Congressional Appropriations Committee Report on the State of Autism Research
Prepared by the National Institute of Mental Health
National Institutes of Health
Department of Health and Human Services
- Executive Summary
- IACC Autism Research Matrix: 12/03
- Specifics of the Autism Research Matrix
- Adoption and Implementation of the Matrix
- Autism Research Highlights
The Conference Report on the Consolidated Appropriations Bill for FY 2003, which included the appropriations for the Departments of Labor, Health and Human Services and Education and related agencies, (Conference Report No. 108-10), requested that the Interagency Autism Coordinating Committee (IACC) convene a panel of expert scientists to evaluate the field of autism research and develop a matrix of action items that could be used in planning for research in the years ahead. This report summarizes the activities that followed this request, which included a 2-day meeting of an expert panel, the development of a draft version of an autism research matrix, the public rollout and discussion of that draft matrix at the recent Autism Summit, and the adoption of an initial version of the matrix by the IACC. The specific action items of the matrix are presented in this document, along with explanatory notes and initial plans for implementation. A background summary of the state of autism research in the major areas of epidemiology, genetics, neurobiology and treatment is also included.
The autism research matrix was developed by a process of reviewing the status of important scientific content areas for autism, identifying roadblocks within these areas, and then formulating activities to overcome the roadblocks. These proposed activities were then placed in a matrix according to the level of risk for their success and the timeframe for undertaking them. The matrix includes content areas of communication and collaboration, characterization of autism, school and community interventions, early intervention, epidemiological studies, specific treatments, neuroscience, screening, and the role of the environment in autism.
In its report on Fiscal Year 2003 budget for the Department of Health and Human Services (HHS), the Committee on Appropriations stated:
The IACC was created in response to a mandate in the Children's Health Act of 2000 (P.L. 106-310), in order to coordinate research and other efforts with respect to autism activities within HHS and the Department of Education (DoE). In addition, HHS has expanded its efforts relevant to autism in several major areas in accordance with other stipulations in the Children's Health Act. The Children's Health Act also requires an annual Report to Congress on overall activities related to autism. This annual report provides an overview of activities at agencies of HHS, including the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the Health Resources and Services Administration (HRSA), and the DoE that constitute the implementation of each section of the Act. Annual reports are available at http://www.nimh.nih.gov/autismiacc/index.cfm.
The state of autism research has advanced substantially in the past year with the increased infrastructure that has permitted expansion of research into the causes and best treatment options for autism. For instance, NIH has now funded a total of eight centers under the Studies to Advance Autism Research and Treatment (STAART) Centers Program http://www.nimh.nih.gov/autismiacc/staartcenters.cfm. These centers complement the 10 Collaborative Programs of Excellence in Autism (CPEA) Centers Network, and two Children's Environmental Health Research Centers that focus on autism. These network activities have expanded while there are also increased numbers of individual grants being funded to support autism research. Over the past few years, NIH has considerably expanded its autism research portfolio and enhanced its coordination of autism research. NIH support of autism research grew from $22 million in FY 1997 to $93 million in FY 2003 with estimated increases to $97 million in FY 2004 and $99 million in the FY 2005 President's Budget request. NIH supports autism research in the areas of genetics, neurobiology, early diagnosis, services and treatment, while the CDC has expanded its efforts in supporting research on the epidemiology of autism. These activities provide a framework for allowing investigators to study important questions about autism.
To summarize, in order to broadly assess the field of autism research in multiple domains, the conferees requested that a panel of scientists be convened to identify roadblocks to understanding the causes and best treatment options for autism. In response to this request, the IACC selected and convened a panel of science experts in autism. This 2-day meeting was held in July 2003 in Bethesda, Maryland. The panel was composed of premier scientists from across the spectrum of autism research.
IACC Scientist Panel Members:
- David Amaral, Ph.D. Beneto Foundation Professor and Director of Research, M.I.N.D. Institute University of California, Davis Center for Neuroscience
- Tony Charman, Ph.D. Senior Lecturer in Clinical Psychology Behavioral and Brain Sciences Unit Institute of Child Health University College, London, England
- Geraldine Dawson, Ph.D. Professor University of Washington
- Daniel Geschwind, M.D., Ph.D. Assistant Professor of Neurology Director Neurogenetics Program University of California, Los Angeles School of Medicine
- Judith Grether, Ph.D. Research Scientist California Department of Health Services Environmental Health Investigations Branch
- Irva Hertz-Picciotto, Ph.D., MPH Professor, School of Medicine Department of Epidemiology and Preventive Medicine University of California at Davis
- Jean Lauder, Ph.D. Professor Department of Cell & Developmental Biology University of North Carolina School of Medicine
- Catherine Lord, Ph.D. Director and Professor of Psychology Autism and Communication Disorders Center University of Michigan
- Samuel Odom, Ph.D. Professor School of Education Indiana University
- Helen Tager-Flusberg, Ph.D. Professor School of Medicine Boston University
- Fred Volkmar, M.D. Professor Yale Child Study Center Yale University
This science panel developed and prioritized goals and activities to overcome roadblocks hindering progress in autism research. These action items were then placed into a matrix reflecting the proposed timing and level of risk of each entry. In August 2003, a draft of the proposed autism research matrix was distributed to all members of the IACC for discussion and approval. In order to obtain public input at the Autism Summit Conference held on November 19 and 20, 2003, the draft matrix was rolled out and there was a presentation of its contents and extensive discussion about it. The IACC provided input and final approval of the draft matrix at the November 21, 2003 IACC meeting. Plans for implementation were also discussed at the IACC meeting, and the IACC will evaluate progress on a yearly basis. The NIH Autism Coordinating Committee will assume the major responsibility for implementation, including documenting in-progress activities and developing initiatives. Implementation is discussed in more detail later in this document. The major roadblocks identified are listed below, followed by the matrix as approved.
Roadblocks to Understanding Causes and Best Treatment Options for Autism:
Characterization of Autism Spectrum Disorders and Associated Genetics
- Lack of consensus regarding the phenomenological distinctions between autism and related developmental problems (e.g. attention problems, specific language impairment, anxiety)
- Lack of a national autism twin registry that allows researchers access to large sample of well-defined twins with at least one twin affected with autism
- Lack of multi-site, high-risk population studies (i.e. subsequent pregnancies and infant siblings of individuals with autism) that will allow for increased knowledge regarding risk factors, early development of autism, and enhanced characterization of the disorder
- Lack of adequate statistical methods and informatics for genotyping studies
- Need for models of successful implementation of screening practices into community settings
- Lack of a tested model for early intervention in children under the age of 2
- Unsatisfactory standardization of outcome measures used in treatment studies
- Difficulties with the review process for grant applications involving autism treatment studies
Role of the Environment in Autism
- Scarcity of organized medical data and common comprehensive assessments across research sites that allow for identification of early markers and risk factors
- Dearth of technology for non-invasive imaging techniques for neuroscience studies (e.g. connectivity research)
- Insufficient knowledge regarding genetic underpinnings of autism (i.e. susceptibility genes) that help facilitate neurobiological research
- Shortage of brains for national registry used for post-mortem studies
- Lack of a formal network for researchers in developmental neurobiology that will allow for enhancement of investigations in this area
School and Community Interventions
- Need for enhanced collaboration with the Department of Education and other relevant service agencies to develop and test efficacious treatments
- Discrepant policies on early intervention/school transition by geographical region
- Unanswered questions about changes in prevalence and characterization, which require repeated cross-sectional, intensive community-based surveys that include clinical evaluations
- Lack of unbiased population-based sample for epidemiological studies
- Restrictions to implementation of epidemiological research due to regulations that limit access to school records
Communication and Collaboration
- Need for enhanced mechanisms to involve voluntary organizations, industries and potential donors in all stages of research design and implementation
- Insufficient coordination between relevant stakeholders and scientists for communicating accurate science findings to the public
IACC Autism Research Matrix: 12/03
|Goals||Short term (1-3 years)||Medium term (4-6 years)||Long term (7-10 years)|
High Risk Research
Short term (1-3 years)
Medium term (4-6 years)
Long term (7-10 years)
Medium Risk Research
Short term (1-3 years)
Medium term (4-6 years)
Long term (7-10 years)
Low Risk Research
Short term (1-3 years)
Medium term (4-6 years)
Long term (7-10 years)
KEY: Red = Characterization of autism (i.e. phenotype); Green = school and community interventions; Grey = epidemiological studies; Orange = early intervention Purple = Specific treatments; Blue = neuroscience; ; Pink = screening; Black = Role of the Environment in Autism and remaining items
The text below is a series of explanatory notes for the entries in the matrix. As requested by the conferees, the matrix will be a living document, subject to ongoing revision. It will be periodically revisited and revised based on achievement of some of the goals as well as on new knowledge and insights.
Specifics of the Autism Research Matrix
The autism research matrix was designed to include goals and activities for the next 10 years and is divided into short-term (i.e., 1-3 years), medium-term (i.e., 4- 6 years) and long-term (7-10 years) goals. The matrix is also divided into three levels according to risk category, where risk is defined both by anticipated difficulty in achieving the goal as well as innovation and potential impact. For example, a goal is considered high-risk research if attempts to reach it will require a high degree of innovation and have a high chance of failure but is of such high importance that it warrants repeated attempts to achieve the goal.
Goals and activities that comprise the autism research matrix generally fall within the following categories: characterization of autism (i.e. phenotype), screening, early intervention, school and community interventions, specific treatments, neuroscience, environmental factors and epidemiology; however, not all items fall into these categories and several items are applicable to more than one of these domains. In fact, for example, the longest term and highest risk goals include preventing cases of autism and determining the causes of autism. In order to achieve these goals, smaller goals will need to be achieved that will allow researchers to combine knowledge of topics such as neuroscience, early detection, and treatment.
The following text summarizes goals and activities in the various separated domains, followed by summaries and explanations of the specific items of the matrix.
Characterization of Autism Spectrum Disorders and Associated Genetics
The general goal in this area is the development and implementation of the Autism Phenome Project, which will provide comprehensive biomedical and behavioral characterization of autism by defining core and associated features, onset, longitudinal course, and subtypes, using various research strategies (e.g., pooling existing data sets, twin studies, samples at high risk for autism, large population-based, case control studies with follow-up). Goals and activities in this area are aimed to lead towards the long-term goals of finding genetic and non-genetic causes of autism and enhancing optimal treatments. Once genetic factors that increase risk for various aspects of the autism phenotype are identified, systematic research into the potential interaction of these specific variables with environmental variables becomes feasible. In order to complete the Autism Phenome Project, biomarkers for autism will need to be determined and longitudinal studies will be needed to identify risk factors for the development of autism in early infancy, but these are only a few phenotypic parameters of the many that comprise the phenome project.
As our knowledge increases about the early development of autism, we now know that there may be signs of autism at quite early ages, perhaps at birth. In order to intervene as early as possible to prevent development of the full symptomatic expression of autism, effective techniques for detecting autism as early as possible need to be developed, and methods for implementing such screening programs into the community need to be developed and evaluated.
The broad goal in this area is to conduct rigorous studies of early interventions in order to optimize the effectiveness of such treatments. The ultimate goal is to develop and test early intervention programs that secondarily prevent symptomatic expression of autism from developing, such that by school age, children who without such intervention may have been diagnosed with autism no longer fit into this diagnostic category. To achieve this, early intervention methods, particularly for the youngest children (i.e., under age 3) still need to be developed, and sophisticated studies are needed to determine which ingredients of early intervention programs are associated with maximum effectiveness.
Research is beginning to show that specific medical and behavioral treatments, and combinations of these treatments, are effective in ameliorating various problems that are often associated with autism. Further research is needed to fully evaluate the efficacy and effectiveness of such treatments. Treatments aimed at improving the "core" symptoms of autism are also beginning to undergo rigorous evaluation, but much development and evaluation are needed in order to successfully identify treatments for core symptoms such as communication deficits, social impairments, and restricted and repetitive behaviors.
Role of the Environment in Autism
In order to achieve the long-term goal of determining both genetic and non-genetic causes of autism and their interactions, shorter term goals include increasing resources for the study of potential environmental factors, and implementing population based epidemiological studies, as well as focused research that examines potential influences of various environmental factors.
Determining the brain systems and mechanisms that play a role in the development and maintenance of autism will require research advances in several areas of neuroscience, including developmental neurobiology, neuroanatomy, neuropathology, neurochemistry and molecular neuroscience. Increased infrastructure is necessary, such as the development of a centralized repository for biological materials as well as various types of database resources.
School and Community Interventions
Most research on interventions thus far has focused on young children and specifically on improving developmental functioning in the areas of language, basic cognitive skills, social functioning and daily living skills. Research is now needed on strategies to improve "real-world" functioning of individuals with autism, throughout their school-age years and beyond. It has also been widely recognized that periods of transition, such as from high school to higher education and/or employment, provide particular challenges for individuals with autism and their families. This effort will involve a range of research methodologies and strategies to include intervention development; testing of efficacy and effectiveness of existing interventions in diverse community settings; determining roadblocks to implementation of, and access to, effective interventions; and strategies for overcoming roadblocks to widespread dissemination.
Recently, studies have begun to examine changing rates of autism, both in small community-based studies as well as in larger, population-based studies. However, studies thus far have examined changing rates only by examining cases retrospectively at separate time points. Studies that prospectively examine prevalence by including comprehensive diagnostic evaluations on children will be necessary to understand fully changes in prevalence rates of autism over time.
Communication and Collaboration
In order to quicken the pace at which research findings are translated into practice within community settings, the goal in this area is to increase the efficiency with which research findings are communicated to other scientists, as well as to practitioners and members of the autism community.
Adoption and Implementation of the Matrix
The IACC has reviewed, edited, and adopted the matrix presented in this report as the initial version of this guiding document. The NIH Autism Coordinating Committee (NIH-ACC) will now assume primary responsibility for devising an implementation plan that will take into account research activities already underway, including the types of private and partnership activities referred to in the conference language requesting the matrix. The NIH-ACC will also develop new initiatives and priorities intended to implement matrix activities and achieve matrix goals. For example, the NIH-ACC is currently reissuing a program announcement to potential grant applicants entitled "Research on Autism and Autism Spectrum Disorders." The following are other examples of activities that address implementation of various components of the 1- to 3-year time frame matrix items.
Characterization of Autism Spectrum Disorders and Associated Genetics:
Resources established for genotype/phenotype studies (i.e. bioinformatics, genetic repository). Several efforts are underway to increase acquisition of genetic material into a centralized repository. The NIMH Center for Genetic Studies encourages and supports the collection and timely sharing of research resources for genetic studies on autism through a repository http://www.nimhgenetics.org. NIH also strongly supports the Autism Genome Project (AGP), sponsored by the National Alliance for Autism Research (NAAR). NAAR has assembled a large consortium of autism researchers, including those utilizing biomaterials from the Autism Genetic Resource Exchange (AGRE) sponsored by the Cure Autism Now Foundation (CAN), to conduct a genome-wide scan of over 1,200 pedigrees collected worldwide. NIH recently funded a fast-track administrative supplements program to encourage the collection and timely sharing of research resources for use in AGP and other genetic studies on autism. Data and DNA on 1,000 families selected because of an individual with autism will be added to NIMH's Human Genetics Initiative for sharing with AGP and the broader scientific community. Additionally, the STAART Centers are currently working on developing protocols to send phenotypic and genetic material to the NIMH Genetics Repository.
Outcome measures improved, to enhance their usefulness in evaluating treatment studies. A workshop in September 2002, entitled "Research on Psychosocial and Behavioral Interventions in Autism: Confronting the Methodological Challenges," provided initial groundwork for this activity (http://www.nimh.nih.gov/events/autismconference.cfm). Since this meeting, workgroups have formed and are currently working on assessing the field with respect to outcome measure for young children, school-aged children and adults. A separate workgroup is focused on issues of research design for outcome studies.
Evaluate sensitivity and specificity of existing screening tools, and continue developing efficacious screening measures. NIH has funded several grants to investigators to evaluate the validity and reliability of newly developed screening tools. For instance, NIH has funded research on the M-CHAT and the Social Communication Questionnaire. The CDC has also funded specific research evaluating effective strategies for implementing screeners into community practice settings.
Randomized clinical trial developed for the evaluation of the effectiveness of early behavioral intervention and moderator variables predicting response to intervention. The University of Washington STAART Center is undertaking such a study that will examine the effects of a specific method of applied behavioral analysis in children from a young age, and compare this treatment with standard community treatment.
Infrastructure, such as enhanced brain acquisition, established for neuropathological investigations, to characterize the morphological aspects of the pathophysiology of autism. In October 2003, NIMH awarded funding for the National Autism Brain Bank, which will create a centralized repository for autism brain tissue and support outreach activities to enhance these resources.
First generation intensive community-based prevalence studies implemented with clinical evaluations to have initial data for detecting changes in prevalence of autism. CDC is currently funding the Centers of Excellence for Autism and Developmental Disabilities Research and Epidemiology (CADDRE), which are implementing community-based prevalence studies in several states.
These activities address specific matrix items. Planning is currently underway for further collaborative work that will use findings from these activities to lay the groundwork for implementation of some of the higher risk and longer time course matrix items. These and other activities are also currently being expanded to include opportunities for voluntary and private funding organizations to participate through partnerships or to implement independent activities but with coordination to ensure maximum effectiveness. Certain present and planned activities include collaboration with other government agencies. The IACC will ensure that the matrix is a living document, and it will, through future iterative processes, use it to help guide further autism research planning at NIH and as a tool for the entire autism community. In closing, the following are some recent highlights of findings in key areas of autism research that reflect on the state of the science at the time of this initial version of the Autism Research Matrix.
Autism Research Highlights
In the past 30 years, over 25 prevalence studies of autism have been conducted internationally. These studies have used varying criteria for autism, and found prevalence estimates ranging from 1.9 to 60 per 10,000 (reviewed in Yeargin-Allsopp, 2002). Given differences in both methods and results among published studies, there is no current consensus regarding autism rates.
The CDC is the Federal agency most directly involved in incidence and prevalence studies of various disorders. One example of a recent (1998) autism prevalence study (though not a full population-based study) conducted by the CDC is the Brick Township, New Jersey study. Findings from this study of children aged 3-10 indicated that the prevalence of strictly defined autism was 4 per 1,000, and the prevalence of autism spectrum disorders was 6.7 per 1,000 (Bertrand et al., 2001). These rates are among the highest that have been reported. In order to provide data from a large population-based study, the CDC conducted the Metropolitan Atlanta Developmental Disabilities Study (MADDS), which found a prevalence rate for the combination of autism, Asperger's disorder and pervasive developmental disorder--not otherwise specified (PDD-NOS) to be 3.4 per 1,000 (Yeargin-Allsopp et al., 2003).
In the past 10 years, researchers have begun utilizing highly sophisticated approaches for identifying candidate genes involved in susceptibility to autism (Folstein & Rosen-Sheidley, 2001). Recent research in the genetics of autism has indicated that several genes (possibly 5 to 10) are involved in autism susceptibility, and comparison of studies involving twins, siblings and other relatives implicates epistatic (e.g. multiplicative) effects among genes (Dawson et al., 2002). However, no susceptibility genes have been confirmed in replicated research studies.
Although no specific genes have been confirmed, researchers are beginning to identify candidate genes that are linked to endophenotypes, or component parts of the disorder. For instance, a recent study found that a gene on chromosome 15 coding for the gamma-aminobutyric acid (GABA) receptor beta3-subunit (GABRB3) is involved in the autistic symptoms of repetitive behaviors and stereotyped patterns (Shao et al., 2003).
While no gene(s) have been found to directly relate to susceptibility of idiopathic autism, there has been much progress in identification of the genetic basis for Rett's Disorder, a variant autism spectrum disorder (ASD) found almost exclusively in females. A mutation in the methyl-CpG-binding protein 2 (MeCP2) gene on the X chromosome was found and is present in most cases of Rett's Disorder (Amir et al., 1999). More recently, mutations on MeCP2 have been found on a small percent of girls diagnosed with autism (Camey et al, 2003), indicating that this specific mutation may be a cause of autism as well as Rett's Disorder for at least some affected girls. A related recent finding has implicated mutations in two neuroligins (NLGN3 and NLGN4) on the X chromosome to be involved in autism spectrum disorders (Jamain et al., 2003).
A recent review highlights the complexities of studying the neurobiology of autism, in that the heterogeneous behavioral expressions of autism may relate to multiple neuropathologic etiologies (Lord, Cook, Leventhal & Amaral, 2000). Nonetheless, neuropathological studies that have employed both post-mortem studies as well as imaging techniques have implicated several areas of the brain to be involved in aspects of autism. Both the medial temporal lobe (MTL), which includes the amygdala, as well as the cerebellum, has been found to be abnormal in several studies (Akshoomoff, Pierce & Courchesne, 2002; Dawson et al., 2002).
A striking recent finding is increased brain volume when children with autism are young, although not at birth or later in life (Aylward, Minshew, Field, Sparks, & Singh, 2002), leading to a theory of brain growth dysregulation underlying autism (Courchesne et al., 2002).
The past 10 years have been marked by an increase in trials of targeted pharmacological interventions aimed at specific behaviors associated with autism. As an example, a study of risperidone, one of a newer class of anti-psychotic medications, was effective and well tolerated for the treatment of serious behavioral disturbance associated with autistic disorder in children aged 5 to 17 (McCracken et al., 2002). Also near completion is a study evaluating the safety and efficacy of methylphenidate in treating over activity, impulsivity, and distractibility in children with autism spectrum disorders. Other treatment research has found a lack of efficacy for specific interventions. For instance, a multisite, double-blind, placebo-controlled study found that porcine secretin is not an efficacious treatment for autism (Owley et al., 2001).
A major effort to synthesize the research literature on early intervention was undertaken by the National Research Council at the request of the U.S. Department of Education's Office of Special Education Programs (National Research Council, 2001). The report reviews converging evidence on the components of effective early intervention models and makes recommendations for further research in this area.
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