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Interagency Autism Coordinating Committee Strategic Plan for Autism Spectrum Disorder Research – 2013 Update

Introduction

The Combating Autism Act (CAA; Public Law 109-416) (PDF - 142 KB) and the subsequent Combating Autism Reauthorization Act (CARA; Public Law 112-32) (PDF - 121 KB) established an Interagency Autism Coordinating Committee (IACC) to advise the Secretary of Health and Human Services on issues related to Autism Spectrum Disorder (ASD). One responsibility of the IACC is the development of a strategic plan for ASD research, to be updated yearly. The IACC Strategic Plan, first issued in 2009, was produced by the IACC, composed of federal officials and public stakeholders, with extensive input from researchers, adults on the autism spectrum, parents, advocates, and the general public that was gathered through a series of meetings and public comment opportunities. This inclusive process ensured that the IACC Strategic Plan reflected diverse perspectives from across the autism community.

The IACC Strategic Plan is organized around seven general topic areas that are represented in the plan as consumer-focused Questions (e.g., Question 1, "When should I be concerned?" which covers the topic of screening and diagnosis). Each Question is assigned a chapter that provides a description of the state of the science in that area. Each chapter also contains a section describing the research and community needs for its relevant Question; the aspirational goal, or long term vision, for each area; and a list of specific long- and short-term objectives.  The objectives were created by the Committee to address critical gaps and opportunities they perceived in the research landscape in 2009.  Each objective also includes a recommended budget that serves as an estimate of how much the Committee projects it might cost to conduct the research-related activities described. The IACC Strategic Plan was updated in 2010 and 2011, adding several new objectives over these years. In 2012, following the reauthorization of the Committee, the plan was updated with advances and new research opportunities.

For the 2013 update of the IACC Strategic Plan, the Committee voted to focus on accountability without adding new objectives or re-writing the previous version.  With access to an extensive portfolio analysis conducted by the National Institutes of Health (NIH) Office for Autism Research Coordination (OARC) linked to every objective, as well as the annual IACC Summary of Advances documents from past years, the IACC reviewed what has been invested in ASD research in the United States since 2008.  Using data from both public and private funders, the IACC determined the level of progress for each of the 78 objectives in terms of the number of projects funded and dollars committed to each objective since 2008.  To assess the return on this investment, the IACC also invited a group of external experts to evaluate how research has supported progress toward the aspirational goals in each of the seven chapters of the IACC Strategic Plan.

This update summarizes both investment and scientific progress across all seven Questions of the IACC Strategic Plan. Most areas have received extensive investment ($1.5 billion expended from 2008-2012 by federal and private funders) and significant progress has been made since the original Plan was published in January, 2009.  According to the PubMed database of biomedical research literature, over 11,000 journal articles on autism have been published since January, 2009, more than double the number published in the preceding 5 years.  The world of ASD research has changed profoundly during this period, with increases in United States ASD prevalence estimates, changes in ASD diagnostic criteria, greater understanding of co-occurring conditions and services needs, and new insights from genetics, environmental studies, and neuroimaging into the biology and etiology of ASD. In addition to this review of the investment and progress, the Committee and external experts identified current research gaps, needs and barriers, as well as new opportunities created by advances in the field, which can provide direction for future investment.

In preparing the 2013 Strategic Plan Update, the IACC also recognized some cross-cutting issues that have emerged with greater urgency since January, 2009.  While much of the research literature has been focused on infants and children, the IACC encouraged more attention to the needs of adults with ASD.  Additionally, because ASD research has frequently been limited to individuals with less severe levels of disability or those who live in communities with greater resources and access to healthcare, the IACC felt that more focus on the most disabled individuals and underserved populations would be essential.  Finally, in both public comments received by the IACC as well as discussions within the Committee meetings, the need for interventions for co-occurring or associated conditions was emphasized, as for many individuals and families these issues are equally or more challenging than the core symptoms of ASD.  Throughout the seven Question areas in the IACC Strategic Plan, the Committee underscored the need for research to focus on developing efficacious, efficient, scalable, and cost-effective interventions, tools, and practices that can be translated into affordable and practical healthcare and service options for the autism community. The Committee also highlighted the urgent need to accelerate translation of scientific discoveries into interventions that can improve quality of life for individuals with autism and their families.

Though this 2013 IACC Strategic Plan Update will inevitably be unable to capture all the changes in the ASD field since 2008, the IACC has endeavored to deliver through this document an accounting of the investments made and how research has evolved since the January, 2009 publication of the original IACC Strategic Plan. This update should be read with two other IACC publications to gain a more complete picture of the autism research landscape. The IACC Autism Spectrum Disorder Research Portfolio Analysis Report describes Federal and non-Federal investments in autism research. The annual IACC Summary of Advances in ASD Research reports in detail specific scientific findings that members of the IACC identify as having significantly advanced the field. Together, with this 2013 IACC Strategic Plan Update, the Committee hopes that these documents will provide a useful overview of the state of autism research at the end of 2013.

Question 1: When Should I Be Concerned?

Introduction

Aspirational Goal: Children at risk for ASD will be identified through reliable methods before ASD behavioral characteristics fully manifest.

When originally framed, Question 1 was directed toward identifying at-risk children by the age of 24 months to facilitate the greatest chance of successful early intervention. Scientific advances since then have shown that, in infants at high genetic risk for ASD due to having an older sibling with autism, symptoms of autism begin to emerge as young as 6 months of age in those who later develop ASD. These new findings suggest that it may someday be possible to screen for children at risk for ASD before the emergence of the full symptoms of autism and early enough to facilitate even more effective intervention. While recent findings have demonstrated this early screening potential in high-risk infant siblings, future challenges include determining whether the same potential for very early identification can be extended to other high risk populations (e.g., very low birth-weight infants) and/or to the general population.

Many of the advances in the screening and diagnosis area have been in development and refinement of screening tests. Moving forward, more attention needs to focus on innovations in diagnostic tools. There also remains a great need for the development of efficient and cost effective screeners for use in children below 18 months of age, as well as more efficient methods of deploying developmental and ASD screening in community settings, including evaluation of effective parent-professional communication strategies for coping with concerns, referrals, follow-up evaluations for services and diagnosis, and linkage to appropriate services and supports. In addition, the development of culturally sensitive diagnostic tools that can be more easily used in both clinical and research settings is urgently needed. Finally, there has been a growing awareness of the need for better tools to diagnose adolescents and adults on the autism spectrum and to provide meaningful assessments of functioning--an issue that is captured in an objective in Question 6 of the IACC Strategic Plan, but may involve adaptation of tools that are currently used to diagnose children.

Progress Toward the Strategic Plan Objectives

The 2011-2012 IACC ASD Research Portfolio Analysis reviewed projects funded by both government agencies and private foundations from 2008-2012. From 2008-2012, the total funding devoted to projects that address Question 1 was $187 million, and if just the years since the publication of the first IACC Strategic Plan in 2009 are considered, the funding for Question 1 related projects was $158 million. On average for each year from 2009-2012, the funding levels for this Question were 35 percent higher than the 2008 level ($29 million) that preceded publication of the IACC Strategic Plan. Also in years 2009-2012, 11 percent of the funding for this Question supported core/other research projects outside of the research gaps covered by the nine objectives in Question 1.

Of the nine specific objectives under Question 1, four objectives addressing development of screening and diagnostic tools, identification of risk biomarkers, and a workshop on ethical issues, met or exceeded the recommended budget and fulfilled the recommended number of projects. Three objectives, concerning determining the utility of genetic tests and developing measures of heterogeneity and symptom severity, partially met the recommended budget and had a number of projects underway. One objective, on understanding the reasons for disparities in screening and diagnosis, was far below the recommended budget and number of projects. The remaining objective, on studies to understand if early diagnosis leads to early intervention and better outcomes, did not have any dedicated funding or projects, though some aspects of this research topic are covered in projects that are categorized elsewhere, such as a project in Question 4 on early intervention (that was preceded by early diagnosis) that also partially addresses the issue of outcomes.

Progress in the Field

Over the past 5 years, progress has been made toward developing tools and practices for more effective screening and diagnosis. New research suggests that existing screening tools, such as the Modified Checklist for Autism in Toddlers (in particular, the new M-CHAT-revised with follow-up interview (M-CHAT-R/F), which is not yet in widespread use)1, 2 and the Infant-Toddler Checklist,3 can be effectively used by pediatricians and other community providers. The M-CHAT-R/F shows promise as a screen for communication and developmental delays and as an ASD screen with the follow-up interview between 18 – 36 months of age. The Infant-Toddler Checklist shows promise as a broadband screen for communication impairments that can identify children with autism between 12 and 24 months and has practical value as the basis of a 5-minute screen during the 1-year well-baby check-up.4 New research suggests that with repeated screening at the ages of 6, 12, and 18 months, it might be possible to identify as many as 95 percent of children with ASD by the age of 24 months. While this represents a remarkable scientific advance, validation and translation of this potential into reality in the general population and in community settings remains an enormous gap.

The clinical reality is that currently only about 20 percent of children with ASD are being identified early (by 3 years of age).5 Barriers to the broader deployment of advanced screening and diagnostic tools include cost and the expertise required to administer the tests. Also, repeat screenings at 6 month intervals beginning at 6 months of age are not being done in practice, despite demonstrated efficacy of such screenings in at-risk infants.6 In addition, it appears that children who are identified in early screens are not always being referred for diagnosis and early intervention, even though there is now strong evidence to suggest the benefit of early intervention.7–9 Thus, we need to better understand the barriers that are preventing caregivers from seeking a diagnostic evaluation after a child fails an autism screen and to identify strategies that will help caregivers navigate the pathway from screening to diagnosis to entry into early intervention. Until this gap between screening and intervention is closed, the potential impact of ASD screening on improving outcomes for individuals with ASD will not be realized.

More needs to be done to raise awareness in the practitioner community of the current capabilities and benefits of early, repeated screenings, early diagnosis, and early intervention. Although not within the scope of a research plan, the severe lack of capacity of professionals to conduct screening and diagnosis and to provide services and supports remains a major stumbling block. Currently, in the United States, over 1 percent of children are estimated to have an ASD and about 15 percent of children are identified with developmental disorders throughout childhood. Although not all developmental disorders are identifiable in the first 3 years of life, research indicates that only an estimated 2.8 percent of infants and toddlers receive early intervention services, suggesting that many children who need early intervention services are not receiving them.10 More complete data are needed to estimate the population and characteristics of children with ASD and other developmental delays that are likely to need early intervention services so that early identification leads to timely evaluation and access to services and supports.

Some progress has been made in understanding the prevalence of ASD in diverse communities, with recent results now suggesting that what initially appeared to be lower prevalence of ASD in some minority populations may instead be a reflection of less effective diagnosis of ASD in those communities.11, 12 There is still a gap, however, in understanding the reasons for disparities in access to screening, diagnosis, referral, and early intervention services. While this issue was targeted by the IACC in the 2009 IACC Strategic Plan, much more work is needed to address this gap, and it should remain the subject of intense focus.

An area of groundbreaking research for Question 1 has been the detection of ASD risk in high risk infants (infant siblings) as young as 6 months of age. Among infant siblings, differences in the development of white-matter tracts have been observed in 6-month-olds who are later diagnosed with ASD.13 A similar population of high risk infants has also been shown to have significant delays in postural development, including slower emergence and mastery of advanced postures such as sitting and, later, standing.14 Additionally, differences in the developmental trajectories of visual attention to social stimuli were identified as a marker of those infant siblings who later developed ASD. Eye tracking technology that gives children a choice between looking at moving geometric patterns or human faces was found to reliably distinguish children with ASD, who prefer to look at the geometric images, as young as 14 months of age.15 A decline in a child's visual attention to the eyes of others during social interactions when he/she is 2 to 6 months of age is another biomarker of infants who are later diagnosed with ASD.16 These exciting results suggest new potential screening tools based on eye tracking technology, which, like other existing tools, must now be validated in other high risk populations and in the general population. If proven efficacious, these tools must be modified for broader use in order to be beneficial to the wider community.

At the molecular level, there has been significant progress in identifying genetic differences in ASD. Mutations associated with genetic risk for ASD can now be identified in about 30 percent of individuals diagnosed with ASD.17–23 This increase in the capability to link cases of ASD with specific genetic markers has risen substantially over the past 5 years, and further progress is anticipated. In order for these genetic markers to be useful from a screening perspective, they too will need to be validated in general populations. Such an advance could also help address the issue of adult diagnosis. It is noteworthy that the overwhelming majority of screening and diagnostic tools currently under development are designed for and are being tested in infants and children, but there is a scarcity of tools that can be used effectively in adults. More effort needs to be focused on developing, adapting, and validating screening and diagnostic tools for use across the lifespan.

Advances in capabilities to detect ASD early create a variety of legal, ethical, and social concerns, and the IACC Strategic Plan update of 2011 recommended that a workshop be held to address these issues. The NIH, the Autistic Self Advocacy Network, and Autism Speaks all held workshops that either directly or partially addressed this topic, fulfilling the original IACC Strategic Plan objective. Still, continued attention to this topic is warranted as the legal, ethical, and social implications of ASD screening will continue to evolve in response to changing technologies.

In 2013, the Diagnostic and Statistical Manual of Mental Disorders (DSM) This link exits the Interagency Autism Coordinating Committee Web site was revised for the release of its fifth edition, consolidating previous ASD diagnoses together into a single "autism spectrum disorder" category.24, 25 The new criteria in DSM-5 raised potential concerns in parts of the autism community that some people who would have previously met the criteria for diagnosis (and potentially benefitted from ASD-specific services) may no longer be diagnosed under the new criteria. Some studies have been conducted to better understand the potential implications of the change in diagnostic criteria,26–28 but more research will be needed to further assess the reliability and validity of DSM-5 ASD criteria, and to understand the impact of these new criteria on diagnosis, prevalence estimates, and access to services. In addition, diagnostic instruments must be adapted to accommodate the new criteria.

Progress Toward the Aspirational Goal:
Children at Risk for ASD Will Be Identified Through Reliable Methods Before ASD Behavioral Characteristics Fully Manifest.

Within the past 5 years, tools and technologies have emerged that have the potential capability to detect children at risk for ASD before the full manifestation of behavioral symptoms, which is the aspirational goal of this Question. The challenges that remain are to develop practical, cost effective tools that will be broadly accessible; validate and adapt these tools for use in a variety of diverse populations; support the development of the needed provider workforce; and deploy these tools so that this capability becomes a clinical reality across communities. Additionally, the link between screening and referral to intervention remains weak, but must be strengthened for the realization of the aspirational goal. Even when early screening takes place and at-risk children are identified in clinical and community settings, almost half the children are not progressing through the system to diagnosis and early intervention and face major roadblocks in the ultimate goal of accessing needed services and supports as early as possible. Future work should focus on identifying and removing the cultural and logistical impediments that may be preventing families and providers from following up on screening results that have identified a child with increased risk for ASD.

In the area of continued screening tool development, there is a need for increased investigation of risk factors in the 0-12 month age group. Currently there is no combination of genetic and behavioral markers in this age group that are reliable indicators of ASD risk. Also, the focus of the search for biomarkers has been on behavior and genetics, but this focus needs to be broadened to include a number of physiologic markers as well (e.g., sleep, autonomic measures, and neurological, metabolic/microbiome, immune, and gastrointestinal (GI) function measures). In addition, in the period prior to the development of language skills, biomarkers such as early motor tone, posture, symmetry, visual attention, and joint attention should be explored further. To improve accuracy of identification, emphasis should be placed on both direct observation and parent report.

In order to increase community usefulness of established tools, more investment is needed for community-based studies with larger sample sizes that will increase knowledge of disparities among various groups in access to screening and in applicability of screening tools. New technologies such as portable device applications (apps), electronic health records (EHRs), and video tasks will also be important for the development of innovative screening methods and screeners that could be used for diagnosis in children and adults. Finally, rigorous validation of existing tools is necessary so the community will know which ones are reliable in which populations.

True realization of the aspirational goal is dependent on progress on the other Questions of the IACC Strategic Plan. While all the Questions are interrelated, the success of screening and diagnosis in terms of its benefit for those identified will depend most heavily on the development and deployment of effective interventions (Question 4) and services (Question 5) that address the needs of the whole spectrum, including those with mild or moderate levels of disability. In addition, while the aspirational goal of Question 1 focuses on early diagnosis in children, there is also a need to greatly strengthen efforts to develop and adapt diagnostic tools for use in adult populations, addressed in Question 6 of the IACC Strategic Plan, in order to enhance the potential to reduce disability and improve quality of life across the lifespan.


References

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Question 2: How Can I Understand What Is Happening?

Introduction

Aspirational Goal: Discover how ASD affects development, which will lead to targeted and personalized interventions.

Over the course of the last several years, a great deal has been learned about altered neurodevelopment in ASD and a few interventions are in the early phases of testing. The knowledge base, however, is still not sufficient to support the long-term goal of personalized interventions. Objectives within Question 2 have also evolved as the science has provided more insight into the complexity of ASD. Specifically, through recent groundbreaking brain mapping and brain imaging research, much has been learned about how the brain develops and how autism unfolds in early development. Insights from syndromic forms of ASD (ASD that is caused by known genetic syndromes) have provided clues about the general mechanisms and genetic pathways that are affected in ASD. Recent studies have also begun to elucidate the role of the immune system in brain development and potentially in autism, and progress has been made in understanding and developing guidelines to address co-occurring conditions such as gastrointestinal (GI) symptoms, sleep disorders, and epilepsy that can greatly impact quality of life for people with ASD. Finally, the biological mechanisms by which specific gene mutations cause syndromic autism are now better understood.

Progress Toward the Strategic Plan Objectives

The 2009 IACC Strategic Plan, which was revised in 2010 and 2011, included nine objectives under the heading of Question 2, encompassing seven short-term objectives and two long-term objectives designed to address gaps in current research on the biological basis of autism. IACC Portfolio Analysis data from 2008-2012 indicated that the cumulative investment in research categorized under Question 2 during this period was $362 million. Approximately half of the investments that align with Question 2 were made in gap areas identified in the IACC Strategic Plan objectives, while the other half were invested in core/other research activities on the underlying biology of autism. The substantial activity in core/other research areas indicates long-standing investment in research toward understanding the biology of autism that has been augmented by growth in emerging areas of scientific research.

Of the nine objectives in Question 2, four objectives (addressing fever and immune system interactions with the central nervous system (CNS), biological pathways of genetic conditions related to autism, biological mechanisms of co-occurring conditions, and specific genotypes that underlie ASD phenotypes) met or exceeded the recommended budget and fulfilled the recommended number of projects. The remaining five objectives (studies on females with ASD, raising awareness of brain and tissue donation, characterization of regression, application of biosignatures to diagnosis, and large scale longitudinal studies of diverse populations with ASD) were below the recommended budget and number of projects. However, some progress has been made on all objectives.

Of note, in 2009, NIH received funds from the American Recovery and Reinvestment Act (ARRA) that were used to support a series of initiatives totaling $122 million over 2 years on key scientific areas. The heterogeneity of ASD was one such area, encompassing research on topics that were responsive to the newly released IACC Strategic Plan for ASD Research, such as basic biology of ASD, biomarkers, risk factors, and treatments. This infusion of new funds helped jumpstart efforts to address IACC Strategic Plan objectives and is reflected in the portfolio across all Questions of the IACC Strategic Plan.

Progress in Longitudinal and Comprehensive Examination of the Biological, Clinical, and Developmental Profiles of Individuals with ASD

Autism is considered a neurodevelopmental disorder that begins in early life, and longitudinal studies are necessary to understand how brain function is altered throughout the lifespan. Indeed, much science points to the prenatal period and the first years of life as the critical window for onset and development of ASD. Recent gene expression studies demonstrated that key ASD-related genes and genetic pathways are activated during specific times in fetal development.1, 2 Furthermore, epidemiological studies have found that prenatal conditions and environmental exposures, such as air pollution and certain medication use, are associated with increased risk, while prenatal vitamin use appears to reduce risk.3–8 A recent small, longitudinal study of infants demonstrated normal eye tracking behavior that then declined over 2-6 months after birth predicted later development of autism.9 Another study found that white matter tracts in infants who develop ASD are detectably different from those of neurotypical children at 6-24 months of age.10 Additionally, a number of imaging studies have demonstrated greater brain volume in ASD, but only during a specific early developmental stage.11 Other functional and structural imaging studies are beginning to uncover correlates of ASD differences in processing of visual12 and language13 inputs. New sophisticated techniques to look at brain structure and function such as resting state magnetic resonance imaging (MRI), resting state electroencephalography (EEG), magnetoencephalography (MEG), and magnetic resonance spectroscopy (MRS) are being used to noninvasively examine neural circuits in ASD. Repeated over time, these measures can help chart neurodevelopment. Such techniques hold the potential to be useful for early diagnosis as well as measure efficacy of therapies that harness neuroplasticity to improve functional deficits.

Progress in the Fields of Fever, Metabolism, and Immunity

Research on the potential relationship between the immune system and ASD has grown considerably over the past 2 years, resulting in several major breakthroughs. In the realm of basic developmental research, immune cells and immune signaling molecules have been identified as essential for establishing stable connections between neurons during early brain development.14, 15 Brain tissue studies of the expression patterns of genes have indicated differences in immune pathways in those with autism compared to that of typically developed individuals.16, 17 Of note, the role of immune genes was not detected in population genetic studies, suggesting a non-genetic basis for the immune differences.1, 2 Specific autoantibodies targeting fetal brain proteins have been found in a subgroup of mothers of children with ASD and in some children with ASD.18 These maternal autoantibodies appear to alter neurodevelopment in non-human primates.19 Further, children born to mothers with these autoantibodies were found to have an abnormal brain enlargement in MRI studies compared to that of typically developing controls and persons with ASD without the antibodies.20 Preliminary research findings suggest that metabolic and immune factors may play a role in ASD in some individuals.21–26 Reports of improved behavior in persons with ASD during periods of fever still remain unexplained, warranting further efforts in this area.27

In addition, there have been intriguing new findings with regard to the role of metabolism in autism. For example, a rare hereditary form of autism that presents with epilepsy and intellectual disability is caused by mutation of a gene that codes for the enzyme BCKDK (Branched chain ketoacid dehydrogenase kinase), which prevents the body from breaking down the essential branched-chain amino acids leucine, isoleucine, and valine after eating food.25 When BCKDK is inactivated, individuals cannot maintain adequate levels of the above mentioned amino acids and they experience a deficiency. The problem can be addressed through amino acid supplementation, but research is needed to determine whether supplementation can reverse the autism symptoms associated with this disorder in humans. In a separate study, preliminary findings have linked a rare form of autism with a gene defect that interferes with the body's ability to manufacture carnitine, an amino acid that helps convert fat into energy, suggesting that another form of autism also may be potentially amenable to treatment through nutritional supplements.26 Further work in this emerging field may yield new insights into the mechanisms of ASD and potential for novel treatments.

Progress in Understanding Neurodevelopment in Females

While ASD affects more males than females, there is a growing awareness that ASD in females may be underdiagnosed, potentially due to differences in the manifestations of ASD in females, such as less disruptive behavioral disorders and stronger ability to recognize emotions in facial expressions, which mask symptoms.28, 29 Multiple familial and genetic studies suggest that female gender may protect against autistic behavior and that more genetic disruptions are required to cause autism in females.30, 31 The abnormal brain growth patterns that have been observed in people with ASD are also more pronounced in females than in males.11, 32, 33 One of the newly funded NIH Autism Centers of Excellence (ACE) networks, including Yale University, the University of California Los Angeles, Harvard, and the University of Washington, is now devoted to understanding this potential "female protective factor".34

Progress in the Field of Brain and Tissue Donation

The research community is in extreme need of brain and other types of tissue to enable important studies. One example of the value of brain tissue is the recent study using modern stereological techniques. In this study, researchers observed that young children with autism have 67 percent more neurons in the prefrontal cortex – the region of the brain centrally involved in higher-order social and communication behaviors.35 Since prefrontal neurons are generated in the second trimester, this neuron excess indicates that abnormal brain development in autism begins before birth. These types of studies can only be performed if appropriate brain tissue is available. The Autism BrainNet This link exits the Interagency Autism Coordinating Committee Web site initiative, a multi-site, private effort supported by the Autism Science Foundation, This link exits the Interagency Autism Coordinating Committee Web site the Simons FoundationThis link exits the Interagency Autism Coordinating Committee Web site Autism Speaks, This link exits the Interagency Autism Coordinating Committee Web site and the Nancy Lurie Marks Family Foundation, This link exits the Interagency Autism Coordinating Committee Web site will target autism specifically and will include an autism-specific brain donation outreach campaign to address this need. In the public sector, NIH recently launched the NIH Neurobiobank which includes samples for research on autism as well as other brain disorders and has an associated online publication "Why Brain Donation? A Legacy of Hope" (PDF - 946 KB) to increase awareness about brain donation. As efforts to collect brain tissue progress, the collection of other biological samples from very young children at risk for ASD is another potential opportunity to facilitate multidisciplinary efforts to establish biomarkers of ASD risk.

Progress in Understanding Genetic Conditions Related to Autism and Synaptic Function

The largest area of scientific progress related to Question 2 has come from studies of the biological processes regulated by genes that either cause syndromic forms of autism (Fragile X syndrome, Rett syndrome, Tuberous Sclerosis) or are associated with increased risk of non-syndromic autism. Overlap has been uncovered in the biological mechanisms that give rise to ASD, especially at the level of synaptic function. For instance, deletion or mutation of the SHANK3 gene is known to cause one type of syndromic autism,36 and the Shank3 protein encoded by this gene was found to play a critical role in the function of glutamatergic synapses – those synapses that transmit neuronal signals using the excitatory neurotransmitter glutamate.37 Glutamatergic neurotransmission was also found to be altered in Fragile X and Tuberous Sclerosis, two other syndromes that often include autism.38, 39 A variety of other rare genetic mutations associated with autism have been found to affect synaptic function, raising the question of whether a common synaptic deficit with multiple causes results in autism. After finding these functional deficits at the synapse, investigators have asked whether it is possible to reverse functional synaptic deficits and indeed this has been demonstrated in some animal models.40 Moreover, early stage clinical trials have been mounted to treat Tuberous Sclerosis with rapamycin, a drug that affects synaptic transmission via effects on mTOR signaling,41 and non-syndromic autism with specific synaptic glutamate receptor antagonists.42 Recent studies have shown that oxytocin can alter synaptic function and that the oxytocin receptor gene may be mutated or epigenetically altered in people with ASD.43–45 Consistent with these findings, exciting new clinical trial data suggest that intranasal oxytocin can improve social function in ASD.46, 47

The new field of epigenetics, the study of DNA modifications (such as methylation – the addition of methyl chemical groups onto DNA, causing the "silencing" of genes) that change over time and affect gene expression, have also been explored in ASD-related research. Recent publications have found that the methylation of DNA occurs in several brain regions in autism.48 One report determined that the DNA in typically developing females is less methylated than that of females with ASD. A similar trend is observed in neurotypical males compared to males with ASD.49 Furthermore, new data suggests that there are various genetic alterations and mutations in neurons that may occur during development.50 Evidence suggesting that DNA hypermethylation may be involved in the development of cerebellar abnormalities associated with ASD has also emerged, thus reinforcing the value of integrative genomic approaches in better understanding the etiology of ASD.51

Progress in Understanding Conditions Co-occurring with Autism

Much progress has been made in understanding the prevalence and biology of conditions that commonly co-occur with ASD, including epilepsy, sleep disorders, gastrointestinal (GI) disturbances, attention deficit hyperactivity disorder, and other psychiatric comorbidities.52–57 A recent study found three distinct patterns of specific co-occurring conditions in persons with ASD, which suggests that such groupings of symptoms may represent distinct etiologies with different genetic and environmental contributions.58 In 2012, an NIH workshop on epilepsy and ASD offered recommendations for next steps and research opportunities to better understand seizure disorders in ASD.59 The workshop report reviewed several studies that identified genetic mutations, malfunctioning ion channels, interneuron deficits, and other factors that may play a critical role in ASD with co-occurring seizure disorders. In the field of sleep, abnormalities in circadian rhythms have been identified as potential cause of sleep disorders in ASD.60 Outside the central nervous system, several recent studies have pointed to differences in gut microbiota as playing a potential role in ASD.61–63 In a recent finding, the common co-occurring issue of gastrointestinal (GI) dysfunction was linked to ASD and treatment with a probiotic ameliorated the bacterial, GI, and behavioral changes in a mouse model,62 suggesting the possibility of probiotic treatments to help a subset of individuals whose ASD is accompanied by GI symptoms. Another common issue reported by families with a member on the autism spectrum in a recent research study is the propensity for children with ASD to wander away from safe environments.64 Currently, though wandering/elopement presents an important safety issue for families with children on the spectrum, there is very limited knowledge regarding the biological basis of this behavior and further research is needed in this area.

Progress Toward the Aspirational Goal

The challenges to understanding the underlying mechanisms of ASD are substantial. One opportunity for expanding the research horizon in ASD is to understand the gender-associated protective factors in females, as this might lead to therapeutic breakthroughs. The roles of the immune system in sculpting neural circuits and in neuroinflammation's response to stress also need further elucidation. It is especially important to be able to gauge the effects of maternal immune processes on the developing fetal brain. Careful longitudinal studies of important neurodevelopmental processes are needed as studies examining single time points are likely to miss important occurrences in this dynamic period of brain development. There is still very little known about why certain children with autism are noted to deteriorate over relatively short periods of time. Ongoing longitudinal studies of high risk children may lead to a better understanding of regression and whether it is a distinct syndrome or part of the continuum of neurodevelopmental abnormalities in ASD. The underlying basis for various disabilities (e.g., verbal vs. non-verbal ASD), specific behaviors, heterogeneity in severity, sleep disorders, and gastrointestinal disturbances remain poorly understood and lack effective treatments. A systems biology approach is thus necessary to understand the multifaceted disturbances that occur in ASD.

Many new tools to further reveal the biological basis of ASD are emerging. Launched in 2013, the President's Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative, which aims to map the interactions of individual brain cells and complex neural circuits, is focused on neurotechnology development. It will advance the ability to characterize the cellular differences in ASD compared to typically developing individuals. It also promises to substantially improve the ability to record brain circuit activity that would be helpful to monitor neurodevelopment or to guide therapy in ASD. One such tool that will promote advances relevant to the BRAIN initiative is Clear, Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY), a new technology that aids in the visualization of human brain structure as well as the localization of proteins, neurotransmitters, and gene expression patterns. This neurotechnology is already being used to study the brain of a person affected by autism.65 Induced pluripotent stem cell (iPSC) technology is another revolutionary tool, which enables scientists to transform cells (drawn from simple skin biopsies) into nerve cells.66, 67 Such methods can be used to research biological phenotypes observed in autism (i.e., synaptic dysfunction),37, 68, 69 examine specific genes and pathways that are differentially regulated, and screen drugs for their ability to ameliorate autistic phenotypes.70 Breakthroughs in RNA sequencing (a technique that reveals which genes are being expressed) and epigenetics now allow powerful new studies of gene regulation in brain tissue. In the world of imaging, the NIH's Human Connectome Project aims to produce a detailed map of brain connections in those with ASD and to visualize how this map changes over time from infancy through childhood. These and other techniques bring together tremendously large amounts of data from a variety of tissues and cells to enable systems biology approaches to understand the connections between different systems, including genetics, brain circuits, the immune system, metabolism, and the microbiome. The richness of the data and the variety of tools needed call for a coordinated approach in which findings are replicated and the tools validated so that they can become clinically useful.


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59 Tuchman R, Hirtz D & Mamounas LA. NINDS epilepsy and autism spectrum disorders workshop report. Neurology. 2013 Oct; 81(18):1630–1636. [PMID: 24089385]

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Question 3: What Caused This to Happen and Can It Be Prevented?

Introduction

Aspirational Goal: Causes of ASD will be discovered that inform prognosis and treatments and lead to prevention/preemption of the challenges and disabilities of ASD.

The original version of the IACC Strategic Plan, published in 2009, identified nine objectives focused on research to identify and deepen the understanding of genetic and environmental causes of ASD.  In 2010 and 2011, several new objectives were added. The new objectives emphasized the need to study how environmental autism risks may differ in vulnerable subgroups, and encouraged research that capitalized on new opportunities and approaches in areas such as epigenetics, the microbiome, animal models of ASD and bioinformatics.  Over the past 5 years, a total of $380 million dollars has been invested to support research under Question 3.  Significant advances have occurred in identifying several new genetic and environmental risk factors, and in the initiation and/or expansion of large epidemiologic studies, many of which are responsive to multiple IACC Strategic Plan objectives. Environmental exposure science within ASD studies, inclusion of diverse populations in etiological research, and the use of new animal models for gene/environment research are areas that have not progressed as quickly and remain significant needs within the field. Continued investment is needed to follow-up on recent advances, to address a wide array of gap areas, and to determine the clinical and public health utility of both genetic and environmental findings.  Leveraging the infrastructure of existing large population-based epidemiology studies that are well positioned to address several important questions about environmental risks for autism is a priority that will require significantly increased investment, in addition to continued efforts to obtain new cohort data to capture environmental risks during the relevant windows of susceptibility.

Progress Toward the Strategic Plan Objectives

The 2011-2012 IACC ASD Research Portfolio Analysis reviewed projects funded by both government agencies and private foundations from 2008-2012.  From 2008-2012, the total funding devoted to projects that address Question 3 was $381 million, and if just the years since the publication of the first IACC Strategic Plan in 2009 are considered, the funding for projects related to Question 3 was $298 million.  Also in years 2009-2012, 96 percent of the total was invested in research gap areas identified by the 15 objectives in Question 3, while 4 percent of the total funding went toward research projects outside the IACC Strategic Plan objectives (in the core/other category).

All of the 15 specific objectives under Question 3 have shown progress in funded projects since the publication of the first IACC Strategic Plan. Four objectives addressing multi-site studies of prenatal environmental factors in high risk families, identification of genetic risk factors in people with ASD, large-scale gene-environment interaction studies, and a workshop on bioinformatics met or exceeded the recommended budget and fulfilled the recommended number of projects.  Eleven objectives, concerning identification of genetic and epigenetic markers, environmental exposure risks, and study of special populations, partially met the recommended budget and had a number of projects underway.

Progress in the Field of Genetic Risk Factors

During the past few years there has been a major revolution in ASD genetics research. Using the newest molecular and epidemiological methods, recent data continues to strongly support the role of genes in ASD, and the understanding of this role has been greatly refined. The emerging picture is one of profound complexity. Rather than an exclusive focus on one kind of variation, genetic variation at all scales (from changes at a single DNA base-pair, through small genetic insertions and deletions and larger copy number variations (CNVs), all the way up to extra chromosomes) must be considered, as all can contribute to ASD risk.1, 2 In addition, both common and rare variation (both mutations that are commonly shared across many individuals with ASD and mutations that are very rare or unique) have been found to play a role in ASD risk.1–3

The emergence of new, high- throughput genetic sequencing (HTS) technologies has provided an opportunity to rapidly identify rare and extremely rare genetic variation that occurs spontaneously (is not inherited) in single genes and can impact ASD risk. Data suggest that if these currently available technologies were to be used in the general ASD population, genetic changes that contribute to ASD risk could be identified in at least 30 percent of individuals with ASD.4–11 While the sample sizes analyzed using HTS to date are still too small to identify many new, individual ASD genes, six or seven new ASD genes have been unambiguously identified from the first 1,000 individuals sequenced,5–8, 11–13 with several more likely candidate genes identified as well.14 There are ongoing studies to examine data from a pool of 9,000 individuals with ASD, together with appropriate controls, for a total of at least 20,000 samples. It is anticipated that analysis of HTS data from this larger pool will double the number of known ASD genes, from the currently known genes that have been identified using other methods.1

Recent data also suggest that approximately 40-60 percent15 of ASD risk can be attributed to inherited, common variation (single nucleotide polymorphisms/SNPs) and it is likely that in the future it will be possible to estimate ASD risk by analyzing multiple genetic markers,16 as has been observed in other disorders. Common risk variants interact with other genes and also with the environment. Gene-environment (GxE) interactions are still suspected to be of major importance in ASD, but further work is needed to elucidate the nature of these interactions.17, 18 Based on the results of several studies, the number of genetic loci (or genetic "regions" that can include multiple genes) associated with ASD is now estimated to be near 1,000,5, 14, 19 representing a surprisingly large proportion of genes in the genome (almost 5 percent of the 22,000 genes in the human genome). This suggests that many different genetic pathways may contribute to the development of ASD, and that further research on developmental trajectories (patterns of child development) could provide the potential to associate genetic changes with specific symptoms and behavioral phenotypes.20, 21

New tools for identifying networks of functionally-related genes (groups of genes that work together to perform a function) that influence brain development, (i.e., those being used in the BrainSpan project22, 23 ) have been applied in ASD.  Results have shown that many of the identified risk genes map strongly to defined brain regions and cortical layers, act during specific developmental time windows within the prenatal period, and/or share the same functional pathways. The hope is that it will be possible to identify a smaller number of genes that are the "key drivers" of these pathways that could then become the priority targets for the development of new medicines.

Progress in the Field of Environmental Risk Factors

In 2008, little was known about environmental risk factors for ASD.  Given what had been revealed about ASD's genetic complexity at that time, it was suspected that environmental exposures and gene-environment interaction would likely be important to fully understanding ASD risk.  The California Autism Twin Study This link exits the Interagency Autism Coordinating Committee Web site published in 2011 demonstrated that the environmental component of ASD etiology is probably quite substantial.24 Recent analysis of non-twin family data (from both simplex and multiplex families)5, 6, 11, 15 also supports the idea that mechanisms beyond inherited gene mutations and de novo, or spontaneous, mutations or copy number variants will be necessary for understanding the complex causes of ASD.  The time around conception and during pregnancy are likely the most important time windows of heightened vulnerability for the development of the brain with supporting evidence from early reports linking autism symptoms to maternal ingestion of drugs such as thalidomide25, 26 and valproic acid,26, 27 and infection with congenital rubella,28, 29 as well as more recent reports showing that maternal intake of prenatal vitamins has a "protective" effect, reducing risk for ASD,30–32 and that many genes that have been identified as linked to autism are expressed in the brain during fetal development.22, 23

Over the past 5 years a modest investment has helped achieve good initial progress in identifying potential environmental ASD risk factors – especially considering the environment broadly as  all influences beyond genetic predisposition. Along with the exposures listed above, factors associated with ASD protection or risk that have been replicated in two or more studies include:  protective effect of prenatal vitamin intake,30–32 and risks from prenatal maternal infection,33, 34 preterm birth,35–38 advanced maternal and paternal age at conception39–45 and short inter-pregnancy interval.46, 47 A recent study also showed elevated risk in mothers who used labor induction medications, but it is not clear whether the risk was associated with induction itself or with conditions that may have created the need for use of induction medications.48 Use of certain prescription medications by mothers during the prenatal period49, 50 has also been suggested as a potential risk factor for ASD, although currently there are conflicts in data from different reports and underlying conditions in the parent might explain these associations.50, 51 Ultrasound is another exposure that has been considered a possible risk, but recent studies have shown no association between ultrasound and ASD risk.52, 53 Recent reviews about potential environmental risk factors have compiled lists of exposures of interest for future studies.54–56

Particularly intriguing are the results of prenatal vitamin intake through supplements and diet, showing a 40 percent reduction in risk of ASD with prenatal vitamin supplements taken in the 3 months before or during the first month of pregnancy, but not during pregnancy months 2-9.30 A trend of decreasing ASD risk as mothers consumed greater daily folic acid intake from foods, vitamins, and supplements in the first month of pregnancy was also reported.31 The 40 percent reduction in risk for women who used folic acid supplements in the time around conception was replicated in a large Norwegian cohort study.32 These findings raise challenging issues for public health education, given that a sizable fraction of pregnancies are not planned.  If they represent causal associations, then by the time a woman recognizes she is pregnant, it may be too late for folic acid supplementation for the purpose of reducing ASD risk in her offspring. They also invoke a number of hypotheses related to epigenetic mechanisms in ASDs.

Among modifiable exogenous exposures, the largest number of studies to date has addressed associations of increased ASD risk with  air pollution exposure during gestation and/or early infancy. Multiple studies have reported significant associations;57–62 two studies examining ozone 60, 62 and three that examined nitrogen dioxide (NO2)59, 61, 62 found significant associations with ASD. There is also now suggestive evidence that exposure to endocrine disrupting chemicals such as pesticides, including organophosphates and phthalates may be associated with ASD.63–68 The role of heavy metals in ASD remains an open question, as to date, too few studies have been done to assess exposure to heavy metals during pregnancy, which is the most etiologically relevant window. Further work is needed on all of these exposures to more clearly establish associations and ensure no residual confounding due to socioeconomic factors, and if the association is causal, to determine in which periods the fetus/infant might be most susceptible. Also, replication of findings with direct individual-level exposure measures, perhaps using biomarkers, is needed. A useful future direction in the area of environmental exposures could be to focus on how shared properties of exposures (such as endocrine disruption) map to specific phenotypes of ASD.

Exposure assessment represents an ongoing challenge for discerning a role for the environment in ASD causation.  Evidence points to pregnancy and the early postnatal period as critical windows of vulnerability, yet, until recently, few studies were collecting relevant data in real time during this period.  To address this challenge, two studies using enriched risk designs (investigating subsequent pregnancies in families where one child has already been diagnosed with ASD), the Early Autism Risk Longitudinal Investigation (EARLI) This link exits the Interagency Autism Coordinating Committee Web site and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), were launched with NIH support.  These studies have captured important and unique pregnancy and birth data and biosamples not possible in other cohorts. However, their ultimate success depends on continued funding of these complex longitudinal projects. The most recent plans proposed for the Main Study of the NIH National Children's Study (NCS) may provide additional opportunities for exploring ASD risk with prevalent exposures, or ones that occur throughout pregnancy and can be measured at birth.

Progress in the Field of Gene-Environment Interaction

Although stressed as a critical area in ASD research, very few studies have focused explicitly on gene-environment interaction.  This is in part due to lack of relevant and testable mechanistic hypotheses emerging from the basic sciences and also to the large logistical and resource challenges of assembling sufficiently-sized study populations with both adequate genetic and environmental data.  Despite these obstacles, in the last 3 years several published examples provide empirical support for the long-suspected notion that the influence of environmental factors on ASD risk can be amplified in individuals with specific susceptibility genotypes. The first of these studies demonstrated that in populations that naturally have a lower level of folic acid due to a gene mutation that affects folate metabolism, the reduction in risk of ASD associated with folic acid supplementation during pregnancy is even stronger than that seen in the general population.31 Another study reported that ASD risk associated with prenatal traffic-related air pollution exposure was greater among children with a specific gene mutation that has been linked to autism.69 While these two findings suggest "proof of concept" regarding how genes may interact with environmental factors to increase autism risk, replication is needed. They also underscore the value of investments made to date in large and well-characterized study populations, and the parallel needs to continue expanding these efforts and to support infrastructure for specimen banking associated with such populations.

An area of both progress and opportunity for gene-environment research relates to epigenetics and ASD. As described in the previous chapter, epigenetics refers to modifications of DNA (such as methylation) that change over time and affect gene expression. The role of epigenetics in syndromic forms of autism is well established, and methylation analysis of blood and postmortem brain tissue now implicate epigenetics in the regulation of autism susceptibility genes.  Most recently, a genome-wide examination of DNA methylation in a small sample of postmortem brains revealed several regions with consistent differences in methylation in ASD cases compared to controls.70 Evidence continues to accrue regarding the ability of environmental factors such as nutrition,71 drugs,72 and psychosocial stress73 to regulate transcription of genes throughepigenetic modifications. This idea has not gained sufficient attention in ASD and merits additional research. Obstacles to further progress in elucidating the environmental epigenomics of ASD are the variability of epigenetic markers between and within tissues and over time. These factors make it difficult to use and interpret data from the kinds of biosamples that are typically available in human ASD studies (peripheral blood obtained after diagnosis), again highlighting the need for longitudinal pregnancy studies.

One final breakthrough is a mechanistic link between the environmental risk factor of paternal age and ASD risk, where a mechanism has been identified around the rate of de novo mutations.  Several studies have shown that advanced paternal age at conception is associated with greater risk of ASD.39, 42–45, 74, 75 Separate studies have shown that older fathers produce sperm with greater numbers of de novo mutations,76 while studies in animals have suggested that there are more profound epigenetic changes in sperm from older fathers.74 The causes of these age-related changes in sperm are not yet known, but further exploration could provide key insights about the interface between genes and the environment.

Progress Toward the Aspirational Goal

Investments in the past 5 years have led to identification of new genetic and environmental factors contributing to ASD risk and identified the importance of the conception and gestational periods for the development of ASD. The new gene findings hold promise for a better understanding of the neurobiology of ASD and the development of novel pharmacotherapies. Rare genetic variants, as they are discovered, create both clinical and research opportunities. Genetic tests are now being routinely carried out in individuals who experience unexplained developmental delays. Chromosome microarray (CMA) is already recommended by the American Academy of Pediatrics (AAP) This link exits the Interagency Autism Coordinating Committee Web site and the American College of Medical Genetics (ACMG),77 and can inform some families about some ASD causes, rare but potentially serious comorbid medical conditions, and, in certain cases, the risk of ASD recurrence in future offspring.

In addition, because these rare variants are often associated with major neurophysiologic effects, they provide the opportunity to develop model systems in cells and in animals, where the basic pathobiology of ASD can be worked out, and where potential new medicines can be examined. This approach, carried out in cells in culture — including human neurons induced from individuals with genetic lesions — and in mice and rats, has led to novel treatment approaches. One of the most exciting developments in the past several years in ASD is the emergence of neurobiologically-defined new medicines for subtypes of ASD. Examples include ongoing trials in Fragile X syndrome, Rett syndrome, and Phelan-McDermid syndrome. All three of these result from clearly identified genetic mutations, and all are associated with very high risk of ASD. In some cases, the same drug is being tried as a treatment for individuals with ASD of unknown cause. Families that have a genetic diagnosis can now identify advocacy and family groups with similar mutations and can also choose to participate in relevant clinical trials. While these first trials are still at early stages, they represent the beginning of personalized medicine in ASD based on an individual's genetic findings.

The most recent findings available about the sibling recurrence risk for ASD have important clinical implications for families.  Whereas earlier results from pooled baby siblings research samples suggest a recurrence risk of approximately 18 percent,78 a more recent population-based registry study in Denmark found a substantively lower risk of about 7 percent.79 The research sample rate may be an over-estimate due to selection bias, while the registry study may under-identify affected siblings (especially milder phenotypes).  Consequently, the best estimate may lie somewhere between 7 and 18 percent.  Notably, the Denmark study also found elevated recurrence among maternal half-siblings, which supports the idea of an etiologic role for maternal genetic factors, maternal intrauterine environment, and other prenatal environmental factors common across pregnancies.

Collectively, the candidate exposures studied to date in ASD represent the "first wave" of findings that were made possible by the initiation or continuation of large autism-focused studies such as Childhood Autism Risk from Genes and Environment (CHARGE) This link exits the Interagency Autism Coordinating Committee Web site and the Center for Disease Control and Prevention (CDC)'s Study to Explore Early Development (SEED). The careful extension of existing population-based cohorts has also been important in understanding candidate exposures because these cohorts have enabled linkage to prospectively collected clinical records and biospecimens.  In many cases, early research investments have focused on establishing study infrastructure and have provided only limited support for analyses.  The need to continue cultivating existing investments in this area cannot be overstated. While findings to date are not yet robust enough to inform public health action, the field is now well positioned to address questions regarding ASD-exposure relationships, as well as the identification of genetically, metabolically, or immunologically susceptible subsets of the population. SEED has completed the first phase of data collection for over 2,700 enrolled children, including genetic and environmental exposure data.  These data are expected to be available for analyses in early 2014.

The progress achieved to date in the field of environmental epidemiology of ASD has occurred despite significant challenges in exposure measurement.  To facilitate exposure measurement, Autism Speaks is funding the development and validation of a brief exposure questionnaire that was created by consensus by leading autism environmental science researchers that can be incorporated into a wide range of studies. Some remaining challenges include the limited amount and timing of collection of banked biospecimens.  Also, analysis of non-persistent chemicals in samples collected after diagnosis does not reflect exposures occurring during early development.  Consequently, many studies have relied on maternal recall of exposures, information available in medical records or various indirect methods of assigning exposures, such as using information about the known exposures associated with the residential location(s) where the mother resided during pregnancy.

These exposure assessment challenges are not unique to the field of ASD, and researchers in many other fields are working toward advancing exposure science. As these advances are made, it will be critically important to ensure that they are rapidly incorporated into ASD studies. Research on technologies to precisely monitor exposures in individuals, to accurately measure markers of exposure in banked blood and brain samples, and to consider the totality of an individual's exposures should be harnessed whenever possible to improve detection of environment-ASD relationships. Advances in the development and application of persistent biomarkers of exposure are especially needed so that analysis of current biospecimens can be used as a record for exposures occurring much earlier in development. Specimen banks such as newborn blood spots by some state governments, and cord blood or stem cells by commercial entities have tremendous potential for use in ASD research where they are available. Similarly, the development of biomarkers for exposure using strands from the often-saved first haircut, or using deciduous teeth may be worthwhile strategies for research investments.

There are several additional areas where more work is needed to meet Question 3 objectives.  The first is use of animal models to explore gene-environment interaction.  As noted under Question 2, there are now a substantial number of genetic mouse models that  exhibit neuropathological and behavioral phenotypes that can be used to study ASD. Work on environmentally-induced models of ASD-like symptoms has been limited primarily to valproate and maternal infection, however, and there have been few efforts to use animal models to explore gene-environment interaction.  Another strategy that warrants attention is the systematic evaluation/screening of candidate exposures for their effect(s) on molecular pathways that have been implicated by ASD genetic studies. For example, a recent study reported that defects in topoisomerases (enzymes involved in DNA replication, repair and epigenetic changes) may contribute to ASD by virtue of their importance in the expression of extremely long genes, which are overrepresented among known ASD risk genes.80 This finding provides new leads for identifying exposures that may affect ASD risk through their impact on topoisomerase function. Further development and use of integrative bioinformatics tools that combine information about toxicants with the genes and pathways implicated in ASD provide another means for identifying and prioritizing candidate exposures for further study in ASD studies.

Finally, additional efforts are needed to address barriers to enrollment and retention of racially and ethnically diverse populations in order to ensure their representation in both epidemiologic and clinical studies. This information is critical for identifying vulnerable subgroups and informing public health prevention efforts.  Enhancing the overall diversity of study populations should also prove helpful in detecting environment-ASD associations, as groups underrepresented in clinical studies are often those with disproportionate exposures.

Overall, while many advances have been made in the past 5 years in autism genetics and the study of environmental risk factors, including studies that have confirmed mid-pregnancy as a key time point of vulnerability for development of ASD, much work remains to be done to identify additional contributors and fully understand their complex interaction. Communication between researchers in the autism field and in other fields will be essential in order for advances in exposure science and genetic studies of other disorders to benefit the autism field. In addition, it will be critically important to maintain investment in and build upon existing infrastructure including birth cohorts, networks and databases to accelerate progress, and to ensure that risk is studied in underrepresented groups, in both girls and boys, and in relation to such factors as socioeconomic background and geography.  A strengthened research base to address these issues will be essential to achieve the aspirational goal of discovering "causes of autism…that inform prognosis and treatments and lead to prevention/preemption of the challenges and disabilities of ASD."


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Question 4: Which Treatments and Interventions Will Help?

Introduction

Aspirational Goal: Interventions will be developed that are effective for reducing both core and associated symptoms, for building adaptive skills, and for maximizing quality of life and health for people with ASD.

A review of the state of the science in 2009 noted that many treatments were in use, but little rigorous evidence existed to support their safety or efficacy.1 At that point, the Committee identified intervention research needs from two quite different approaches. One approach, dependent on progress in the basic and translational research areas covered under Questions 2 and 3, called for novel, targeted interventions based on an understanding of the molecular mechanisms of ASD. The other approach, related to the applied research and real-world deployment of tools and services covered in Questions 5 and 6, called for rigorous studies to test the efficacy and safety of interventions that were already in wide use, including behavioral and complementary medicine approaches.

Question 4 in the 2009 IACC Strategic Plan included six objectives, with an additional six objectives (including some with multiple parts) added in the revisions in 2010 and 2011. Altogether, the most recent version of the IACC Strategic Plan recommended a wide range of studies under Question 4, including 19 randomized clinical trials, 20 model system studies to identify treatment targets, and one workshop. The total recommended budget was $283 million across all 12 objectives.

Progress Toward Strategic Plan Objectives

The 2011-2012 IACC Portfolio Analysis reviews ASD projects funded by both government agencies and private organizations from 2008 to 2012. Based on this analysis, the cumulative investment in projects categorized in Question 4 from 2008 to 2012 was $309 million. Focusing on 2009 to 2012, the period after publishing the 2009 IACC Strategic Plan, the total investment was $255 million. This means that on average, the yearly investment in the research area targeted by Question 4 during this period was 18 percent higher than in 2008 ($54 million). It is important to note that from 2009 to 2012, roughly 90 percent of the investments assigned to Question 4 aligned with one of the 12 objectives, which address gap areas in the portfolio, and about 10 percent of the objectives address core/other activities that were not specific to any objective and may represent emerging areas of research not yet captured by the IACC Strategic Plan objectives.

Because most clinical trials require several years for completion, the snapshot of 2012 may be helpful for assessing the current cross-agency portfolio of activities relating to treatments and interventions for ASD. There were 269 projects funded in 2012 at a cost of $64 million, with 240 projects distributed among each of the 12 objectives and 29 projects ($3.9 million) assigned to core/other activities, thus demonstrating the broad range of research currently taking place in this area.

The research portfolio related to four of the objectives was considered to have met the recommended budget and number of projects, including those that called for randomized controlled trials (RCTs) addressing co-occurring conditions, development of model systems, early intervention trials, and studies on interventions for non-verbal/minimally verbal individuals. Eight objectives partially met their recommended number of projects and/or budgets. These objectives included testing safety and efficacy of interventions, investigating biological signatures, health promotion, medication trials, interventions to prevent recurrence in siblings, medications to treat co-occurring conditions, community studies evaluating intervention effectiveness, and a workshop on clinical subtypes and treatment personalization (with regard to the last objective, it was deemed only partially met because the relevant workshops and activities that took place were not exclusively focused on the topic mentioned in the objective, though some of the activities incorporate not only meetings/discussion, but also implementation of projects). 

As noted above, there were 269 active projects in 2012 that were responsive to Question 4, with the large number of studies reflecting the wide variety of research into treatments and interventions for ASD. Despite the numerous avenues currently being pursued, however, many funded psychosocial, behavioral, medication and other biomedical intervention trials are being conducted with small budgets, suggesting that these projects are under-powered to provide the needed evidence for efficacy or safety. It is important to note that some of these projects are exploratory, and thus are appropriately funded with smaller budgets as an initial step, prior to larger scale investment if the strategies yield promising results. Additionally, the absence of therapeutic targets or consensus outcome measures makes interpretation of positive or negative results difficult, although as this field matures and the research moves forward, this problem is likely to resolve.

Again, reflecting the very early stage of intervention development for ASD, nearly one-third of the funding aligned with Question 4 was invested in one objective: the standardization and validation of model systems (such as cellular and animal models) to identify molecular targets or circuits for treatment development. Several objectives that address the assessment of current treatments received less investment. In particular, testing the safety and efficacy of widely-used treatments ($1.3 million in 2012) and studies of interventions for either secondary conditions ($1 million in 2012) or co-occurring conditions (less than $1 million in 2012) received relatively little investment, indicating a need to increase work in these areas. In developing the IACC Strategic Plan, the Committee emphasized the need for research to develop treatments for those most severely disabled by ASD, including those who are minimally verbal. Encouragingly, examination of the research portfolio showed strong growth in research on minimally verbal ASD, reflecting the interest of the research community in seeking to develop new approaches to help this population. Continued investment in this area will be vital to progress.

Overall, there has been considerable activity on Question 4 since the launch of the IACC Strategic Plan in 2009. While the overall financial investment roughly matches and, in many areas exceeds, the recommendations put forth in the IACC Strategic Plan, it is too early to assess the impact of these investments. Although clinical trials of pharmacological interventions for core symptoms of ASD are now underway, they require several years for completion, analysis, and reporting, resulting in very few published findings to date.2 Preclinical studies, which have a shorter delivery time have, however, yielded some remarkable insights, especially on mice with mutations that model syndromic forms of ASD, such as Fragile X or Rett Syndrome.3, 4 In affected mice, experimental treatments reverse the syndrome both in development and in adulthood.5 While these studies give hope, the relationship of syndromic autism (ASD caused by known genetic syndromes) to idiopathic autism (autism of unknown cause) is not clear. Furthermore, in many areas of neuroscience, efficacy of treatments in mice has not translated into efficacy of treatments in human patients. In summary, while there have been significant advances in the areas of genetics and neurobiological studies, the advances have not yet been translated into a full pipeline of molecular, cellular, and systems targets for interventions. The recent interest of pharmaceutical companies in investing in autism has been an encouraging development, as partnerships between government, nonprofit organizations and pharmaceutical companies will be essential to filling the pipeline toward development of new pharmacotherapies for ASD.

The clinical research agenda is also very much a work in progress. The development of Autism Speaks' Autism Treatment Network (ATN) This link exits the Interagency Autism Coordinating Committee Web site and the entry of industry into this area are both promising changes, providing potential venues and support for future trials. While in 2008, only six clinical trials for ASD were listed in ClinicalTrials.gov, currently there are 92 ASD intervention trials recruiting subjects in the United States, including pharmacological studies to address core symptoms.

Recent developments in clinical trials on the use of the naturally occurring hormone oxytocin to address social impairments have yielded promising results. In an initial pilot RCT funded by Autism Speaks, researchers administered oxytocin nasal spray or a placebo to 25 children and teens twice a day for 2 months.6 The children who received oxytocin showed greater improvement in social behaviors compared to those who received the inactive nasal spray. Preliminary results from a larger, follow-on, NIH-funded clinical trial have demonstrated that a single spray of intranasal oxytocin can normalize brain function when performing social tasks, suggesting that oxytocin may be able to enhance social function in children.7 Further research on the efficacy of oxytocin therapy alone and in combination with behavioral therapy will be important areas for future study.

In addition to research on treating core symptoms, other efforts are providing insights into managing the symptoms associated with co-occurring conditions such as attention deficit hyperactivity disorder (ADHD),8–10 epilepsy,8, 9, 11, 12 and disturbances in sleep,13–17 immunity,18, 19 metabolism,20–24 and gastrointestinal (GI) function.25–28 Reflecting the growing focus on co-occurring conditions, in 2012, the Health Resources and Services Administration (HRSA) funded the Autism Intervention Research Network for Physical Health (AIR-P) and the ATN published empirically-validated physician guidelines for the assessment and treatment of GI, sleep, and ADHD symptoms in children with ASD.17, 27–34 In addition, the American Academy of Pediatrics (AAP) This link exits the Interagency Autism Coordinating Committee Web site  published guidelines for treatments of core symptoms, associated symptoms, and the use of complementary and alternative treatments.35

Several clinical trials of behavioral interventions were completed in the last 5 years with some notable successes. These early behavioral intervention trials demonstrated efficacy for significantly improving cognitive, language, and social abilities, as well as adaptive behavior, and have indicated that the improvements seen are maintained over time.36–41 For example, the Early Start Denver Model (ESDM) This link exits the Interagency Autism Coordinating Committee Web site has been shown to be effective in improving cognitive, language, social, and adaptive behaviors as well as in reducing the severity of ASD diagnosis.36, 41 In order to facilitate translation of the ESDM to the community, ongoing effort is focusing on alternate delivery of the intervention, such as through telehealth, community group settings, and parent-delivered approaches.37, 41 Another recent trial of a low intensity and brief intervention called JASPER (Joint Attention Symbolic Play Engagement and Regulation) This link exits the Interagency Autism Coordinating Committee Web site demonstrated significant improvement compared with community treatment.38 The relatively lower intensity of the intervention suggests that JASPER could be widely implemented.

Progress also is being made in educational intervention research. A recent comparative study of LEAP (Learning Experiences and Alternative Program for Preschoolers and their Parents), TEACCH (Treatment and Education of Autistic and Related Communication Handicapped Children), and non-model specific special education intervention approaches showed that in high-quality special education classrooms, all approaches were effective in improving symptom severity, as well as social, behavioral, and communication skills.42 The study found that the quality of the classroom, rather than the specific intervention method, was the most important indicator of how much the child's symptoms improved. Future work on educational intervention approaches will be important not only to develop effective strategies, but also to learn which approaches will work best in specific subsets of children or in particular settings.

As progress on the development of interventions continues, research into biomarkers remains a high priority, and is vital to success in this field. First, identification of molecular and behavioral biomarkers of ASD would help to stratify the population so that treatments could be targeted to those who are most likely to benefit. For example, while as many as 50 percent of children will respond well to behavioral interventions, there is still a lack of biomarkers that can accurately predict response and help match individuals with appropriate treatments.

Additionally, biomarkers are essential as key indicators to establish when therapies are working. Biomarkers showing treatment response can be used to help researchers determine the best age and the best dose (in the case of behavioral interventions, low versus high intensity) at which to deliver therapy to achieve the maximum benefit in terms of brain and behavioral development of children with ASD. Along these lines, a recent study demonstrated that early intensive behavioral intervention correlated with positive change in EEG activity that was associated with improvements in social behavior, providing the first demonstration of a physiological biomarker to indicate the effect of a behavioral treatment.43

Additional biomarkers of treatment success are needed. Until it becomes possible to biologically measure treatment response, negative results from pharmacological and behavioral interventions will be difficult to interpret and positive results may not definitely indicate the requisite dose or duration of treatment. In addition to an improved ability to measure the initial response to treatments, there is also a need for longitudinal studies to evaluate the long-term outcomes of treatments and interventions, including measures of quality of life.44 In summary, autism treatment research remains a young field that shows promise, and the focus must now be on identification of consensus outcome measures (including biomarkers) that are both robust and sensitive to change.

A wide range of treatments with varying degrees of evidence to support them are widely used for ASD. The "practice to research" approach, in which information on interventions that are already in use is collected from large health care systems, registries, from clinical networks such as the ATN, and through virtual, self-reporting networks such as the Interactive Autism Network (IAN), This link exits the Interagency Autism Coordinating Committee Web site could prove useful for assessing current interventions in real-world settings. If fully developed for ASD, the practice to research approach promises to be a fruitful strategy for collecting data on treatment effectiveness, leading more quickly to randomizedclinical trials.

New technologies, including devices to serve as social prosthetics (to provide social feedback or information) or tools for communication assistance, are exciting opportunities for the next generation of interventions in ASD. For example, the National Science Foundation (NSF) currently funds a project to develop a robot designed to act as a social therapy tool, providing an opportunity for individuals with ASD to practice social interactions in a safe and comfortable way without the complexities that are found in human interactions. New technologies are also being used to improve communication abilities of those people with ASD who are minimally verbal. In the future, devices will likely be used in combination with behavioral interventions and medications to create personalized treatments. The combinations of devices, behavioral interventions, and medications will be a profound challenge for research design and regulatory approval, but may prove most useful for children and adults with complex needs.

Along with progress in developing interventions for ASD, there will continue to be a need for access to reliable information about interventions that can be accessed by providers and families considering intervention choices. Encouragingly, the past 5 years have seen the publication of several systematic reviews of interventions as well as the launch of new tools, such as a publicly accessible "Interventions, Treatments and Therapies for Autism" database that provides lay-friendly information about autism interventions (supported by Research Autism in the United Kingdom).45–47

Progress Toward Aspirational Goal

Interventions that are effective for reducing both core and associated symptoms, for building adaptive skills, and for maximizing quality of life and health for people with ASD, will likely need a stronger foundation from the preceding IACC Strategic Plan questions; in particular, information about the stratification of ASD into subtypes (so that interventions can be tailored) and a deeper understanding of the biology of ASD (so that interventions can be effective). While in the past, serendipitous findings based on clinical observation have led to treatments for neuropsychiatric disorders without a deep understanding of the underlying biology, it is anticipated that investment in understanding the mechanisms underlying ASD will facilitate the development of the next generation of treatments. In addition, continued improvement of behavioral, educational and technological interventions will be important. Early intervention to restore a normal developmental trajectory must remain a high priority.

There are now several medications that are being tested in RCTs that are expected to be completed in 2014 or 2015. However, to date, progress on reducing core symptoms has been most evident with early behavioral interventions. The efficacy of these treatments is powerful evidence that ASD core symptoms can be treated, even if medications or devices which might be more rapid and more accessible have yet to be developed. Looking forward, future clinical trials will need to assess quality of life measures as well as reducing symptoms. In addition, effort should be made to scale up interventions that are effective in lab settings so that they may serve the broader community.

Progress has also been made in the development of treatments for several co-occurring conditions, and this continues to be an important avenue of ASD research. Associated conditions and symptoms such as epilepsy, ADHD, anxiety and depression are already being treated effectively, with both medications and behavioral interventions, although more work to improve these approaches and explore the combination of medical and behavioral approaches is needed. Recent guidelines on the management of co-occurring conditions such as sleep disturbances, ADHD, and gastrointestinal (GI) issues are a clear sign of progress for families and providers,17, 27–30, 32–34 with the hope that more evidence-based guidelines will be developed in the future.

Future efforts will need to address the needs of the ASD population across the lifespan. Much of the effort to develop treatments to date has focused on children, yet based on the larger proportion of life that is spent in adulthood, it is possible that the number of adults with ASD may be much larger than the number of children with ASD. Future studies must include development of treatments and interventions for individuals of all ages, including adults and adolescents, as well as children. In addition, treatments must address the needs of the entire spectrum of needs, including those who are minimally verbal individuals and those with intellectual disabilities. Furthermore, interventions must be tailored to the needs of individuals from diverse communities in a manner that is culturally responsive, and parents need to have access to high quality sources of information about available interventions.

While the field of ASD intervention has made important strides in the past 5 years, the need for a wider variety of effective intervention options to meet varying needs remains an outstanding goal. Partnerships between government and private organizations and involvement of families and individuals affected by ASD in research will be essential as the community continues to work toward the aspirational goal of developing interventions that will help all people with ASD to build adaptive skills and maximize quality of life and health.


References

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Question 5: Where Can I Turn for Services?

Introduction

Aspirational Goal: Communities will access and implement necessary high-quality, evidence-based services and supports that maximize quality of life and health across the lifespan for all people with ASD.

The 2009 IACC Strategic Plan, which was revised in 2010 and 2011, delineated nine objectives related to Question 5, which include four short-term objectives and five long-term objectives to address gaps in current policy and services research that will benefit the autism community. These objectives call for studies and demonstration projects addressing issues such as: ways to improve access to services in traditionally underserved populations, developing successful models for self-directed care, evaluating how best to coordinate services across multiple state and local agencies, studying and improving health and safety and reducing mortality in individuals with ASD, implementing and disseminating interventions that have been proven efficacious, and evaluating cost effectiveness of services. The total recommended budget was $71 million across all nine objectives for this question.

Progress Toward Strategic Plan Objectives

The 2011-2012 IACC Portfolio Analysis reviewed projects funded by both government agencies and private foundations from 2008 – 2012. Based on this analysis, the cumulative investment from 2008 – 2012 in projects categorized to Question 5 was $124 million. Approximately 70 percent of the investments assigned to Question 5 were in gap areas addressed by the Question 5 objectives, while 30 percent were in areas covered by the core/other category, which may represent areas of ongoing, mainstream efforts or emerging research areas that have not been captured in the IACC Strategic Plan objectives.

Of the nine specific objectives under Question 5, three objectives addressing access to services and implementation of evidence-based interventions in diverse populations, and evaluation of training for service and support providers, met or exceeded the recommended budget and fulfilled the recommended number of projects. The objective regarding studies to address dental health issues of people with ASD met the recommended number of projects, but the projects were done with less funding than was projected in the budget recommendation and only covered dental services for children. Four specific objectives were far below the recommended budget and number of projects. These include objectives regarding evaluation of state and local coordination of community-based services, projects to examine health, safety, and mortality issues, testing evidence based services for community living settings, and evaluation of programs to increase health and safety. Additionally, one objective, on studies to examine how self-directed community-based services impact individuals across the ASD spectrum, did not have any funding in the past 2 years, though there were some projects in this objective category in earlier years. The committee felt, however, that even with the earlier projects, they did not adequately cover some of the key community-based services, such as those related to employment and housing.

Overall, considerable progress was made in some areas of the services research field related to these nine Question 5 objectives. A growing body of research examines the best strategies to implement evidence-based autism interventions in diverse community settings—especially schools. Large-scale randomized implementation and effectiveness trials have shown that, with appropriate organizational and individual supports, evidence-based interventions developed in university-based research settings can be implemented with fidelity in community settings and result in more positive outcomes than standard community care.1 Implementation science (the study of approaches to delivery of services) is developing within the autism field. It will be important for the autism field to rapidly assimilate new developments from the general implementation science field, such as methods for addressing organizational, provider and consumer level factors to improve services and outcomes, in order to optimize delivery of autism interventions in community settings.

In a related development, the National Professional Development Center on Autism Spectrum Disorders, supported by the U.S. Department of Education (ED), now provides community education and service providers with free information on evidence-based practices for children and adolescents with ASD. The center has also made great progress on the development of web based training programs This link exits the Interagency Autism Coordinating Committee Web site for the dissemination of early educational intervention best practices to states. This provides an opportunity for research examining the effects of such resources on implementation in both rural and urban settings. In the medical arena, with support from Autism Speaks and the Health Resources and Services Administration (HRSA), a wide range of physician and parent tool kits,2 and the first empirically-supported physician guidelines for the treatment of gastro-intestinal conditions,3, 4 sleep conditions,5, 6 and attention deficit hyperactivity disorder (ADHD)7, 8 are now available, defining standards of care and increasing the ability of practitioners to appropriately treat these conditions in service delivery settings. In the realm of safety issues, the Department of Education issued a resource document for restraint and seclusion in 2012 that provided guidance to schools on limiting restraint and seclusion while promoting positive behavioral supports and interventions as a safe and effective alternative.9 Additionally, the first research studies of ASD-associated wandering have been done10, 11 and progress has been made by the National Autism Association This link exits the Interagency Autism Coordinating Committee Web site in developing toolkits This link exits the Interagency Autism Coordinating Committee Web site and information for preventing wandering and by the Department of Justice and the National Center for Missing and Exploited Children This link exits the Interagency Autism Coordinating Committee Web site on quickly and appropriately responding to ASD wandering incidents to reduce injury and mortality.12, 13

The passage and implementation of the Affordable Care Act (ACA) creates the opportunity for states to include behavioral treatments for individuals with ASD as part of their essential health benefits. This determination was based on the growing body of evidence supporting the efficacy of behavioral interventions and provides an example of how scientific advances can support policy changes that benefit the community. The extent to which states will include behavioral treatment coverage within their plans and the effects of the adoption of these benefits on treatment and outcomes remains unclear. Additionally, more than 30 States have explicitly listed autism as a related condition or explicitly included autism in the definition of people served under the State's Medicaid Home and Community Based Services waiver for people with intellectual disabilities, and 10 states offer waivers that specifically cover Applied Behavioral Analysis (ABA). Similar policy changes have been taking place in the military. As of July 25, 2013, TRICARE, the medical benefit plan of the military health system, extended coverage of ABA to non-active duty family members in addition to active duty family members that previously had coverage for this service.

Since 2010, the Centers for Medicare & Medicaid Services (CMS) has undertaken several activities that have provided new information about ASD services available in the community. In 2010, CMS issued a report entitled Autism Spectrum Disorders (ASDs) Services Final Report on Environmental Scan This link exits the Interagency Autism Coordinating Committee Web site (PDF - 2 MB) that describes the results of an extensive literature review of the scientific evidence regarding the efficacy, effectiveness, safety, and availability of ASD-related services and supports, including those funded through federal sources, that support daily living for people of all ages with ASD.14 In 2011, CMS also issued a report on a nine-state study entitled, Report on State Services to Individuals with Autism Spectrum Disorders (ASD) (PDF - 884 KB), which assessed the implementation of evidence-based promising practices through the lens of state experience, summarizing the current state of ASD-related services covered by Medicaid and other sources in each of the nine states.15 The report describes the types of services and supports provided by state and local governments, the sources of funding for programs, and the policy, staffing and implementation issues that states and localities encounter in the administration of programs that serve people with ASD. CMS also issued a report, Autism Spectrum Disorders (ASD): State of the States of Services and Supports for People with ASD (PDF - 2 MB), in 2014. This study assessed existing state programs and supports for families living with ASD in 50 states and the District of Columbia, providing a comprehensive view of services that received support from various federal sources and were made available through state programs across the country.

Internationally, there is also increased focus and funding aimed at monitoring and improving access to services for people with ASD. In 2012, the United Nations (UN) General Assembly unanimously passed a resolution, "Addressing the socioeconomic needs of individuals, families and societies affected by autism spectrum disorders, developmental disorders and associated disabilities," This link exits the Interagency Autism Coordinating Committee Web site calling on governments to monitor and report as well as improve access to healthcare, education, training, and intervention programs for persons with ASD and other developmental disabilities.16 In 2013, the executive board of the World Health Assembly, governing body of the World Health Organization (WHO), adopted the resolution "Comprehensive and Coordinated Efforts for the Management of Autism Spectrum Disorders."17 The resolution was co-sponsored by more than 50 countries and supported by all, including the United States.

A wealth of descriptive studies over the last five years has quantified the economic and health impact of autism on families. In one recent study, the economic cost of autism in the United States was updated, showing a substantial increase in cost across a variety of domains. The overall cost of ASD in the US is now estimated at $137 billion per year and the cost of providing care for each person with an ASD ranges from $1.4 million to $2.3 million over their lifespan, a number that is impacted by intellectual disability of the person.18 This is a dramatic increase from the 2007 estimate of $35 billion per year. Drivers of costs associated with ASD included special education services19 and parental productivity loss.20 These costs were substantially smaller, however, than those related to residential care and individual productivity loss for individuals with ASD in adulthood.

Recent research has also provided a much better and more sophisticated understanding of disparities in the delivery of care to children and adults with ASD. Studies have moved beyond examining disparities in age of diagnosis to examine disparities in components of the diagnostic experience and in service use post-diagnosis.21, 22 Recent findings suggesting that the lifespan of people with ASD is similar to that of typically-developing peers (except in cases where comorbid conditions and accidents cause premature mortality) point to the need for more research to understand and address both comorbid conditions and the challenges of aging with ASD.23

Progress Toward the Aspirational Goal

Health disparities in the diagnosis and treatment of autism now are well described but poorly addressed. Studies must move from observational to experimental, in which strategies to reduce disparities are developed and tested. One issue of particular importance may be whether improving quality of care in traditionally underserved geographic regions is enough to ameliorate disparities, or if instead interventions targeted toward specific cultural and ethnic groups are needed. The Committee highlighted the need for the research portfolio to focus on developing practical, affordable and culturally-competent services and support approaches that can be used in a variety of settings, and for these approaches to be able to be adapted to the required scale to meet community needs.

While considerable strides have been made toward understanding the best ways to implement evidence-based practices in community settings, there is much work left to do in bringing interventions to scale. One barrier to studies that address related issues is the lack of strong, ongoing community-academic partnerships. These partnerships are necessary to conduct field research on effectiveness, implementation and scale-up of evidence-based practices. The Department of Education Institute of Education Science (IES) offered a partnership Request For Applications (RFA) in 2013 and NIMH previously supported a Research Infrastructure Support Program (RISP) mechanism to develop and maintain this type of infrastructure. On a related note, most implementation or effectiveness studies have examined one intervention at a time in single service systems. Many, if not most, individuals with ASD receive multiple services concurrently in response to complex needs. Methods are needed to account for, and perhaps coordinate or simplify this complexity.

Progress in this area also has been hampered by some significant measurement issues. Currently there are few instruments that are appropriate for use at the population level to measure either availability or quality of services, or outcomes of these services. State agencies already may collect some of these important measures or may have the infrastructure to do so, suggesting the need for a different type of public-academic partnership. This measurement is urgently needed to provide a benchmark for the success of different programs at improving the health of the population and to identify models of excellence.

One important recent development is the investment by the NIH in a series of three initiatives to support research on services implementation across the lifespan, with the goals of addressing the challenges of improving outcomes for children, adolescents and adults. The first initiative targets models for coordination of ASD identification, evaluation, and early intervention services for children with ASD within the first two years of life, including tests of the feasibility and effectiveness of interventions across settings.24 The second focuses on models to assist adolescents with ASD to transition to adult supports and services while preventing lapses in services and supports, enhancing functioning across settings, and maintaining or improving ASD symptoms, general health, safety, and quality of life.25 The third addresses development of adult ASD service strategies that concern areas of employment and training, social relationships, physical and mental health, and independent functioning, including community housing and safety, alone or in combination, with the ultimate goal of improving behavioral, functional and health outcomes.26 Awards for all three initiatives are expected in 2014.

In the past several years, while important strides have been made in estimating the economic impact of autism, there is still a need for more information on the cost effectiveness of services that can help support policy decisions. New cost effectiveness research should take a lifespan approach to assess long-term costs and benefits. Economic cost is not the only cost however, and should not be examined at the expense of other potential benefits of intervention. The concept of "social return on investment" may be an important one to examine. One possibility to address both types of return on investment is to take advantage of ongoing or recently completed randomized trials to continue to follow both the experimental and control conditions to determine the long-term impacts of these interventions.

In the past 5 years, the IACC and private organizations have helped raise a new level of public awareness of safety issues such as seclusion, restraint and wandering that have had significant impact on the ASD community.27, 28 Some initial steps toward disseminating information and data gathering activities have begun, but much more progress is needed in order to reduce the number of incidents, injuries and deaths associated with these preventable circumstances.

Overall, there are many opportunities for increased investment in ASD services research to fill important gaps in knowledge about what services are needed, how to best deliver them, which services work for which communities and strategies to increase uptake of best practices across settings. With infusion of additional support, infrastructure such as state demonstration programs that have been established within the past 5 years could provide an important opportunity for new research partnerships that could yield valuable information about services approaches in real-world settings. Such innovative approaches and resulting research data will be needed in the future to support progress toward the IACC Question 5 aspirational goal of creating an environment where "communities will access and implement necessary, high-quality, evidence-based services and supports that maximize quality of life and health across the lifespan for all people with ASD."


References

1 Mandell DS, Stahmer AC, Shin S, Xie M, Reisinger E, Marcus SC. The role of treatment fidelity on outcomes during a randomized field trial of an autism intervention. Autism Int. J. Res. Pract. 2013 May; 17(3):281–295. [PMID: 23592849]

2 Autism Speaks. Tool Kits. This link exits the Interagency Autism Coordinating Committee Web site

3 Coury DL, Ashwood P, Fasano A, Fuchs G, Geraghty M, Kaul A, Mawe G, Patterson P, Jones NE. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics. 2012 Nov; 130 Suppl 2S160–168. [PMID: 23118247]

4 Furuta GT, Williams K, Kooros K, Kaul A, Panzer R, Coury DL, Fuchs G. Management of constipation in children and adolescents with autism spectrum disorders. Pediatrics. 2012 Nov; 130 Suppl 2S98–105. [PMID: 23118260]

5 Sikora DM, Johnson K, Clemons T, Katz T. The relationship between sleep problems and daytime behavior in children of different ages with autism spectrum disorders. Pediatrics. 2012 Nov; 130 Suppl 2S83–90. [PMID: 23118258]

6 Malow BA, Byars K, Johnson K, Weiss S, Bernal P, Goldman SE, Panzer R, Coury DL, Glaze DG. A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents with autism spectrum disorders. Pediatrics. 2012 Nov; 130 Suppl 2S106–124. [PMID: 23118242]

7 Sikora DM, Vora P, Coury DL, Rosenberg D. Attention-deficit/hyperactivity disorder symptoms, adaptive functioning, and quality of life in children with autism spectrum disorder. Pediatrics. 2012 Nov; 130 Suppl 2S91–97. [PMID: 23118259]

8 Mahajan R, Bernal MP, Panzer R, Whitaker A, Roberts W, Handen B, Hardan A, Anagnostou E, Veenstra-VanderWeele J. Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics. 2012 Nov; 130 Suppl 2S125–138. [PMID: 23118243]

9 US Department of Education. Restraint and Seclusion Resource Document (PDF - 1 MB) 2012 May.

10 Solomon O, Lawlor MC. 'And I look down and he is gone': narrating autism, elopement and wandering in Los Angeles. Soc. Sci. Med. 1982. 2013 Oct; 94106–114. [PMID: 23890970]

11 Anderson C, Law JK, Daniels A, Rice C, Mandell DS, Hagopian L, Law PA. Occurrence and family impact of elopement in children with autism spectrum disorders. Pediatrics. 2012 Nov; 130(5):870–877. [PMID: 23045563]

12 National Autism Association. Big Red Toolkit. This link exits the Interagency Autism Coordinating Committee Web site

13 Lowery R. Missing Children With Special Needs. (PDF - 986 KB) 2013 Jul.

14 Young J, Corea C, Kimani J, Mandell DS. Autism Spectrum Disorders (ASDs) Services Final Report on Environmental Scan. This link exits the Interagency Autism Coordinating Committee Web site (IMPAQ International, 2010 Mar). 112.

15 Centers for Medicare & Medicaid Services. Report on State Services to Individuals with Autism Spectrum Disorders (ASD) (PDF - 884 KB) 2011 Apr.

16 United Nations General Assembly. Resolution 67/82: Addressing the socioeconomic needs of individuals, families and societies affected by autism spectrum disorders, developmental disorders and associated disabilities. This link exits the Interagency Autism Coordinating Committee Web site 2012 Dec.

17 The World Health Organization, Executive Board. Resolution EB133. R1: Comprehensive and coordinated efforts for the management of autism spectrum disorders. This link exits the Interagency Autism Coordinating Committee Web site (PDF - 45 KB) 2013 May.

18 Mandell DS. Estimating the Economic Costs of Autism. 2012 Mar.

19 Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. Economic Burden of Childhood Autism Spectrum Disorders. Pediatrics. 2014 Mar; 133(3):e520-9. [PMID: 24515505]

20 Cidav Z, Marcus SC, Mandell DS. Implications of childhood autism for parental employment and earnings. Pediatrics. 2012 Apr; 129(4):617–623. [PMID: 22430453]

21 Liptak GS, Benzoni LB, Mruzek DW, Nolan KW, Thingvoll MA, Wade CM, Fryer GE. Disparities in Diagnosis and Access to Health Services for Children with Autism: Data from the National Survey of Children's Health: J. Dev. Behav. Pediatr. 2008 Jun; 29(3):152–160. [PMID: 18349708]

22 Cidav Z, Lawer L, Marcus SC, Mandell DS. Age-Related Variation in Health Service Use and Associated Expenditures Among Children with Autism. J. Autism Dev. Disord. 2013 Apr; 43(4):924–931. [PMID: 22941343]

23 Bilder D, Botts EL, Smith KR, Pimentel R, Farley M, Viskochil J, McMahon WM, Block H, Ritvo E, Ritvo RA, Coon H. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study. J. Autism Dev. Disord. 2013 May; 43(5):1196–1204. [PMID: 23008058]

24 National Institute of Mental Health. RFA-MH-14-100. Services Research for Autism Spectrum Disorder across the Lifespan (ServASD): Research on Early Identification and Linkage to Services for ASD (R01). 2013 May;

25 National Institute of Mental Health. RFA-MH-14-101. Services Research for Autism Spectrum Disorder across the Lifespan (ServASD): Pilot Research on Services for Transition-Age Youth (R34). 2013 May;

26 National Institute of Mental Health. RFA-MH-14-102. Services Research for Autism Spectrum Disorders across the Lifespan (ServASD): Pilot Studies of Services Strategies for Adults with ASD (R34). 2013 May;

27 Interagency Autism Coordinating Committee. IACC Letter to Secretary Sebelius on Wandering. 2011 Feb;

28 Interagency Autism Coordinating Committee. IACC Letter to the Secretary on Seclusion and Restraint. 2011 Sep;

Question 6: What Does the Future Hold, Particularly for Adults?

Introduction

Aspirational Goal: All people with ASD will have the opportunity to lead self-determined lives in the community of their choice through school, work, community participation, meaningful relationships, and access to necessary and individualized services and supports.

Positive, early childhood experiences can help increase the likelihood of better outcomes in adulthood. However, gains that were hard-won in childhood are at risk of losing traction during the period of new challenges associated with the transition to adulthood. The nature and availability of supportive services change dramatically as youth age out of eligibility for special education.1, 2 Families and adults on the autism spectrum need to navigate an entirely new terrain of services. The social-ecological context of development, which encompasses how individuals interact with the communities and systems around them, also changes radically upon leaving secondary school.

Adulthood brings new challenges related to the attainment and performance of social roles, shifts in family roles and relationships as parents age, and coping with the accumulation of a lifetime of financial and psychological stressors. Co-occurring mental health conditions also present an area of great challenge for many adults on the autism spectrum.3, 4 For some, adulthood may also introduce new abilities, declining impairment severity, discovery of new ways to participate and contribute in communities, and new opportunities for achieving health and well-being. For others, particularly those with significant intellectual impairment, severe behavioral and communication challenges persist into adulthood, often with additional complications such as epilepsy.5 As in other stages of life, there must be a wide variety of approaches available to adults to reflect the broad diversity of challenges found in home and community contexts and to support improved outcomes for people across the entire autism spectrum.

The 2009 IACC Strategic Plan emphasized the need for research on individual-level interventions to improve outcomes for adults with ASD. This remains an important area for research, and some progress has been made. However, there have been important changes in thinking over the past few years about how best to support the success of adults on the autism spectrum. There have been calls for research performed in real-world settings that focuses on outcomes related to quality of life, and interventions that target the social environment and not just the individual. There also has been a growing recognition of the need for researchers to build the evidence base through partnerships with community agencies and businesses that are developing promising innovations rather than in academic research settings.

Progress Toward Strategic Plan Objectives

The 2009 IACC Strategic Plan, including revisions in 2010 and 2011, called for eight objectives within Question 6 that the Committee viewed as gap areas. Under this question there are four short-term objectives and four long-term objectives that highlight the need for research about transitioning youth, adult diagnosis, and adult interventions. The total recommended budget was $54 million across all eight objectives for this question.

Of the eight objectives under Question 6, three objectives address the impact on quality of life for adults utilizing various services, including  aspects of the service delivery system such as educational and health services , specialized training for direct care providers, and interventions and services received during childhood. The recommended number of projects was fulfilled for these objectives and the recommended budgets were partially met. Two objectives regarding the evaluation of existing disability programs for their effectiveness in meeting the needs of transitioning youth and adults and the development of community-based interventions partially met the recommended budget levels and had active projects underway to accomplish the objective. Another two objectives, with projects to develop methods to identify adults and link them to services, and to conduct implementation research of services for adults, were far below the recommended budget and number of projects. Finally, one objective to conduct comparative effectiveness research to examine community-based interventions, services, and supports for adults has had only 2 projects in the past 5 years, and in the most recent 2 years did not have any funding or projects. The Committee raised the question of whether there are yet enough empirically solid adult interventions to make it possible to conduct comparative effectiveness studies.

The Committee noted that an overarching issue in the current organization of the IACC Strategic Plan objectives was that  grouping of several distinct topics into each objective made it challenging to assess progress, and that future iterations might potentially benefit from further division into discrete topics such as community housing, life transitions, employment, and services/supports for older adults.

There have been several notable advances in research in this area over the past 5 years.  A number of studies have begun describing young adult outcomes,6 service needs and access,7 and service program models.2 Systematic reviews have examined extant research on services and interventions.8 Examples of community-based participatory research have also emerged, such as adaptation of surveys to allow for more active participation of adults with ASD in reporting on health care experiences.9 In one such survey, when compared with the general population, adults with ASD reported several concerns such as lower satisfaction with patient-provider communication and higher odds of unmet physical and mental healthcare needs, providing useful information about specific parts of the healthcare experience that can be improved.9

Despite these advances, the rate of production of scientific knowledge about the experience of autism in adulthood remains very low. The generalizability of findings from many of these studies is limited by small sample sizes, lack of information about the socioeconomic and ethnic-racial characteristics of study subjects, and issues with research design and methodology.8, 10, 11 The quality of studies conducted through 2011 regarding vocational programming,12 pharmacology,13 social skills interventions,10 and psychosocial interventions,14 remains in an emergent state.

The growing number of adults with autism due to increased awareness and diagnosis, as well as the transition of children and adolescents into adulthood has reinforced the sense of urgency around research that can guide national policy recommendations for supports and models of employment, community living, and continued education.  Much growth in ASD program innovations is occurring outside of the traditional academic realm,15 and this body of practice-based knowledge should be incorporated along with more traditional research efforts as an important driver of future investigations.

Progress Toward the Aspirational Goal

Longitudinal data on life course pathways and outcomes, evaluation of service innovations in partnership with community agencies, understanding the positive contributions people on the autism spectrum can make to society, financial impacts on families, and improved ability to measure outcomes at the population level are all areas of research where work is required to continue progress toward the aspirational goal. The majority of a typical lifespan is spent in adulthood. However, this is the stage of life that is still the least understood in ASD. In recent years, awareness of the needs of adults on the autism spectrum has increased to some extent, and more data on services gaps and outcomes have become available. For example, results of a recent meta-analysis suggest that adults with ASD experience a lower quality of life than adults without ASD, and that this trend extends into older adulthood.16

Given the relatively limited existing data, more research focus should be directed toward understanding how ASD unfolds across the lifespan by conducting longitudinal studies that extend into adulthood. Longitudinal studies have paid dividends in basic science knowledge for other developmental disorders like Fragile X syndrome and Down syndrome and have the potential to yield similar benefits for autism. In addition, more detailed studies of the needs of adults on the spectrum are required to better understand the nature of these needs and to determine which services will best support individuals across the lifespan with the greatest return on investment for society.

Several seminal studies have been published that provide basic epidemiological description of the prevalence and correlates of various outcomes of the transition into early adulthood, along with risks and protective factors. Through these, we are learning more about the high prevalence of co-occurring health and psychiatric disabilities in adults,4, 17 and the need for physicians with specialized training to provide care for adults with ASD.7 Analysis of state developmental disability services data found the rate of self-injurious and destructive behaviors was twice as high in middle-aged adults with ASD and intellectual impairment compared to those with only intellectual disability, signaling the urgency of treatment and policy to address severe behavioral problems.18 A follow-up to a 1980s statewide autism prevalence study in Utah to investigate mortality among individuals with ASD found that elevated mortality risk associated with ASD appeared to be related to the presence of co-occurring medical conditions and intellectual disability rather than ASD itself, suggesting the importance of access throughout life to coordinated medical care for this high risk sub-population.19

Cohort studies have revealed a high rate of complete disconnection of young adults from any work or education during the first several years after high school – greater than 50 percent during the first two years after exiting high school.20 The rate of disconnection was higher compared to youth with other disabilities even after adjusting for correlates. The latest research data indicate that outcomes are particularly poor for young adults from socially disadvantaged families and for those who have greater levels of impairment. 20–22

Employment has been a particular area of research focus. One recent study found that for adults with ASD, the rate of ever having a paid job in the first eight years after high school is about 50 percent - much lower than among youth with other types of disability.22, 23 In addition, the types of jobs were limited in range, and average rate of pay was not adequate to support independent living.22, 23 The study also found that even among people with ASD who had severely impaired conversational abilities, approximately one-fifth did become employed, highlighting the potential for employment even among those with high levels of impairment.22 In another study, researchers found that adults with ASD who engaged in work had greater vocational independence and were more likely to have fewer maladaptive behaviors and improved activities-of-daily-living skills five years later.23, 24 Research findings also suggest that vocational outcomes are better for individuals who do not work in sheltered workshop settings prior to participating in supported employment.25 Recent work toward development of vocational indexes that can facilitate standardized measurement of a full range of vocational and educational outcomes will enhance researchers' ability to study trajectories of development during adulthood and measure the impact of interventions and services aimed at promoting independence.26

Over the past 5 years, more knowledge has been gained about the social and mental health issues faced by adults on the autism spectrum. Research suggests that the experience of social isolation is more pronounced in young adults with ASD than those with other types of disabilities.27, 28 Increased levels of loneliness appear to have a negative effect on mental well-being.29 With regard to residential status, research has found that young adults on the autism spectrum are more likely to have lived at home, to never have lived elsewhere on their own, and to have required more supervision compared to adults with other disability types.21

In the arenas of intervention and services research, which are more thoroughly addressed in Questions 4 and 5 of the 2013 IACC Strategic Plan Update, much research has focused on psychosocial interventions with noted improvement with use of methods like applied behavior analysis and social cognition training.14, 30 Development and adaptation of social skills interventions for people with severe intellectual disability is a continuing need.10

What Gaps Have Emerged in the Past Two Years?

Several gaps—and opportunities—have become clear in the past two years. Using the World Health Organization (WHO)'s biopsychosocial framework for understanding disability, several areas for further ASD adults services research efforts can be defined.31 Overall, currently there is a limited knowledge base regarding the needs of adults on the autism spectrum as they relate to severity of impairment at all levels. The Committee noted particular urgency for increasing research directed at understanding and meeting the needs of those on the more severely-affected end of the autism spectrum, and for the development of services approaches and service delivery models that will improve quality of life for adults with severe disability. These include approaches to address issues of employment, housing, health, social life, recreation and other issues that influence how a person with ASD integrates into adult society.

Research gaps within the medical/health arena (the "biological" level of analysis in the WHO framework) include the limited understanding of the course of co-occurring health conditions through adulthood, limited research on the course of neurological development in later stages of life, and limited studies of the long-term outcomes associated with use of various types of interventions. Programs of research addressing questions about the maturation and aging process in disability conditions such as Fragile X syndrome and Down syndrome may represent opportunities for asking similar scientific question about the process of aging in ASD.

Gaps in the mental and behavioral health arenas (the "psychological and behavioral" level of analysis in the WHO framework) include continued difficulty describing the heterogeneity of the autism spectrum in ways that are informative for treatment planning and policy making. Developing strategies for intervening in complex cases with both severe developmental and mental health challenges remains an area where the knowledge base needs to be expanded. With increasing awareness of co-occurring conditions that affect people with ASD and recent data suggesting that co-occurring conditions such as epilepsy can be a cause of elevated mortality, it is important to understand the pattern of emergence of these conditions in order to anticipate and work toward prevention of the secondary effects of these added challenges. There is a strong need for more studies that characterize the heterogeneity of development and outcomes in ASD in middle and later stages of adulthood.

There also continue to be major gaps in knowledge at the "social and population health" levels of analysis. There is limited knowledge of the ways in which people on the autism spectrum contribute to communities and society. Strategies being examined in health and mental health services research, such as peer mentoring and navigation, may represent opportunities for adaptation. A growing autism self-advocacy movement increases opportunities for collaborative research partnerships. With respect to adults who remain dependent on their families for care, very little is known about the needs of these individuals and what approaches will provide the greatest help to families planning for the transition when parents are no longer able to care for their dependent adult child.

Identification and surveillance of autism in adults, and development of screening and diagnostic tools for use in adult populations also remain important needs. There is an ongoing study to adapt the Autism Diagnostic Observation Schedule (ADOS) modules 1 and 2 for use in adults, but multiple projects testing different approaches would be optimal. It is important for the tools that are being developed to be efficient so they can be readily employed in large, community based settings. There is also a need for screening and diagnostic tools to be adaptable to different settings and cultural contexts, including international settings. For example, a study conducted in 2012 illuminated the need for adaptation of diagnostic tools for Latino populations.32 Along with the development of screening and diagnostic tools, attention needs to be focused on ensuring that there is an available network of services for those who receive a diagnosis and that diagnosis does not inadvertently result in a loss of services and supports.

Outcome measures are needed for quality of life in adults with ASD. It is important to understand what outcomes are meaningful to adults with ASD and their families. Person-centered outcomes strategies and measures should be developed. Achieving validity and reliability of such measures across the lifespan and full range of the autism spectrum remains a significant challenge.

ASD affects multiple domains and many adults are simultaneously involved in different types of services and interventions. Research is needed to better understand the challenges entailed in navigating the service system and how family finances are impacted over the lifespan. Most research remains focused on one intervention at a time, not taking into account the complexity of systems of care in real-world settings. There is little understanding of how nonprofit and government service providers and systems are adapting to the growing number of adults on the spectrum. Advances in conceptualizing and measuring social return on investment and patient preferences could be adapted to build a stronger basis upon which to study the population-level benefits of societal investment in adult services.

As mentioned in the preceding chapter on Question 5, NIH has recently launched a series of three initiatives to support research on services implementation across the lifespan, with the goals of addressing the challenges of improving outcomes for people with ASD across the lifespan.  Of relevance to Question 6, one of the initiatives focuses on models to assist adolescents with  ASD to transition to adult supports and services while preventing lapses in supports and services, enhancing functioning across settings, and maintaining or improving ASD symptoms, general health, safety, and quality of life.33 Another addresses development of adult ASD service strategies that concern areas of employment and training, social relationships, physical and mental health, and independent functioning including community housing and safety, alone or in combination, with the ultimate goal of improving behavioral, functional and health outcomes.34 Awards are expected in 2014.

Some exciting developments in other sectors and fields may hold promise for adaptation and examination in the context of ASD research. Much growth in ASD program innovation is occurring outside of the traditional academic realm, highlighting a need for more community-based research and research on promising practices that can be replicated and adapted in various settings. There is growing interest in social networks and health outcomes, especially because of the concerns of many parents about what will happen to their child after they are gone. Significant advances have been made in other fields in investigating complex systems, social networks, and factors related to successful knowledge translation and program implementation. Much could be gained by fostering transdisciplinary research to leverage these and other advances being made in other fields. The field of continuous quality improvement is receiving a lot of attention in health services research; the corresponding potential for building practice-based evidence remains largely untapped in ASD, providing an opportunity for future studies.

A number of states have created dedicated autism agencies or bureaus and state-level ASD advisory commissions. There is a growing interest among these stakeholders in improving systems for collecting data about services and outcomes. Combined with technological advances in data aggregation and mining, there is an opportunity to pilot test methods for obtaining these data using community-, state-, and national level population indicators of unmet needs, services access, and outcomes.

Summary and Recommendations

Since the release of the IACC Strategic Plan in 2009, the adult services research field has made some important advances, including gathering of new data on the services available across the states, information about how adults are interacting with the service system, and data on the service needs of adults on the autism spectrum. Data have shown tremendous gaps in the service system that need to be addressed by innovative services approaches that are cost-effective and can be adapted to use in a broad variety of settings. While recent systematic reviews about adult interventions and services have noted the need to increase the evidence base to support access to services,14 the research field is beginning to yield promising randomized controlled trial results35 that have already influenced service provision in many states and service providers and businesses have been rolling out innovative promising practices. Moving forward, partnerships between academic researchers and state, local and private service providers will play an important role in building a body of practice-based evidence that can support effective service provision strategies. This work may also be helpful in filling the gap in effective methods for measuring population level outcomes that can indicate whether efforts implemented at agency and community levels are translating to improvements in the well-being of the population.  While adult services remain a major frontier in autism research, increased investment in this area holds great potential to strengthen the service system with approaches and practices grounded in a strong evidence base, with the ultimate goal of providing all people with ASD with access to the services and supports they need to maximize their health, fully participate in community life, and live self-determined lives.


References

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2 Smith LE, Greenberg JS, Mailick MR. Adults with autism: outcomes, family effects, and the multi-family group psychoeducation model. Curr. Psychiatry Rep. 2012 Dec; 14(6):732–738. [PMID: 23015048]

3 Tsakanikos E, Sturmey P, Costello H, Holt G, Bouras N. Referral trends in mental health services for adults with intellectual disability and autism spectrum disorders. Autism Int. J. Res. Pract. 2007 Jan; 11(1):9–17. [PMID: 17175570]

4 Joshi G, Wozniak J, Petty C, Martelon MK, Fried R, Bolfek A, Kotte A, Stevens J, Furtak SL, Bourgeois M, Caruso J, Caron A, Biederman J. Psychiatric comorbidity and functioning in a clinically referred population of adults with autism spectrum disorders: a comparative study. J. Autism Dev. Disord. 2013 Jun; 43(6):1314–1325. [PMID: 23076506]

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6 Anderson DK, Liang JW, Lord C. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J. Child Psychol. Psychiatry. 2013 Dec.[Epub ahead of print] [PMID: 24313878]

7 Bruder MB, Kerins G, Mazzarella C, Sims J, Stein N. Brief report: the medical care of adults with autism spectrum disorders: identifying the needs. J. Autism Dev. Disord. 2012 Nov; 42(11):2498–2504. [PMID: 22427260]

8 Shattuck PT, Roux AM, Hudson LE, Taylor JL, Maenner MJ, Trani JF. Services for adults with an autism spectrum disorder. Can. J. Psychiatry Rev. Can. Psychiatr. 2012 May; 57(5):284–291. [PMID: 22546060]

9 Nicolaidis CRaymaker D, McDonald K, Dern S, Boisclair WC, Ashkenazy E, Baggs A. Comparison of healthcare experiences in autistic and non-autistic adults: a cross-sectional online survey facilitated by an academic-community partnership. J. Gen. Intern. Med. 2013 Jun; 28(6):761–769. [PMID: 23179969]

10 Walton KM, Ingersoll BR. Improving social skills in adolescents and adults with autism and severe to profound intellectual disability: a review of the literature. J. Autism Dev. Disord. 2013 Mar; 43(3):594–615. [PMID: 22790427]

11 Warren Z, Taylor JL, McPheeters ML, Worley K, Veenstra-Vander Weele J. Future Research Needs: Interventions for Adolescents and Young Adults With Autism Spectrum Disorders: Identification of Future Research Needs From Comparative Effectiveness Review No. 65. (Agency for Healthcare Research and Quality (US), 2012). at <http://www.ncbi.nlm.nih.gov/books/NBK121979/> [PMID: 23447831]

12 Taylor JL, McPheeters ML, Sathe NA, Dove D, Veenstra-Vanderweele J, Warren Z. A systematic review of vocational interventions for young adults with autism spectrum disorders. Pediatrics. 2012 Sep; 130(3):531–538. [PMID: 22926170]

13 Dove D, Warren Z, McPheeters ML, Taylor JL, Sathe NA, Veenstra-VanderWeele J. Medications for adolescents and young adults with autism spectrum disorders: a systematic review. Pediatrics. 2012 Oct; 130(4):717–726. [PMID: 23008452]

14 Bishop-Fitzpatrick L, Minshew NJ, Eack SM. A systematic review of psychosocial interventions for adults with autism spectrum disorders. J. Autism Dev. Disord. 2013 Mar; 43(3):687–694. [PMID: 22825929]

15 Autism Speaks. Employment Think Tank Report. (2012Jun;). at <http://www.autismspeaks.org/sites/default/files/as_think_tank_exec_summary_web1.pdf This link exits the Interagency Autism Coordinating Committee Web site (PDF - 2 MB)>

16 Van Heijst BF, Geurts HM. Quality of life in autism across the lifespan: A meta-analysis. Autism Int. J. Res. Pract. 2014 Jan. [Epub ahead of print] [PMID: 24443331]

17 Kohane ISMcMurry A, Weber G, MacFadden D, Rappaport L, Kunkel L, Bickel J, Wattanasin N, Spence S, Murphy S, Churchill S. The co-morbidity burden of children and young adults with autism spectrum disorders. PloS One. 2012 7(4):e33224. [PMID: 22511918]

18 Kats D, Payne L, Parlier M, Piven J. Prevalence of selected clinical problems in older adults with autism and intellectual disability. J. Neurodev. Disord. 2013 5(1):27. [PMID: 24066979]

19 Bilder D, Botts EL, Smith KR, Pimentel R, Farley M, Viskochil J, McMahon WM, Block H, Ritvo E, Ritvo RA, Coon H. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study. J. Autism Dev. Disord. 2013 May; 43(5):1196–1204. [PMID: 23008058]

20 Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, Wagner M, Taylor JL. Postsecondary education and employment among youth with an autism spectrum disorder. Pediatrics. 2012 Jun; 129(6):1042–1049. [PMID: 22585766]

21 Anderson KA, Shattuck PT, Cooper BP, Roux AM, Wagner M. Prevalence and correlates of postsecondary residential status among young adults with an autism spectrum disorder. Autism Int. J. Res. Pract. 2013 Sep. [Epub ahead of print][PMID: 23996904]

22 Roux AM, Shattuck PT, Cooper BP, Anderson KA, Wagner M, Narendorf SC. Postsecondary employment experiences among young adults with an autism spectrum disorder. J. Am. Acad. Child Adolesc. Psychiatry. 2013 Sep; 52(9):931–939. [PMID: 23972695]

23 Cimera R, Burgess S. Do adults with autism benefit monetarily from working in their communities? This link exits the Interagency Autism Coordinating Committee Web site J. Vocat. Rehabil. 2011 May; 34(3):173–180.

24 Taylor JL, Smith LE, Mailick MR. Engagement in Vocational Activities Promotes Behavioral Development for Adults with Autism Spectrum Disorders. J. Autism Dev. Disord. 2013 Nov. [Epub ahead of print]; doi:10.1007/s10803-013-2010-9 [PMID: 24287880]

25 Cimera RE, Wehman P, West M, Burgess S. Do sheltered workshops enhance employment outcomes for adults with autism spectrum disorder? Autism. 2012 Jan; 16(1):87–94. [PMID: 21610189]

26 Taylor JL, Seltzer MM. Developing a vocational index for adults with autism spectrum disorders. J. Autism Dev. Disord. 2012 Dec; 42(12):2669–2679. [PMID: 22466690]

27 Orsmond GI, Shattuck PT, Cooper BP, Sterzing PR, Anderson KA. Social participation among young adults with an autism spectrum disorder. J. Autism Dev. Disord. 2013 Nov; 43(11):2710–2719. [PMID: 23615687]

28 Shattuck PT, Orsmond GI, Wagner M, Cooper BP. Participation in social activities among adolescents with an autism spectrum disorder. PloS One. 2011 6(11):e27176. [PMID: 22110612]

29 Mazurek MO. Loneliness, friendship, and well-being in adults with autism spectrum disorders. Autism Int. J. Res. Pract. 2013 Oct. [Epub ahead of print] [PMID: 24092838]

30 Kandalaft MR, Didehbani N, Krawczyk DC, Allen TT, Chapman SB. Virtual reality social cognition training for young adults with high-functioning autism. J. Autism Dev. Disord. 2013 Jan; 43(1):34–44. [PMID: 22570145]

31 World Health Organization. Resolution 54.21. International Classification of Functioning, Disability and Health (ICF). 2001 May. at <http://www.who.int/classifications/icf/en/>

32 Magaña S, Smith LE. The use of the autism diagnostic interview-revised with a latino population of adolescents and adults with autism. J. Autism Dev. Disord. 2013 May; 43(5):1098–1105. [PMID: 22972501]

33 National Institute of Mental Health. RFA-MH-14-101. Services Research for Autism Spectrum Disorder across the Lifespan (ServASD):  Pilot Research on Services for Transition-Age Youth (R34). 2013 May. at <http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-101.html>

34 National Institute of Mental Health. RFA-MH-14-102. Services Research for Autism Spectrum Disorders across the Lifespan (ServASD):  Pilot Studies of Services Strategies for Adults with ASD (R34). 2013 May. at <http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-102.html>

35 Landa RJ, Holman KC, O'Neill AH, Stuart EA. Intervention targeting development of socially synchronous engagement in toddlers with autism spectrum disorder: a randomized controlled trial. J. Child Psychol. Psychiatry. 2011 Jan; 52(1):13–21. [PMID: 21126245]

Question 7: What Other Infrastructure and Surveillance Needs Must Be Met?

Introduction

Aspirational Goal: Develop and support infrastructure and surveillance systems that advance the speed, efficacy and dissemination of ASD research.

The original IACC Strategic Plan, launched in 2009, was structured around only six Questions. In 2010, the IACC recognized that grouping the topics of research infrastructure, workforce, and ASD surveillance into a separate chapter would highlight these issues that are critically important to research success and help the Committee track investments and evaluate progress in this area in the same organized, rigorous manner that is used in the rest of the IACC Strategic Plan. Over the past 5 years, a total of $158 million dollars has been invested in building and maintaining the ASD research infrastructure to support needed research and surveillance efforts. Many of the original infrastructure needs identified in 2009 have been accomplished, but continued investment is critical in order to develop, maintain, and build on these valuable new resources. 

Progress Toward the Strategic Plan Objectives

The IACC ASD Research Portfolio Analyses reviewed projects funded by both government agencies and private foundations from 2008-2012. From 2009-2012, the total funding devoted to projects pertaining to Question 7 was $158 million. On average for each year from 2010-2012, the funding levels for this Question were doubled from the 2009 level ($16 million) and the number of funded projects was also more than twice as high. Additionally, in years 2009-2012, 27 percent of the total funding went toward core/other research projects that were not aligned with the research gaps covered by the 16 objectives in Question 7.

Of the 16 specific objectives within Question 7, 8 objectives addressing basic and clinical data sharing and dissemination, workforce expansion, and model-systems resources met or exceeded the recommended budget and fulfilled the recommended number of projects. Four objectives, concerning documenting the services available in each state, expanding biobanks, and expanding surveillance infrastructure partially met the recommended budget and had a number of projects underway. Four more objectives did not have any funding or projects. Two of these objectives, focused on a needs assessment for database linkage and a funding mechanism for rapid replication of research results, remain a high priority. The objective concerning development of a web tool for prevalence estimates was fulfilled through several projects that encompassed multiple conditions including autism; the intended goal was achieved, although it was done outside the autism portfolio. The intent of the objective to disseminate best practices in service provision through the publication of "Promising Practices" papers was not completed; this goal may have been superseded by other types of best practice dissemination methods (e.g., web pages, tool kits, presentations at conferences), so the objective in its current form was not viewed by the Committee as a high priority to continue.

Infrastructure

Over the past 5 years there has been a significant rise in data sharing among researchers, increased availability of biological samples, expanded surveillance efforts, substantial investment in building the ASD research workforce and major improvement in dissemination of research results to the community.

Databases have been developed to house and provide researchers with access to valuable research data collected from those affected by autism as well as neurotypical subjects. In addition, in 2011 the NIH Office of Autism Research Coordination (OARC) developed and launched a new database, the IACC Portfolio Analysis Web Tool, that gathers data on federal and non-profit supported ASD research-related projects together into one place, enabling broad public access to detailed information about these projects, as well as searching, sorting and graphics to facilitate further analysis and monitoring of progress over time.

The Interactive Autism Network (IAN), This link exits the Interagency Autism Coordinating Committee Web site developed by the Kennedy Krieger Institute, is a tool designed to match scientists with research subjects to enhance the pace of research. The IAN network has also greatly facilitated rapid research on issues of symptom severity and intervention. For example, in 2011 when concerns about the impacts of autistic wandering behavior were brought to the IACC's attention through a public presentation at an IACC meeting, members of the IACC and other organizations were able to work with the IAN network within a period of 3 months to launch and complete a study involving over 1,200 children utilizing the IAN database. Results of the study indicated that almost 50 percent of children with ASD had wandered.1 In conjunction with this rapid study, a new International Classification of Diseases (ICD-9) code to track autistic wandering in health records was almost immediately implemented and the American Academy of Pediatrics (AAP) This link exits the Interagency Autism Coordinating Committee Web site issued new guidelines that included wandering in patient-family anticipatory guidance, alerting parents of children with ASD to the prevalence of wandering so that they could take preventive measures.2

The National Database for Autism Research (NDAR), funded by the NIH, is a rich resource that includes genomic data and imaging studies as well as other types of data for use in ASD research. NDAR has become the standard data repository for the ASD research community. In January 2010, the NIH began including an expectation for data sharing in most of its awards, requiring that human subject data be deposited in a broadly accessible database. In 2012, 81 percent of NIH-funded human subjects grants were contributing data to NDAR. NDAR also supports data sharing from other funders of autism research including the Autism Science Foundation, the Centers for Disease Control and Prevention (CDC), the Department of Defense, and the State of New Jersey. NDAR has also now linked to IAN and the Autism Speaks supported Autism Genetic Resource Exchange (AGRE) This link exits the Interagency Autism Coordinating Committee Web site and Autism Tissue Program (ATP), This link exits the Interagency Autism Coordinating Committee Web site enabling researchers to access data in those repositories.

To date, NDAR has facilitated the sharing of data on 70,000 research subjects with much more expected in the next 24 months. Also, the rich "omics" (genomics, proteomics, transcriptomics, metabolomics, etc.) and imaging datasets have been de-identified and protected in the computational cloud, enabling an unprecedented array of resources, techniques and computational software to be used collaboratively by the research community. The results of such efforts along with categorization of data into common concepts like IQ, language and executive function enable users to query and pull down data from across multiple sources and disciplines, maximizing the utility of the data and driving scientific discovery. NDAR data have been cited in publications, and access requests have been substantial. Over 300 researchers at 75 laboratories from 10 countries applied for and were granted access to NDAR in 2013. 

Aggregated data in NDAR, among its federated partners and the labs sharing data are available to the general public (see NDAR Query).3 NDAR now supports harmonized receipt of all human subjects research data, including clinical, imaging, genomics, proteomics, electroencephalogram (EEG), eye tracking, and task- based functional magnetic resonance imaging (fMRI) data. Figure 1 provides a summary of the shared research subjects data now available in NDAR. The NIMH Repository and Genomics Resource (NIMH-RGR) This link exits the Interagency Autism Coordinating Committee Web site is another key resource that has played an important role in supporting research by providing access to biological samples from more than 150,000 well- characterized, high quality patient and control samples from a wide-range of mental disorders, including autism. The number of samples in the NIMH Genomics Repository has increased to more than 27,000, many with extensive phenotype/genotype information. The NIMH repository has also started collecting induced pluripotent stem cell (iPS) lines and fibroblasts. In terms of DNA, this represents a two-fold increase since 2008.

In addition to genomics and cell line samples, brain tissue is another critically important resource needed to further autism research. Unfortunately, brain tissue samples have actually declined in number during the past 5 years due to a freezer malfunction in 2012 that resulted in the loss of more than half of the existing samples from the largest autism brain repository in the United States. The brains lost have not yet been replaced in terms of numbers, and it may take several years to fully recover. In 2013, only nine new ASD brains were added to existing repositories. Despite these challenges and setbacks, there is a concerted effort both publicly and privately to increase the number of brain tissue samples. In 2013, NIH launched a new NIH Neurobiobank initiative. This repository will collect and standardize brain tissue samples for research on ASD as well as other brain disorders. The initiative includes a publication to increase awareness of brain donation, "Why Brain Donation? A Legacy of Hope." (PDF - 946 KB) In addition, a group of private funders including the Autism Science Foundation, This link exits the Interagency Autism Coordinating Committee Web site Autism Speaks, This link exits the Interagency Autism Coordinating Committee Web site the Nancy Lurie Marks Family Foundation, This link exits the Interagency Autism Coordinating Committee Web site and the Simons Foundation, This link exits the Interagency Autism Coordinating Committee Web site recently launched the AutismBrainNet, This link exits the Interagency Autism Coordinating Committee Web site a multi-site effort to increase the numbers of ASD-specific brain samples. Their efforts will also include an ASD-specific outreach and education plan to encourage tissue donation. 

Launch of NDAR Increases Number of Subjects Whose Data are Shared

Figure 1. In 2009, essentially all human subjects data being shared within the autism research community were contained in two separate databases—the Autism Speaks AGRE and ATP data repositories—and totaled approximately 4,000 subjects.  In 2009, NDAR was collecting data, but its data sharing capabilities were not launched until 2010. Since the launch, NDAR has continued to both collect and make data available to researchers. By 2013, the total number of research participants for whom data were available for study through NDAR had dramatically increased, with data now available for 70,000 subjects. This includes data collected by NDAR as well as the AGRE and ATP datasets, all of which are now available through NDAR. In addition, by 2013 a wide variety of data types was available, with many subjects in the databases having multiple data types available. Examples of the kinds of data shared through NDAR include imaging data, genomes, proteomes, clinical data, and exposures data.

Figure 1. In 2009, essentially all human subjects data being shared within the autism research community were contained in two separate databases—the Autism Speaks AGRE and ATP data repositories—and totaled approximately 4,000 subjects. In 2009, NDAR was collecting data, but its data sharing capabilities were not launched until 2010. Since the launch, NDAR has continued to both collect and make data available to researchers. By 2013, the total number of research participants for whom data were available for study through NDAR had dramatically increased, with data now available for 70,000 subjects. This includes data collected by NDAR as well as the AGRE and ATP datasets, all of which are now available through NDAR. In addition, by 2013 a wide variety of data types was available, with many subjects in the databases having multiple data types available. Examples of the kinds of data shared through NDAR include imaging data, genomes, proteomes, clinical data, and exposures data.

NIMH Repository and Genomics Resource (NIMH-RGR) Sample Summary 2008-2013

Phenotypic
Category
Number of subjects
with DNA/LCL/CPL1 samples
Number of subjects
with samples and phenotypic2 data in distribution3 (% non-caucasian4)
Number of total
affected cases in distribution (independent cases5)
Number of Multiplex
families (Trios)
Number of subjects
with fibroblast lines (iPSC6) in distribution
Autism (2013) 28,288 15,676 (17%) 6,278 (4,222) 1,553 (3,387) 21 (25)
Autism (2012) 27,240 14,628 (17%) 5,938 (3,906) 1,530 (3,179) 0 (0)
Autism (2011) 25,890 9,822 (24%) 4,252 (2,479) 1,431 (1,860) 0 (0)
Autism (2010) 23,421 8,601 (20%) 3,842 (2,128) 1,386 (1,630) 0 (0)
Autism (2009) 19,824 6,434 (19%) 3,001 (1,598) 1,125 (1,209) 0 (0)
Autism (2008) 14,887 6,434 (19%) 3,001 (1,598) 1,125 (1,209) 0 (0)

Table 7. Summary of sample number and type for Autism specific samples included in the NIMH Genomics Repository.1 LCL, Lymphoblastoid Cell Line; CPL, Cryopreserved Lymphoblasts 2 Phenotypic data includes clinical interviews, DIGS (Diagnostics Interview for Genetics Studies) & DSM variables.  Samples include unaffected family members.3 Distributions are NIMH sample collections with phenotypic data available for distribution to authorized investigators.4 Non-Caucasians include Black, Hispanic, American Indian and Asian.5 Subjects are unrelated.6 Induced pluripotent stem cell lines produced by NIMH Genomics Repository Stem Cell facility.

Surveillance

Updated estimates published in 2012 from the CDC's Autism and Developmental Disability Monitoring Network (ADDM) indicate that 1 in 88 children has been identified with ASD, based on an average taken across multiple ADDM network study sites across the United States.4 The ADDM network, which uses a methodology based on review of health and education records, has been the CDC's primary United States surveillance initiative. It currently includes 12 sites, and data are now available over multiple years, which enables researchers to examine prevalence trends as well as characteristics that are changing in the population and average age at diagnosis. The ADDM infrastructure has laid the foundation to expand surveillance to younger children in six ADDM sites. In addition, ADDM investigators have initiated data linkage and analytic projects to better understand characteristics of the population of children with identified ASD. These include evaluations of perinatal characteristics, parental age, medication use, participation in the juvenile justice system, hazardous air pollutant exposures, phenotypic characteristics, and changes in prevalence over time, among others. The ADDM Network has established a system to provide updated ASD prevalence estimates and has enabled a better understanding of the needs of the community. In addition to ADDM, the National Survey of Children's Health (NSCH), This link exits the Interagency Autism Coordinating Committee Web site using telephone survey methodology, reported ASD prevalence estimates that were consistent with ADDM estimates.5 The 2009-2010 National Survey of Children with Special Healthcare Needs infrastructure was used for the 2010 follow-up study, "Survey of Pathways to Diagnosis and Services," to better understand how children with ASD are identified and treated.6 A workshop was held in 2011 to summarize the state of the science and needs in evaluating trends in ASD prevalence.7

There are also many private organizations, and groups outside the United States monitoring prevalence and service data. Autism Speaks has supported a population-based screening effort at an ADDM Network site to evaluate how many children with ASD are potentially being missed by current ascertainment methods. Autism Speaks has also initiated the Global Autism Public Health Initiative (GAPH) This link exits the Interagency Autism Coordinating Committee Web site to support awareness and epidemiologic studies of ASD in sites around the world. There have also been efforts in the United Kingdom to examine the prevalence of ASD. A study in children using a comprehensive diagnostic assessment method found a prevalence of 1.16 in 100, and a study in adults using a population based survey and diagnostic assessment approach found a similar prevalence of .98 in 100.8–10 In South Korea, a population based study that used diagnostic assessments found a prevalence of 1 in 38, and that two-thirds of cases of ASD identified were unrecognized and untreated, highlighting a need for improved screening, diagnosis and services.11

There is increasing international focus on surveillance of prevalence and services. In 2012, the United Nations (UN) General Assembly This link exits the Interagency Autism Coordinating Committee Web site unanimously passed a resolution, "Addressing the Socioeconomic Needs of Individuals, Families and Societies Affected by Autism Spectrum Disorders, Developmental Disorders and Associated Disabilities," This link exits the Interagency Autism Coordinating Committee Web site calling on governments around the world to monitor and report as well as improve access to healthcare, education, training, and intervention programs for persons with ASD and other developmental disabilities.12 In 2013, the executive board of the World Health Assembly, governing body of the World Health Organization (WHO), This link exits the Interagency Autism Coordinating Committee Web site adopted a complementary resolution, "Comprehensive and Coordinated Efforts for the Management of Autism Spectrum Disorders."13 (PDF - 45 KB) These resolutions indicate growing commitment to address ASD on a global level.

Health disparities are another area of high interest within the field of surveillance. ADDM Network study results initially showed autism prevalence in some minority groups was lower than in in whites, but more recent data have begun to close the gaps with prevalence in minorities and whites becoming more similar, suggesting that the difference is not in actual prevalence but instead may reflect differences in diagnosis (e.g, later diagnosis, missed diagnosis, etc. in minority communities).4,14–16 More research is needed to better understand the role of cultural issues, access to services and other issues in this phenomenon.

ASD is also being studied in immigrant populations to learn more about ASD in diverse populations. In 2013, results from a study of ASD prevalence among diverse populations of children in Minneapolis, Minnesota, collaboratively supported by CDC, NIH, Autism Speaks, and the Association of University Centers on Disabilities (AUCD), This link exits the Interagency Autism Coordinating Committee Web site showed that while Somali children had a similar prevalence of autism to white children and a higher prevalence than in non-Somali black children or Hispanic children, that the prevalence of intellectual disability among children with ASD was much higher in Somalis.17 Additional studies will be needed to understand the reasons for these differences. A study by Swedish researchers investigated the relationship between parental immigration status and risk of ASD, taking into consideration the importance of region of origin, timing of immigration and autism subtypes.18 They found that children of immigrant parents were at increased risk of ASD with intellectual disability, especially when parents immigrated from countries with a low human development index. That risk was also higher when immigration occurred around pregnancy, but elucidation of the reasons for these differences will require further research.

Despite efforts to track the age of diagnosis and increased capability to diagnose ASD earlier, the average age of diagnosis in the United States has remained relatively constant. The proportion of children being diagnosed earlier has improved, however, with ADDM data indicating that the proportion of children diagnosed by age 3 increased from 12 percent in 2002 to 18 percent in 2008.4 In addition, due to changes in diagnostic criteria and greater community awareness, more cases are being identified when they were initially missed. As the prevalence of ASD has increased, a greater number of children have been identified with ASD — specifically those with ASD without intellectual disability and, as mentioned earlier, among racial and ethnic minority groups. Children without intellectual disability or with fewer ASD characteristics tend to be identified at later ages. Thus, while more children are being identified, much work needs to be done to identify children with ASD and other developmental delays earlier and more equitably so that all of those in need of services can be connected to appropriate services and supports as early as possible.

The surveillance infrastructure may present opportunities for more in-depth data collection related to services, treatment, and co-occurring conditions to complement data currently collected and identify opportunities for improving diagnosis and treatment of children with ASD. A future challenge to the accuracy of trends in prevalence may result from the implementation of the new DSM-5 diagnostic criteria for ASD. Because ADDM has collected detailed descriptions of the clinical findings for each child, the system is poised to evaluate how prevalence estimates may be influenced by these updated criteria.

Future efforts must focus on encouraging more families from diverse backgrounds to participate in ASD research, join registries, and donate biological samples. Also, as the ability to collect and link data grows, it is crucial to pay greater attention to issues of privacy, security and ethical use of data. 

Progress Toward the Aspirational Goal

Progress toward the Question 7 aspirational goal to "develop and support infrastructure and surveillance systems that advance the speed, efficacy and dissemination of ASD research" has been rapid over the past 5 years. As demonstrated by the above tables, the numbers of shared subjects and samples have doubled at minimum, and in some cases increased by orders of magnitude. This increase in the availability of resources advances the speed and efficacy of ASD research. The sharing of these resources through initiatives such as NDAR, IAN, and AGRE demonstrate effective dissemination of resources, and fuel the cycle of increased research speed and efficacy. In terms of research infrastructure, the aspirational goal will be met as long as current support is continued and current momentum is maintained.

Surveillance systems have also progressed over the past 5 years, allowing the tracking of prevalence, age of diagnosis, and other trends over time. As awareness of ASD has grown in the community and diagnostic criteria have broadened, more children have been identified with ASD, especially those without intellectual disability and among racial and ethnic minority groups, who tend to be identified at later ages. Thus, while more children are being identified, advances leading to earlier identification for children across all cultural backgrounds and across the entire spectrum and will be critical to ensure that all of those in need of services can receive them as early as possible. With the surveillance infrastructure now in place, there is an opportunity to use it for more in-depth data collection related to services, treatment, and co-occurring conditions to complement data currently collected and identify opportunities for improving diagnosis and treatment of children with ASD.

The progress toward meeting the goal of dissemination and communication of autism research findings has been significant. Many government and private organizations and groups including Simons Foundation, Autism Speaks, Autism Science Foundation, Interactive Autism Network, NIH and the CDC regularly share lay-audience friendly summaries of recent research findings and new interventions to raise community awareness. Future efforts must focus on encouraging more families from diverse backgrounds to participate in ASD research, join registries, and donate biological samples. Throughout the process of ASD surveillance and infrastructure expansion, it will also be important to maintain focus on ethical issues surrounding the privacy of research participants and security of data. The initial steps toward the aspirational goal to "develop and support infrastructure and surveillance systems that advance the speed, efficacy and dissemination of ASD research" have begun, but continued investment and broader outreach will be needed to ensure that the benefits of ASD research and access to the highest quality interventions, services and supports are attainable for all communities across the United States and around the globe.


References

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12 United Nations General Assembly. Resolution 67/82: Addressing the socioeconomic needs of individuals, families and societies affected by autism spectrum disorders, developmental disorders and associated disabilities. This link exits the Interagency Autism Coordinating Committee Web site 2012 Dec;

13 The World Health Organization, Executive Board. Resolution EB133. R1: Comprehensive and coordinated efforts for the management of autism spectrum disorders. This link exits the Interagency Autism Coordinating Committee Web site 2013 May;

14 Autism and Developmental Disabilities Monitoring Network Surveillance Year 2000 Principal Investigators & Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders--autism and developmental disabilities monitoring network, six sites, United States, 2000. Morb. Mortal. Wkly. Rep. Surveill. Summ. Wash. DC 2002. 2007 Feb; 56(1):1–11. [PMID: 17287714]

15 Autism and Developmental Disabilities Monitoring Network Surveillance Year 2002 Principal Investigators & Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders--autism and developmental disabilities monitoring network, 14 sites, United States, 2002. Morb. Mortal. Wkly. Rep. Surveill. Summ. Wash. DC 2002. 2007 Feb; 56(1):12–28. [PMID: 17287715]

16 Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators & Centers for Disease Control and Prevention (CDC). Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006. Morb. Mortal. Wkly. Rep. Surveill. Summ. Wash. DC 2002. 2009 Dec; 58(10):1–20. [PMID: 20023608]

17 Hewitt A, Gulaid A, Hamre K, Esler A, Punyko J, Reichle J, Reiff M. Minneapolis Somali autism spectrum disorder prevalence project: Community report 2013. (University of Minnesota, Institute on Community Integration, Research and Training Center on Community Living, 2013 Dec).

18 Magnusson C, Rai D, Goodman A, Lundberg M, Idring S, Svensson A, Koupil I, Serlachius E, Dalman C. Migration and autism spectrum disorder: population-based study. Br. J. Psychiatry J. Ment. Sci. 2012 Aug; 201109–115. [PMID: 22361019]

Conclusion

Progress

The 2013 IACC Strategic Plan Update details the progress that has been made on the scientific questions and investment recommendations of the IACC Strategic Plan. Of the 78 specific IACC Strategic Plan objectives, 73 have fully met or partially met the recommended budget. Overall, approximately $1.5 billion in public and private research funding has been dedicated to ASD projects over the past 5 years, with an average funding increase of 39 percent across the IACC Strategic Plan Questions for the period following its initial release in 2009. This increased investment has brought forth a range of scientific advances in all areas of the IACC Strategic Plan.

The state of the science has dramatically changed in the ASD field since 2008, reflected in a significant increase over time in the number of journal publications related to ASD research.1 While biological differences in individuals with ASD were hypothesized earlier, now there are data demonstrating specific changes in the genome and epigenome,2–20 gene expression,21, 22 cell structure and function,23–29 brain connectivity,30–32 and behavior33–35 that have been linked to the causes and underlying biology of ASD. Over the past 5 years, genetic studies have revealed that genetic variation ranging from changes in single bases to alteration of large regions of DNA or even extra chromosomes can contribute to ASD risk, and that both inherited and spontaneous mutations can play a role.2–4 Several environmental factors have emerged as potential contributors to ASD risk in the past 5 years, including: prenatal maternal infection,36, 37 preterm birth,38–41 advanced maternal and paternal age at conception,42–48 short inter-pregnancy interval,49, 50 as well as some data suggesting that exposure to air pollution,51–56 phthalates57–59 and pesticides60–62 during pregnancy may also increase risk. Vitamin intake, particularly folic acid,63–65 during the pre-conception period has been identified as a possible protective factor against ASD risk, while both the genetic and environmental data now point to the early months of gestation as a critical period for the development of ASD.

Advances in screening tools such as the Modified Checklist for Autism in Toddlers (M-CHAT) and the Infant-Toddler checklist, with an emphasis on early and repeated screenings, now make it possible to set a realistic future goal to identify 95 percent of children with ASD before the age of 24 months.66–69 New technologies to detect differences in eye-tracking patterns, and new research on white matter tract development and posture control in infants also introduce the potential to detect ASD as early as 2-6 months of age.30, 33–35 This ability for early ASD detection, however, will depend on large community-based validation studies of screening in the general population and only will become clinically useful if efficient, cost effective tools can be designed around these new capabilities. It will also be critical to ensure that following a positive early screening result, parents readily seek diagnosis and intervention, and that there are effective early interventions available. Recent clinical trials of behavioral interventions have demonstrated their positive impact on outcomes and have begun to provide the evidence base needed to support the widespread use of these advances in the community.70–75 However, more needs to be done to make these therapies affordable and scalable to large and diverse community settings, and efforts are needed to increase the number of children who progress from identification in early screens to diagnosis and early intervention. Disparities in access to diagnosis and treatment based on resources, ethnicity, and gender remain another significant challenge.

Studies of animals that carry gene mutations that, in humans, cause syndromic forms of autism have demonstrated that in animals symptoms can be reversed both in early development and in adulthood.76, 77 While these studies may not directly translate to humans, they indicate that some symptoms of autism may be amenable to treatment even later in life, they identify possible drug targets, and they provide a pathway for developing treatments for the core symptoms of ASD. Clinical trials in toddlers have demonstrated the value of early behavioral intervention, with gains in behavior and function as well as the first demonstration of measurable changes in brain activity in response to intervention.70–75, 78 Several trials are currently underway, ranging from exploratory trials of novel interventions to tests of treatments that are already in current use in the community. Over the past 5 years, a large clinical network has been developed, several pharmaceutical companies have become engaged in ASD research, and new technologies have emerged that may prove transformative. This field still requires standardized, sensitive outcome measures and biomarkers that can both stratify the heterogeneous ASD population and serve as rapid indicators of clinical response. 

Recent studies have revealed the tremendous service needs within the community, with data showing that young adults transitioning out of the educational system frequently lose their services access and often have limited opportunities for employment and independent housing.79–82 While more data are required on the needs of adults with ASD so that services can be more appropriately targeted, there is already an opportunity to collect data on the effectiveness of current services being delivered in the community through projects such as federally-funded state demonstration projects. In some cases, it may also be possible to do comparative studies that could begin to make improvements in services for adults in the near term.

One of the most encouraging signs of progress has been the expansion of research infrastructure over the past 5 years, helping the scientific community embrace a culture of data integration and sharing. Several large scale government-funded research centers, privately funded efforts, and some public-private collaborative projects have been built in the past 5 years. The National Database for Autism Research (NDAR), an NIH-funded hub that stores and shares aggregate data, from exomes to images, has grown to include over 70,000 human subjects. Efforts such as the government-funded NIH Neurobiobank and the privately-funded Autism BrainNet This link exits the Interagency Autism Coordinating Committee Web site have been established to try to expand the supply of available brain and other tissue samples for ASD and brain disorder research. In addition, the Interactive Autism Network (IAN) This link exits the Interagency Autism Coordinating Committee Web site and Autism Genetic Resource Exchange (AGRE) This link exits the Interagency Autism Coordinating Committee Web site give families the opportunity to share data and participate in new models of more rapid, interactive clinical trials, expanding the possibilities for future research.

Relative to many other areas of biomedical research, ASD science is still a young field. While the past 5 years have seen rapid growth and substantial scientific progress, the Committee recognizes the large gap that still remains between advances made in research settings and practical benefits that are ready to be delivered to individuals and families living with ASD today. We remain far from the overall intention of the IACC Strategic Plan to foster research that will yield tangible improvements in quality of life for people with ASD across all settings and communities. An intensified effort will be needed to ensure that recent promising discoveries are rapidly translated into clinical practice and services that will improve quality of life for individuals with ASD.

In conducting this review, the Committee recognized several core needs that spanned across multiple areas on the research portfolio:

Future Directions

History may identify the past 5 years as an inflection point for our understanding of ASD. Increased investments from both private and government sources, improved resources for research, and expanded communities of scientists entering this field all provide hope that recent progress will accelerate. Many new areas of science, from the microbiome to social prosthetics, may transform our understanding of ASD with entirely new tools for interventions. One of the greatest challenges will be finding the right balance between science that can immediately improve quality of life for individuals with ASD and science that seeks to gain fundamental knowledge about ASD with the promise of prevention or cure in the future. The ASD community has a diversity of views on how to set this balance, with some focused on identifying the causes with the goal of preventing ASD, reducing disability or finding a cure, while others focus on accommodation, inclusion, and acceptance. In the near term, science can serve both sets of goals to develop a deeper understanding of the many forms of ASD and enhance interventions, services and supports that can offer individuals with ASD opportunities for independence and full participation in community life.

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Appendix

ASD Research Progress on IACC Strategic Plan Objectives: Summary of Years 2008 to 2012

The tables include data (project numbers and funding) from Federal and private funders of ASD research for years 2008 through 2012, as aligned with the objectives of the 2011 IACC Strategic Plan. They also include summaries (based on discussions during the 2013 IACC Strategic Plan Update Workshop) of progress on reaching the goals of each objective, as well as remaining gaps, needs, and opportunities. Please note the following:

During the updating of the Strategic Plan from 2008 to 2010, the wording and numbering of objectives changed. Data included in each Portfolio Analysis Report from 2008 to 2012 was categorized at the time with respect to the most recent iteration of the Strategic Plan where the objectives had changed. For the purpose of this five-year comparison, data from the Portfolio Analyses conducted in 2008 and 2009 were aligned with the most recent objectives, found in the 2011 Strategic Plan. The full wording of the 78 objectives listed in the 2011 Strategic Plan is depicted in the left column of the table.

The middle five columns of the table contain the data (project numbers and funding) for each individual year from 2008 to 2012, with the objective number (as it appeared in the annual Portfolio Analysis) listed above it. The IACC recommended budget listed below the project data represents the most updated budget listed in 2011 Strategic Plan. If the recommended budget has been revised since 2008, the year the revision took place is found in parentheses following the budget figure. Therefore, if there is no mention of a revision, the IACC recommended budget has remained constant from 2008 to 2011. The annual project status for each objective from 2008 to 2012 is indicated within the table by colored highlighting of the objective number. An objective is considered active if its status is green or yellow, and inactive if its status is red.

The far right column of the table lists the sum of the total funding aligned with each objective from 2008 to 2012. Highlighting of each total gives an indication of the progress toward fulfilling each objective.


1 Please note that while the green, yellow and red indicators suggest a funding status for each year and that looking across all years may give some indication of a trend, that some agencies and organizations provide all the funding for multiyear grants in a single year, resulting in the appearance of "less funding" in other years, but that projects fulfilling the objectives may still have been ongoing in the years where the funding appears to be less. Thus, it is important to note the numbers of projects in looking across the chart, and to keep in mind that in a series, where, for example, most of the indicators are green, that the objective is likely to be largely "complete" according to the funding-based measure.

2 Reasons why funding for certain projects may not have been captured in the portfolio analyses include projects that were supported by funding that was not specific for autism (i.e., projects that benefited autism but were supported by general neuroscience or developmental disorder funding) or projects supported by funders that did not participate in the portfolio analysis in a given year.

About the IACC

The Interagency Autism Coordinating Committee (IACC) is a federal advisory committee charged with coordinating all activities concerning autism spectrum disorder (ASD) within the U.S. Department of Health and Human Services (HHS) and providing advice to the Secretary of HHS on issues related to autism. It was established by Congress under the Children's Health Act of 2000, reconstituted under the Combating Autism Act (CAA) of 2006, and renewed under the Combating Autism Reauthorization Act (CARA) of 2011.

Membership of the Committee includes a wide array of Federal agencies involved in ASD research and services, as well as public stakeholders, including self-advocates, parents of children and adults with ASD, advocates, service providers, and researchers, who represent a variety of perspectives from within the autism community. This makeup of the IACC membership is designed to ensure that the Committee is equipped to address the wide range of issues and challenges faced by families and individuals affected by autism.

Under the CAA, the IACC is required to (1) develop and annually update a strategic plan for ASD research, (2) develop and annually update a summary of advances in ASD research, and (3) monitor Federal activities related to ASD.

Through these and other activities, the IACC provides guidance to HHS and partners with the broader autism community to accelerate biomedical research and enhance services with the goal of profoundly improving the lives of people with ASD and their families.

IACC Member Roster

Chair

Federal Members

Public Members

Alternates

The following individuals serve as alternates for IACC members.


Strategic Plan Update External Planning Group Members

The Committee would like to thank the following external experts who volunteered their time to assist with the development of the 2013 IACC Strategic Plan Update.


OARC Staff List



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Copyright Information
All material appearing in this report is in the public domain and may be reproduced or copied. A suggested citation follows.

Suggested Citation
Interagency Autism Coordinating Committee (IACC). IACC Strategic Plan for Autism Spectrum Disorder (ASD) Research —2013 Update. April 2014. Retrieved from the U.S. Department of Health and Human Services Interagency Autism Coordinating Committee website: http://iacc.hhs.gov/strategic-plan/2013/index.shtml.