SFARI scientific perspectives

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Last modified: July 16, 2018

The landscape of autism research has changed dramatically since SFARI issued its first request for applications in 2007. It is now truly a multidisciplinary field, attracting top researchers from around the world. Since 2007, SFARI has committed more than $380 million in external research support to more than 480 investigators in the U.S. and abroad in service of our mission: to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.

The SFARI science team often gets asked some version of the question, “What kind of science will get me SFARI funding?” Unfortunately, this is an impossible question to answer given the complexities and multidisciplinary nature of the field and our inherent uncertainties about where the next major advance may come from. That said, we want to be as transparent as possible with researchers, whom we view as partners in this quickly moving and challenging field.

Below are our views on various scientific topics, many of which we’ve expressed in previous blog posts. Given the importance of these views in guiding our funding process, we feel these perspectives deserve a more lasting place on our website. We view this page as a living document, one that we plan to update as the science and our viewpoints evolve.

As an overarching principle, we are particularly interested in projects that try to bridge different levels of understanding, especially by connecting insights from genes to molecular mechanisms to neural circuits to behavior. The causes of autism are almost always multifactorial, but given the recent advances in the understanding of genetic risk for autism, we feel that working within a “genes to biology to behavior to therapeutics” framework provides a rigorous and tractable way forward for now. For an overview of why the genetics is bedrock, see SFARI Investigator Matthew State discuss the current state of autism genetics.

As a first step, when preparing a proposal, we strongly recommend that applicants familiarize themselves with SFARI’s current and past grant portfolio, as well as SFARI-generated resources. We have put tremendous effort into the development of these resources, and we hope you will take full advantage of the knowledge gained in thinking about how your work might complement, but not duplicate, existing efforts.

Regardless of the exact science proposed, SFARI is deeply committed to supporting rigorous, reproducible data that is readily shared with the scientific community. The supposed lack of reproducibility in biomedical science has become a widely discussed topic1, so in support of this important issue, SFARI has created a list of methodological and statistical considerations for potential SFARI grant applicants.

Genetics

The most current estimates of autism risk indicate that approximately 80 percent of the risk results from genetic alterations2. Depending on the statistical cutoff, nearly 100 genes have strong evidence implicating them as risk factors for ASD. Several hundred additional genes have been implicated with lower levels of confidence. Applicants can find more information about autism candidate genes and evolving community-based gene scores at SFARI Gene, an online database providing a convenient and comprehensive way to become familiar with the genetic landscape of autism. SFARI Gene lists hundreds of genes that have been implicated in ASD by various means but, importantly, also provides a scoring system (with 1 being the highest confidence and 6 being lowest confidence) to rate the strength of the evidence based on a range of criteria. We generally consider strong candidate risk genes (i.e., a false discovery probability under 10 percent) to be those with scores of 1, 2 or S (genes underlying syndromes that are frequently accompanied by an autism diagnosis). SFARI Gene is updated quarterly, but given the rapid pace of the field, we recommend that you pay careful attention to the most recent primary literature and reviews as well.

With such large numbers of candidate genes, the research community will need to replicate results from the Simons Simplex Collection (SSC) and other collections in larger populations. While an exhaustive characterization of the genetic landscape of autism is probably neither feasible nor necessary in the short term, a better understanding of each class of genetic risk variant — from small to large and from common to rare — is an important goal, keeping in mind that de novo and familial influences likely contribute to some extent in every case3. Discovery of genes that only modestly elevate or reduce autism risk will require genetic characterization of much larger populations of individuals with autism than are presently available.

Given SFARI’s extensive investments in the genetics of ASD to date, prospective applicants are strongly encouraged to familiarize themselves with the data available from SFARI-supported cohorts, past and current genomics-focused RFAs and related informatic tools to think carefully about how their research would complement SFARI’s ongoing efforts. Genetic and phenotypic data collected for some of the SFARI-supported cohorts can be requested through SFARI’s central database system, SFARI Base. Researchers planning genetic studies should also be cognizant of other autism gene discovery efforts and be prepared to justify the uniqueness of their proposed studies. We welcome novel and complementary efforts to identify risk variants of any sort.

From genes to biological mechanisms

Given that a clearer picture of the landscape of autism genetics is now emerging, we prioritize science that increases our understanding of how alterations in particular ASD risk genes cause changes in cells and circuits, especially pathways and circuits that are likely to be evolutionarily conserved in humans.

Experimental systems, such as rodents — and in recent years, Drosophila, C. elegans, zebrafish, non-human primates, postmortem tissue and induced pluripotent stem cells (iPSCs) — provide critical platforms to explore the molecular, cellular and circuit mechanisms underlying ASD. SFARI is open to using these and other compelling organisms/systems for autism-relevant studies.

SFARI emphasizes construct validity over face validity when choosing an experimental system; we prioritize proposals that start with an experimental system that recapitulates a mutation in a risk gene or an epidemiological factor that can be linked to ASD with high confidence. For rodent models in particular, behavioral resemblance to the human disorder (e.g., in the BTBR mouse strain) — such as social interaction deficits or repetitive behaviors — can be a useful functional readout of the function of the underlying circuits in that species, but such behavioral phenotypes on their own do not have sufficient etiological validity to constitute a strong autism model. As discussed in a recent NIMH Workgroup on Genomics Report, it may be superficial and misleading to accept phenocopies of human characteristics as predictive endpoints for translation.

SFARI is continuing its efforts to make mouse, rat and iPSC models of high-risk autism genes and copy number variants identified in human genetic studies available to researchers. For a list of mouse and rat models currently available because of SFARI efforts, please visit our autism mouse and rat model websites. For more information on available iPSC lines, how to request them and our perspectives on experimental considerations, please visit our iPSC models page.

In addition to rodent and cellular models, SFARI makes postmortem human tissue available through the SFARI-funded Autism BrainNet, a collaborative network for the acquisition of postmortem brain tissue for research.

Human subjects studies

For work in the clinical realm, SFARI prioritizes research that is grounded in biology. Although we recognize the value of other types of research, such as optimizing behavioral interventions, we hope that, over the long term, focusing on biological mechanisms will lead to effective interventions. We welcome proposals that use noninvasive methods, such as functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG), to directly examine the human biology of autism. Such approaches can help advance ‘forward’ translation to biomarkers and objective outcome measures as well as ‘back’ translation to studies of neural mechanisms in experimental systems.

It should be noted, however, that given the heterogeneity of ASD, we place a premium on the use of sufficiently powered and well-characterized cohorts. We’ve learned from our own efforts as well as the experiences of previous grantees that recruitment and retention is far more difficult, time-consuming and costly than many researchers anticipate. Therefore, unless there is a compelling reason for a new cohort, we recommend that researchers collaborate with existing teams that already have a study group and pay careful attention to ascertainment biases that can influence the results. We also believe that it is no longer sensible to study individuals with ASD without knowing something about their genetic background or, at a minimum, including a collection of biospecimens for future studies and analyses. We will work with investigators who need advice about such logistics while preparing their applications.

Examples of well-characterized cohorts include the SFARI-supported SSC, Simons Variation in Individuals Project (Simons VIP) and Simons Foundation Powering Autism Research for Knowledge (SPARK); genetic data is available (or will be forthcoming) for all or many of these participants. In addition to genetic data, multiple other types of data and biospecimens are available for those cohorts (medical history, psychometric testing, brain imaging, etc.). SPARK in particular has an active Research Match program, allowing researchers to apply to recruit its more than 38,000 participants with ASD. We encourage researchers interested in recruiting SFARI cohort participants for their own studies to familiarize themselves with the research match process and to contact collections@sfari.org to learn about the availability of individuals suitable for the proposed study.

We hope this webpage provides the community with some insight on our evolving scientific perspectives and priorities. We welcome constructive feedback (sciencerfa@simonsfoundation.org) and look forward to updating this page in the coming months.

References

  1. Challenges in irreproducible research. Nature Special Archive Collection
  2. Sandin S. et al. JAMA 318, 1182-1184 (2017) PubMed
  3. Robinson E.B. et al. Proc. Natl. Acad. Sci. USA 111, 15161-15165 (2014) PubMed
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