACKGROUND A reliable diagnosis of autism can be made as early as 24 months, yet in many children diagnoses are made much later. A delay in diagnosis translates into a missed opportunity to provide early intervention services and to improve outcomes. The aim of the current study was to review the literature on early detection approaches in primary care and other community settings in the United States. METHODS A search was conducted of the peer-reviewed and gray literature to identify studies published from January 1990 through January 2013 testing approaches to enhance the early detection of autism in community settings in the United States. RESULTS The search identified 40 studies describing 35 approaches, which were grouped into the following categories: awareness (n = 4), routine screening (n = 21), and practice improvement to enhance screening (n = 10). Awareness approaches were associated with positive changes in knowledge of autism-related topics. Routine screening yielded high or increased rates of screening and referrals; however, few studies assessed the effect of screening on age at diagnosis or services enrollment. Practice improvement approaches resulted in increased screening and referral rates and highlighted the importance of adopting a multipronged approach to enhance early detection. CONCLUSIONS Although studies that tested screening approaches in community settings found positive results, the effectiveness of such efforts on reducing time to diagnosis and services enrollment remains largely untested. The fact that few studies reported outcomes beyond rates of referral indicates the need for enhanced methodological rigor, particularly with respect to length of follow-up and quality of measures used.

Autism screening and diagnosis in low resource settings: Challenges and opportunities to enhance research and services worldwide.

Most research into the epidemiology, etiology, clinical manifestations, diagnosis and treatment of autism is based on studies in high income countries. Moreover, within high income countries, individuals of high socioeconomic status are disproportionately represented among participants in autism research. Corresponding disparities in access to autism screening, diagnosis, and treatment exist globally. One of the barriers perpetuating this imbalance is the high cost of proprietary tools for diagnosing autism and for delivering evidence‐based therapies. Another barrier is the high cost of training of professionals and para‐professionals to use the tools. Open‐source and open access models provide a way to facilitate global collaboration and training. Using these models and technologies, the autism scientific community and clinicians worldwide should be able to work more effectively and efficiently than they have to date to address the global imbalance in autism knowledge and at the same time advance our understanding of autism and our ability to deliver cost‐effective services to everyone in need. Autism Res 2015, 8: 473–476.

A Global Public Health Strategy for Autism Spectrum Disorders

In recent years, there has been increasing awareness about autism spectrum disorders (ASD) around the world, including in low and middle income countries. Unlike countries in Western Europe and North America where infrastructure and capacity are available to help meet some of the needs of individuals with ASD, little expertise or capacity exists in most of the developing world. In 2008 Autism Speaks launched the Global Autism Public Health (GAPH) Initiative to facilitate the development of systematic and sustainable solutions for enhancing global autism awareness, research, training and service delivery. In the last 3 years Autism Speaks has established collaboration with stakeholders from over 20 countries who are working alongside dedicated local and international stakeholders to effect change. In this article, the GAPH framework is described, along with a few brief case examples that illustrate how the framework for implementation of the model can occur. GAPH is still in its infancy but has the potential to have significant impact through inclusive collaboration with local and international stakeholders to develop effective and sustainable public health solutions for disseminating best practices and delivering tangible benefits to individuals with ASD and their families. Autism Res 2012, 5: 211–217.

Autism Spectrum Disorders in Africa: Current Challenges in Identification, Assessment, and Treatment: A Report on the International Child Neurology Association Meeting on ASD in Africa, Ghana, April 3-5, 2014.

Prevalence of autism spectrum disorders has increased over recent years, however, little is known about the identification and management of autism spectrum disorder in Africa. This report summarizes a workshop on autism spectrum disorder in Africa under the auspices of the International Child Neurology Association and the African Child Neurology Association through guided presentations and working group reports, focusing on identification, diagnosis, management, and community support. A total of 47 delegates participated from 14 African countries. Although there was a huge variability in services across the countries represented, numbers of specialists assessing and managing autism spectrum disorder was small relative to populations served. Strategies were proposed to improve identification, diagnosis, management and support delivery for individuals with autism spectrum disorder across Africa in these culturally diverse, low-resource settings. Emphasis on raising public awareness through community engagement and improving access to information and training in autism spectrum disorder. Special considerations for the cultural, linguistic, and socioeconomic factors within Africa are discussed.

Global services and support for children with developmental delays and disabilities: Bridging research and policy gaps

Pamela Collins and colleagues explain the research and policy approaches needed globally to ensure children with developmental delays and disabilities are fully included in health and education services.

Autism: a (key) piece of the global mental health puzzle

Once considered rare, autism is today recognized as an emerging global public health issue. Though the term emerging is traditionally reserved for describing new or rapidly spreading infectious diseases, the recent upsurge in reported prevalence has communities and public health officials worldwide scrambling to uncover ‘cause(s)’ of the autism ‘epidemic.’ Recent research suggests that broadening diagnostic criteria and changes in reporting practice can explain a portion, but not all, of the increase in prevalence over time (Hansen et al. 2015). Regardless of whether autism rates are truly rising and why, there has been an undeniable increase in global awareness as a consequence of these unanswered questions. You can hardly go a day without seeing a story on autism appear in mainstream media. And you would be hard pressed to find a major landmark not lit up blue for World Autism Awareness Day on April 2nd. Some, however, wonder if autism is receiving a disproportionate amount of attention. After all, it is just one in a host of childhood developmental and mental health conditions impacting communities in every corner of the world, every day. We believe that there is a tremendous opportunity to strategically leverage the current emphasis on autism awareness, advocacy, and research in a way that will also benefit those struggling with other developmental and mental health challenges. Autism or autism spectrum disorder (ASD) is a group of developmental neurological conditions characterized by deficits in social communication and the presence of restricted or repetitive behaviors. ASD symptoms vary by person from mild to severe; some individuals have strong intellectual and language abilities, whereas others are cognitively impaired and may require life-long care. Many suffer from medical problems such as seizure and sleep disturbances (Doshi-Velez et al. 2013), as well as co-occurring mental health disorders including depression (Simonoff et al. 2008). Additionally, research from the USA and UK suggests that ASD typically affects the health and wellbeing of the entire family (Cidav et al. 2012) and poses significant long-term economic burden for society, with much of the cost attributable to long-term care and lost wages (Buescher et al. 2014). While ASD transcends social, cultural and geographic boundaries, research outside of high-income countries and among underserved populations is severely lacking, and the vast majority of research to date is limited to children. Converging science suggests that ASD affects approximately 1% of the population globally (Elsabbagh et al. 2012). However, research methodologies and, consequently, prevalence estimates, range widely across studies. Findings from more recent research suggest that 1% may be a gross underestimate of ASD * Address for correspondence: Andy Shih, Ph.D., Autism Speaks, 1 E 33rd Street, 4th Floor, New York, NY 10016, USA. (Email: ashih@autismspeaks.org)

Autism screening and diagnosis in low resource settings: Challenges and opportunities to enhance research and services worldwide: Enhancing Autism Research and Services Worldwide

Most research into the epidemiology, etiology, clinical manifestations, diagnosis and treatment of autism is based on studies in high income countries. Moreover, within high income countries, individuals of high socioeconomic status are disproportionately represented among participants in autism research. Corresponding disparities in access to autism screening, diagnosis, and treatment exist globally. One of the barriers perpetuating this imbalance is the high cost of proprietary tools for diagnosing autism and for delivering evidence‐based therapies. Another barrier is the high cost of training of professionals and para‐professionals to use the tools. Open‐source and open access models provide a way to facilitate global collaboration and training. Using these models and technologies, the autism scientific community and clinicians worldwide should be able to work more effectively and efficiently than they have to date to address the global imbalance in autism knowledge and at the same time advance our understanding of autism and our ability to deliver cost‐effective services to everyone in need. Autism Res 2015, 8: 473–476.

Brief Report: A Survey of Autism Research Priorities Across a Diverse Community of Stakeholders

Inclusion of stakeholder voices in the allocation of research funding can increase the relevance of results and improve community engagement in research. We describe the results of an online survey that gathered input from community stakeholders regarding autism research priorities. A demographically diverse sample of respondents (N = 6004; 79.1% female; 72.5% ages 30–59; 86.4% USA) completed the survey. Results indicated a preference for applied relative to basic science topics, though both basic and applied science areas were rated as important. Respondents gave their highest ratings to research focused on co-occurring conditions, health and well-being, adult transition, and lifespan issues. These results can guide decision-making by public and private funders when developing science funding priorities and engaging in science dissemination activities.

Autism screening and diagnosis in low resource settings

Most research into the epidemiology, etiology, clinical manifestations, diagnosis and treatment of autism is based on studies in high income countries. Moreover, within high income countries, individuals of high socioeconomic status are disproportionately represented among participants in autism research. Corresponding disparities in access to autism screening, diagnosis, and treatment exist globally. One of the barriers perpetuating this imbalance is the high cost of proprietary tools for diagnosing autism and for delivering evidence‐based therapies. Another barrier is the high cost of training of professionals and para‐professionals to use the tools. Open‐source and open access models provide a way to facilitate global collaboration and training. Using these models and technologies, the autism scientific community and clinicians worldwide should be able to work more effectively and efficiently than they have to date to address the global imbalance in autism knowledge and at the same time advance our understanding of autism and our ability to deliver cost‐effective services to everyone in need. Autism Res 2015, 8: 473–476.