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

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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."


Question 3 Cumulative Funding Table

IACC Strategic Plan Objectives 2008 2009 2010 2011 2012 Total
Coordinate and implement the inclusion of approximately 20,000 subjects for genome-wide association studies, as well as a sample of 1,200 for sequencing studies to examine more than 50 candidate genes by 2011. Studies should investigate factors contributing to phenotypic variation across individuals who share an identified genetic variant and stratify subjects according to behavioral, cognitive, and clinical features.

IACC Recommended Budget: $43,700,000 over 4 years
3.2
$4,065,392
14 projects

3.S.A
$13,926,663
11 projects

3.S.A
$16,688,932
14 projects

3.S.A
$2,207,214
7 projects

3.S.A
$1,699,432
6 projects

$38,587,633
3.S.A. Funding: The recommended budget was partially met, and is approaching the recommended budget.

Progress: Progress has been made on this objective through the funding of several GWAS and sequencing projects. The current number of 6,000 GWAS subjects falls short of the goal of 20,000, but the number of whole exome sequences far exceeds 1,200, and could also reach 6,000 in the next year. Whole exome sequencing has identified 7-10 candidate genes, and promises to move closer to the goal of 50 in the future. Progress is being made in CNV studies. Overall, the work is on target.

Remaining Gaps, Needs, and Opportunities: More subtyping and genotype-phenotype work outside of syndromic forms of autism, as well as natural history studies, are needed.
 
Within the highest-priority categories of exposures for ASD, identify and standardize at least three measures for identifying markers of environmental exposure in biospecimens by 2011.

IACC Recommended Budget: $3,500,000 over 3 years
3.3
$713,227
4 projects

3.S.B
$0
0 projects

3.S.B
$0
0 projects

3.S.B
$0
0 projects

3.S.B
$100,000
1 project

$813,227
3.S.B. Funding: The recommended budget was not met; the funding allocated to projects specific to this objective falls far short of the recommendation.

Progress: There has been progress on the understanding of exposures, but more work needs to be done to apply this directly to autism research.  Progress has made through methodological advances embedded in epidemiological studies funded by NIEHS, but those projects are not captured by the Portfolio Analysis because they are not specific to autism.

Remaining Gaps, Needs, and Opportunities: The primary obstacle to completion of this objective has been availability of funding to identify and validate exposure markers. There is a need for biomarkers of exposure; exposomics should be a priority area for future research.
 
Initiate efforts to expand existing large case-control and other studies to enhance capabilities for targeted gene-environment research by 2011.

IACC Recommended Budget: $27,800,000 over 5 years
3.4
$4,703,867
4 projects

3.S.C
$8,033,454
9 projects

3.S.C
$4,824,779
8 projects

3.S.C
$5,714,408
10 projects

3.S.C
$3,626,803
9 projects

$26,903,311
3.S.C. Funding: The recommended budget was nearly met, but work still needs to continue on this objective.

Progress: The funding allocated to this area so far has primarily supported building infrastructure that can now be expanded to include more subjects, more data, and more analytical projects.  Studies such as the MARBLES (Markers of Autism Risk in Babies Learning Early Signs) cohort study and the CHARGE (Childhood Autism Risks from Genetics and the Environment) study are included under this objective.

Remaining Gaps, Needs, and Opportunities: Continued benefit will be derived from past investments as these resources are expanded and pooled.
 
Enhance existing case-control studies to enroll racially and ethnically diverse populations affected by ASD by 2011.

IACC Recommended Budget: $3,300,000 over 5 years
3.5
$84,628
2 projects

3.S.D
$103,827
3 projects

3.S.D
$0
0 projects

3.S.D
$0
0 projects

3.S.D
$0
0 projects

$188,455
3.S.D. Funding: The recommended budget was not met; the funding allocated to projects specific to this objective falls far short of the recommendation.

Progress: The UCLA ACE center coded to 3.L.B. reflects some progress on this objective. CADDRE also includes racially diverse participants from multiple urban centers.  Overall, however, both funding and outcomes related to this objective are far below the goal.

Remaining Gaps, Needs, and Opportunities: There is a need for studies around high exposure, low socioeconomic status populations.
 
Support at least two studies to determine if there are subpopulations that are more susceptible to environmental exposures (e.g., immune challenges related to infections, vaccinations, or underlying autoimmune problems) by 2012.

IACC Recommended Budget: $8,000,000 over 2 years
N/A

3.S.E
$1,739,200
13 projects

3.S.E
$1,162,679
10 projects

3.S.E
$419,215
5 projects

3.S.E
$287,218
5 projects

$3,608,312
3.S.E. Funding: The recommended budget was partially met.

Progress: Several projects were funded in this area, going beyond the minimum recommended by the committee, but the projects have been smaller than what was expected. However, even with smaller studies, a large amount of data has been collected relating to immunological conditions in children and mothers.

Remaining Gaps, Needs, and Opportunities: More work is needed to analyze and interpret available data.
 
Initiate studies on at least 10 environmental factors identified in the recommendations from the 2007 IOM report "Autism and the Environment: Challenges and Opportunities for Research" as potential causes of ASD by 2012.

IACC Recommended Budget: $56,000,000 over 2 years (revised in 2010)
3.1
$7,600,673
19 projects

3.S.F
$2,952,960
14 projects

3.S.F
$166,362
5 projects

3.S.F
$0
3 projects

3.S.F
$75,000
1 project

$10,794,995
3.S.F. Funding: The recommended budget was partially met.

Progress: There has been a significant decrease in the number of studies related to this objective.

Remaining Gaps, Needs, and Opportunities: Further work in this area is needed, and work should focus on identifying the directionality of associations between environmental factors and ASD (causal, reactive, or independent) in order to be applied to prevention and the development of therapeutics. Sophisticated methods that are being applied in other fields need to be brought into autism research.
 
Convene a workshop that explores the usefulness of bioinformatic approaches to identify environmental risks for ASD by 2011.

IACC Recommended Budget: $35,000 over 1 year
*This objective was completed in 2011
N/A

N/A

3.S.G
$0
0 projects

3.S.G*
$46,991
1 project

3.S.G*
$0
0 projects

$46,991
3.S.G. Funding: The workshop identified in this objective was funded and held by NIEHS in 2011.

Progress :A workshop on this topic, "Autism and the Environment: New Ideas for Advancing the Science," was convened by the National Institute of Environmental Health Sciences (NIEHS) in 2010. (a meeting report is available). Therefore, this objective has been completed.

Remaining Gaps, Needs, and Opportunities: Next steps for this area include the need to develop an exposome. A forum for the sharing of new technologies and standardized assessments would also be useful in moving this field forward.
 
Support at least three studies of special populations or use existing databases to inform our understanding of environmental risk factors for ASD in pregnancy and the early postnatal period by 2012. Such studies could include:
  • Comparisons of populations differing in geography, gender, ethnic background, exposure history (e.g., prematurity, maternal infection, nutritional deficiencies, toxins), and migration patterns; and
  • Comparisons of phenotype (e.g., cytokine profiles), in children with and without a history of autistic regression, adverse events following immunization (such as fever and seizures), and mitochondrial impairment. These studies may also include comparisons of phenotype between children with regressive ASD and their siblings.
Emphasis on environmental factors that influence prenatal and early postnatal development is particularly of high priority. Epidemiological studies should pay special attention to include racially and ethnically diverse populations.

IACC Recommended Budget: $12,000,000 over 5 years
N/A

N/A

3.S.H
$1,527,866
13 projects

3.S.H
$4,657,095
16 projects

3.S.H
$4,096,317
13 projects

$10,281,278
3.S.H. Funding: The recommended budget was partially met, and is approaching the recommended budget.

Progress: The funded projects cover the objective well; there are 32 projects that are related to this objective, though more projects focus on use of databases than on special populations. A positive element of progress for this objective is the existence of large monitoring databases and projects that capitalize on those resources, such as iCARE and MINERvA.

Remaining Gaps, Needs, and Opportunities: While progress is being made in this area, and it must be maintained in order to achieve this objective.
 
Support at least two studies that examine potential differences in the microbiome of individuals with ASD versus comparison groups by 2012.

IACC Recommended Budget: $1,000,000 over 2 years
N/A

N/A

3.S.I
$53,960
3 projects

3.S.I
$439,971
4 projects

3.S.I
$255,332
6 projects

$749,263
3.S.I. Funding: The recommended budget was partially met.

Progress: The number of projects in this area has been growing, with 6 projects in 2012. The number of funded projects is large relative to the amount of funding, indicating that each of the projects is small, which suggests that these projects will not be sufficient in scope to complete this objective.

Remaining Gaps, Needs, and Opportunities: The high cost of required technology could be a barrier to the completion of this objective. These smaller pilot studies are potentially underpowered. The question of sample availability is important for this objective, along with raising researcher awareness of sample repositories.
 
Support at least three studies that focus on the role of epigenetics in the etiology of ASD, including studies that include assays to measure DNA methylations and histone modifications and those exploring how exposures may act on maternal or paternal genomes via epigenetic mechanisms to alter gene expression, by 2012.

IACC Recommended Budget: $20,000,000 over 5 years
N/A

N/A

3.S.J
$5,072,389
15 projects

3.S.J
$5,341,237
19 projects

3.S.J
$6,122,724
22 projects

$16,536,350
3.S.J. Funding: The recommended budget was partially met, and the annualized recommended budget targets were met for all 3 years since the objective was introduced; therefore, the funding for this objective is on track. If this funding trend continues, the objective's recommended budget will be met within the recommended 5 year timeframe.

Progress: More than the recommended number of projects have been funded, with 22 projects supported in 2012. This is a growing area of research, and the current momentum in this area should be maintained.

Remaining Gaps, Needs, and Opportunities:  An important technological need for this objective is the development of robust epigenetic measurements for small biological samples, such a blood spots. A possible barrier to research in this area is the availability and preservation quality of these samples. Large funded studies such as MARBLES might provide an opportunity to collect samples. If samples are made available, that may catalyze research in this area.
 
Support two studies and a workshop that facilitate the development of vertebrate and invertebrate model systems for the exploration of environmental risks and their interaction with gender and genetic susceptibilities for ASD by 2012.

IACC Recommended Budget: $1,535,000 over 3 years
N/A

N/A

3.S.K
$733,922
5 projects

3.S.K
$463,841
3 projects

3.S.K
$90,000
3 projects

$1,287,763
3.S.K. Funding: The recommended budget was partially met. However, the yearly funding decreased significantly from 2010-2012. It should be noted that this objective overlaps partially with 2.S.B., which is focused on research on sex differences in ASD, and 4.S.B., which focuses on development of animal models that can be used for understanding molecular and neural pathways that can be targeted by interventions. Genetic pathways that play a role in gender differences and other molecular and neural pathways may interact with environmental factors, so funding for these objectives could reflect progress on the goals of 3.S.K.

Progress: Projects by Tychele Turner at Johns Hopkins and Donna Werling at UCLA that are using animal models to investigate sex differences in autism are coded to 2.S.B. The following 2010 workshop sponsored by NIEHS, Autism and the Environment: Advancing the Science, touched on this topic, but it was not the main focus of the workshop.

Remaining Gaps, Needs, and Opportunities:  The development of animal models for more broad ASD research is coded to question 4, and the use of such models to answer environmental exposure questions is a next step for this objective.
 
Conduct a multi-site study of the subsequent pregnancies of 1,000 women with a child with ASD to assess the impact of environmental factors in a period most relevant to the progression of ASD by 2014.

IACC Recommended Budget: $11,100,000 over 5 years
3.7
$2,742,999
1 project

3.L.A
$3,740,812
2 projects

3.L.A
$2,971,093
2 projects

3.L.A
$2,864,377
1 project

3.L.A
$2,875,202
2 projects

$15,194,483
3.L.A. Funding: The recommended budget for this objective was met, but emphasis on this objective should continue in the future.

Progress: The Group is concerned about the lack of continued funding for EARLI. More positively, projects analyzing the previously collected EARLI data are in process. Also, the MARBLES project contributes toward the goal of studying  the interaction of genetic and environmental factors beginning during pregnancy, but, since it is not a multi-site study, and is also a continuation of an existing study funded as a pilot under a UC Davis Children's Center grant, funding for MARBLES is coded to 3.S.C, which overlaps somewhat with this objective.

Remaining Gaps, Needs, and Opportunities:   A barrier to this type of work is the extremely high cost of building the necessary infrastructure. With MARBLES and previously with EARLI, there has been some progress on infrastructure. It is important to maintain these cohorts where possible, to collect a wide range of samples, and to use them for multiple studies to capitalize on investments made.
 
Identify genetic risk factors in at least 50% of people with ASD by 2014.

IACC Recommended Budget: $33,900,000 over 6 years
3.8
$37,043,410
83 projects

3.L.B
$49,905,587
79 projects

3.L.B
$34,432,884
60 projects

3.L.B
$25,383,346
59 projects

3.L.B
$23,041,231
74 projects

$169,806,458
3.L.B. Funding: The recommended budget was met. Significantly more than the recommended minimum budget was allocated to projects specific to this objective.

Progress:  Further work is needed to identify genetic risk factors in at least 50% of people. Currently, whole exome analysis predicts that a genetic risk factor can be identified for 20% of people; inclusion of CNV data might push this toward 30%.

Remaining Gaps, Needs, and Opportunities: The initial budget recommendation for this objective was made based on the assumption that GWAS studies would provide risk factor identification, but sequencing has proven more fruitful. Since this technique is more expensive, a higher budget will be required to meet the goal of 50%.
 
Determine the effect of at least five environmental factors on the risk for subtypes of ASD in the prenatal and early postnatal period of development by 2015.

IACC Recommended Budget: $25,100,000 over 7 years
3.6
$1,803,628
13 projects

3.L.C
$1,992,228
10 projects

3.L.C
$820,320
10 projects

3.L.C
$379,913
5 projects

3.L.C
$353,000
5 projects

$5,349,089
3.L.C. Funding: The recommended budget was partially met, and several projects were funded, but it appears there is a downward trend in funding for these projects over time. This objective partially overlaps with 3.L.A.

Progress: Epidemiological studies coded to other objectives (e.g., EARLI) may also represent progress in this area.

Remaining Gaps, Needs, and Opportunities:  A barrier to the completion of this objective is the undefined nature of ASD subtypes, both phenotypically and etiologically, lack of prenatal samples, and the lack of longitudinal follow-up of at-risk subgroups. This field is still developing and needs support.
 
Support ancillary studies within one or more large-scale, population-based surveillance and epidemiological studies, including United States populations, to collect data on environmental factors during preconception, and during prenatal and early postnatal development, as well as genetic data, that could be pooled (as needed) to analyze targets for potential gene/environment interactions by 2015.

IACC Recommended Budget: $44,400,000 over 5 years
3.9
$17,297,788
29 projects

3.L.D
$9,135,505
12 projects

3.L.D
$11,464,011
10 projects

3.L.D
$11,567,250
10 projects

3.L.D
$13,549,160
12 projects

$63,013,714
3.L.D. Funding: The recommended budget was met. Significantly more than the recommended minimum budget was allocated to projects specific to this objective.

Progress: The funds allocated to this objective to date have been used for data collection and the development of infrastructure, with most of the studies coded to this area relating to CDC's CADDRE program.

Remaining Gaps, Needs, and Opportunities:  Continued funding will be needed to support data analysis. Both molecular and environmental data are needed.
 
Not specific to any objective (Core/Other Activities) 3.Core/ Other Activities
$6,791,008
52 projects

3.Core/ Other Activities
$8,512,980
39 projects

3.Core/ Other Activities
$1,312,450
7 projects

3.Core/ Other Activities
$724,770
5 projects

3.Core/ Other Activities
$315,607
3 projects

$17,656,815
Total funding for Question 3 $82,846,620
221 projects

$100,043,216
192 projects

$81,231,647
162 projects

$60,209,628 148 projects

$56,487,025
162 projects

$380,818,136

Table 3: Question 3 Cumulative Funding Table, see appendix for a color-coding key and further details.

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35 Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D Marlow N. Psychiatric disorders in extremely preterm children: longitudinal finding at age 11 years in the EPICure study. J. Am. Acad. Child Adolesc. Psychiatry. 2010 May; 49(5):453–463.e1. [PMID: 20431465]

36 Limperopoulos C, Bassan H, Sullivan NR, Soul JS, Roberston RL Jr, Moore M, Ringer SA, Volpe JJ, du Plessis AJ. Positive Screening for Autism in Ex-preterm Infants: Prevalence and Risk Factors. Pediatrics. 2008 Apr; 121(4):758–765. [PMID: 18381541]

37 Pinto-Martin JA, Levy SE, Feldman JF, Lorenz JM, Paneth N, Whitaker AH. Prevalence of Autism Spectrum Disorder in Adolescents Born Weighing  <2000 Grams. Pediatrics. 2011 Oct; 128(5):883–891. [PMID: 22007018]

38 Schieve LA, Rice C, Devine O, Maenner MJ, Lee LC, Fitzgerald R, Wingate MS, Schendel D, Pettygrove S, van Naarden Braun K, Durkin M. Have secular changes in perinatal risk factors contributed to the recent autism prevalence increase? Development and application of a mathematical assessment model. Ann. Epidemiol. 2011 Dec; 21(12):930–945. [PMID: 22000328]

39 Durkin MS, Maenner MJ, Newschaffer CJ, Lee LC, Cunniff CM, Daniels JL, Kirby RS, Leavitt L, Miller L, Zahorodny W, Schieve LA. Advanced parental age and the risk of autism spectrum disorder. Am. J. Epidemiol. 2008 Dec; 168(11):1268–1276. [PMID: 18945690]

40 Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry. 2012 May; 51(5):477–486.e1. [PMID: 22525954]

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42 Puleo CM, Schmeidler J, Reichenberg A, Kolevzon A, Soorya LV, Buxbaum JD, Silverman JM. Advancing paternal age and simplex autism. Autism. 2012 Jul; 16(4):367–380. [PMID: 22180389]

43 Reichenberg A, Gross R, Sandin S, Susser ES. Advancing paternal and maternal age are both important for autism risk. Am. J. Public Health. 2010 May; 100(5):772–773; author reply 773. [PMID: 20299637]

44 Van Balkom ID, Bresnahan M, Vuijk PJ, Hubert J, Susser E, Hoek HW. Paternal age and risk of autism in an ethnically diverse, non-industrialized setting: Aruba. PloS One. 2012 7(9):e45090. [PMID: 22984615]

45 Sasanfar R, Haddad SA, Tolouei A, Ghadami M, Yu D, Santangelo SL. Paternal age increases the risk for autism in an Iranian population sample. Mol. Autism. 2010 1(1):2. [PMID: 20678245]

46 Cheslack-Postava K, Liu K, Bearman PS. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics. 2011 Feb; 127(2):246–253. [PMID: 21220394]

47 Gunnes N, Suren P, Bresnahan M, Hornig M, Lie KK, Lipkin WI, Magnus P, Nilsen RM, Reichborn-Kjennerud T, Scholberg S, Susser ES, Oyen AS, Stoltenberg C. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013 Nov; 24(6):906–912. [PMID: 24045716]

48 Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013 Oct; 167(10):959–966. [PMID: 23938610]

49 Croen LA, Connors SL, Matevia M, Qian Y, Newschaffer C, Zimmerman AW. Prenatal exposure to β2-adrenergic receptor agonists and risk of autism spectrum disorders. J. Neurodev. Disord. 2011 Dec; 3(4):307–315. [PMID: 21874331]

50 Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013 346f2059. [PMID: 23604083]

51 Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N. Engl. J. Med. 2013 Dec; 369(25):2406–2415.  [PMID: 24350950]

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53 Grether JK, Li SX, Yoshida CK, Croen LA. Antenatal Ultrasound and Risk of Autism Spectrum Disorders. J. Autism Dev. Disord. 2009 Sep; 40(2):238–245. [PMID: 19728066]

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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.


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