Today, we’re announcing our annual request for applications (RFA) for SFARI Pilot and Research Awards. Letters of intent (LOIs), the short statements that precede full applications, are due no later than 9 October, 2015.

As we do every year, we’ve updated this column to provide a better picture of how the SFARI science team makes decisions on research proposals. Although the fundamentals remain the same, there have been a number of notable changes as a result of advances in the field and our evolving view of SFARI’s priorities.

In the past few years, SFARI has received roughly 400 LOIs for each annual RFA. In a single recent year, LOI requests totaled over $300 million, but our budget for new grants was only around $18 million. (Investigator-initiated awards make up approximately one-third of SFARI’s annual budget of roughly $60 million.) Judging from previous years, the vast majority of LOIs that we receive in this cycle will no doubt describe important and interesting work — and it would be great if SFARI could fund all of them — but that is unfortunately not possible.

Clearly, we have to make tough choices about which applicants to invite to submit full proposals. We know it can be challenging to describe work in three pages. If we feel an application is not likely to be competitive for one reason or another, however, we prefer to tell the applicant early, rather than after he or she has invested more effort.

Although our decisions at this point are mostly binary (either yes or no to a full application), we do advise some applicants to consider submitting more streamlined full proposals, for example, by reducing a request for a SFARI Research Award to a Pilot Award.

How we interpret which applications are likely to best support SFARI’s mission is, of course, nuanced and evolves as new results emerge. But there are a few general guidelines that have emerged from previous grant review panels, and from multiple internal and external discussions, that influence our decisions. We outline these below.

The issues in autism research are complex, and deciding which projects are most relevant to our mission is one of our greatest challenges. One might argue that autism is a result of altered brain development and function, so any project that aims to understand the brain — especially a brain system whose function has been linked to autism — is relevant. But SFARI’s funding is finite, and to fulfill our mission, we need to maintain a tighter focus.

One goal of our annual open RFA is to cast a broad net for the best new ideas — many of which we cannot anticipate and are often made possible by emerging new technologies, so we hesitate to be too precise in listing the types of grants we are looking for. But given recent advances on many fronts, the time seems ripe to bridge different levels of understanding in a push for a more coherent picture of autism. This will involve connecting insights from genes to circuits to behavior, so we especially encourage grants with this broad outlook.

For work in the clinical realm, we favor research that is grounded in biology. Over the long term, we hope this approach will lead to effective interventions. We recognize the value of other types of work, such as research into improvements of behavioral therapies or assistive technologies, but we generally prioritize studies that focus on elucidating biological mechanisms.

Genetics:

We have supported, and continue to support, a number of large-scale efforts aimed at defining the genetic risk variants for autism spectrum disorder (ASD). These have primarily centered on gene discovery in the Simons Simplex Collection (SSC), a repository of samples and data ascertained from families with one ASD-affected child, unaffected parents and, in the majority of cases, at least one unaffected sibling. A large proportion of this collection (approximately 2,500 families) has now been analyzed genome-wide at the level of copy number variations (CNVs)^1,2 and exome sequences ^3-7. Genetic data resulting from these studies are available to the research community via SFARI Base and other data repositories.

Whole-genome sequencing (WGS) has recently been initiated for 540 families of the SSC and is projected to be complete in early 2016. The first batch of WGS data is expected to be available to the entire research community later this year. SFARI announced the “Whole-Genome Analysis for Autism Risk Variants” RFA in July 2015, which aims to fund applications proposing innovative and efficient analyzes of the WGS data. We hope to award multiple grants through this mechanism by October 2015. We do not encourage submissions to our annual RFA that would have been appropriate for this targeted RFA without specific prior discussions with a member of the SFARI science team.

SFARI has helped to establish a “genetics-first cohort” through the Simons Variations in Individuals Project (Simons VIP), in which individuals are recruited based on their genetic diagnosis independent of an autism diagnosis ⁸. The Simons VIP initially focused on one of the most recurrent genetic events identified in the SSC, 16p11.2 CNVs, but now has expanded to recruit individuals with other genetic events that are frequently associated with features of ASD (including 1q21.1 CNVs and 37 single genes). In addition to biospecimens (blood and fibroblasts), a wealth of data spanning from whole-exome sequencing data to structural and functional MRI data is available for most of the participants in the Simons VIP, and we encourage applications that propose novel ways to analyze this multi-dimensional dataset.

Table 1. Highest ranking candidate autism risk genes (ranked according to SFARI Gene Scoring Module)

At least 40 highly ranked risk genes (see Table 1) and several hundred other genes have been implicated in ASD. (Applicants can find more information about autism candidate genes and evolving community-based gene scores at SFARI Gene). With such large numbers of candidate genes, the research community will need to replicate results from the SSC and other collections in larger populations and prioritize genes using innovative and integrative methods (bioinformatics and others) to gain a complete picture of genetic risk factors contributing to ASD. In support of such approaches, SFARI announced the “Functional Screen of Autism-Associated Variants” RFA in early 2015. We hope that the results of the five grants awarded under this RFA will help to prioritize genes and facilitate future studies. As mentioned above, we do not encourage submission of grant applications previously submitted to one of our targeted RFAs.

Given SFARI’s extensive investments in the genetics of ASD to date, prospective applicants are strongly encouraged to familiarize themselves with the initiatives outlined above (and the data already available) and to think carefully about how their research would complement SFARI’s ongoing efforts. Researchers planning genetic studies should also be cognizant of the efforts of other autism gene discovery efforts in the broader community (e.g.^9,10) and evaluate whether their planned studies will contribute substantial new insight into the genetic basis of autism.

From genes to biological mechanisms:

Every year, we receive a large number of applications that propose to use rodent models — and in recent years, Drosophila, C. elegans, zebrafish and induced pluripotent stem cells (iPSCs) — to explore the molecular and cellular mechanisms underlying ASD. Given that a clearer picture of the landscape of autism genetics is now emerging, we see this focus on understanding how alterations in particular genes translates into relevant changes in cells and circuits as a new frontier. In particular, documenting points of convergence for molecular pathways, cells, circuits and systems will be critical for a coherent understanding.

Rodent models:

We believe that making well-characterized mouse models readily available is key for attracting top talent to work on autism. Therefore, SFARI continues to help to make mouse models of high-risk autism genes and CNVs available through The Jackson Laboratory (see Table 2). We recommend that applicants review the list of autism mouse models available via this resource.

Table 2. Autism mouse models available at The Jackson Laboratory

Here are a few other factors to consider when working with rodent models: Our scientific review committees have stressed the importance of including heterozygous mutants in studies, as most individuals with autism are heterozygous for the autism risk variant. In addition — to shed light on the skewed gender distribution in autism (~4:1, male: female) — researchers should strongly consider including female animals, in addition to males, in proposed experiments. When incorporating mouse behavior as a core feature of a proposal (e.g., using a behavioral aberration to identify the causal changes in circuit activity), SFARI recommends attention to strain differences and a focus on behaviors that have been shown to be altered consistently across multiple labs; reproducibility may be more important than the similarity of a given mouse behavior to a human behavior known to be affected in autism.

We strongly encourage basic science applications with the possibility of high translational impact. As an example, it has been shown that correcting the genetic lesion of MECP2 can reverse characteristic symptoms in a mouse model of Rett syndrome, even in adulthood ¹¹. Such experiments are potentially paradigm-shifting, as they suggest that early neurodevelopmental defects may be repaired or compensated for later in life. However, this doesn’t seem to hold true for a mouse model of another ASD-related neurodevelopmental disorder, Angelman syndrome. For this model, re-expression of the deleted gene UBE3A in adulthood was found to rescue only a few symptoms, whereas an early embryonic re-expression led to full recovery ¹². This suggests that the most beneficial time for treatment might differ from child to child depending on the underlying etiology of their ASD. To have an impact on potential clinical interventions there is a need for such studies to be replicated, and importantly, to be extended to other genetic models.

SFARI is currently supporting the creation of a rat model of fragile X syndrome (expected to be available in fall 2016) and is considering the generation of other rat knockout models for ASD-associated genes. A number of rat models of interest to autism researchers are commercially available, for example, via SAGE Labs. Rats show a richer behavioral repertoire compared to mice and are often preferred for in vivo electrophysiological recordings due to their larger size. Furthermore, tools for genetic manipulation are catching up quickly with those available for mice, making rats a potentially attractive alternative to mice to study the links between neural circuit activity and behavior.

Zebrafish and iPSC approaches:

Because high-throughput screens for possible therapeutic compounds or phenotypic changes benefit from automation and large sample numbers, zebrafish models and iPSCs have received a lot of attention recently in ASD research, and SFARI will continue to consider proposals in these areas. Zebrafish has the advantage that the species allows for high-throughput screens with a behavioral readout, whereas iPSC-derived neurons are suited for screens looking at cellular or molecular phenotypes. When designing iPSC experiments, careful consideration should be given to the controls. Since the advent of the CRISPR/Cas9 system has made genome editing more accessible, review boards often want isogenic controls included in the experimental design, either to correct an ASD mutation in patient-derived cells or to create an ASD-associated mutation in a control cell line.

Clinical and translational studies:

SFARI supports the development of outcome measures and biomarkers for use in clinical studies as well as the objective measurement of treatment responses in studies of therapeutic interventions. We recently awarded five grants in response to the targeted RFA “Novel Outcome Measures for ASD Clinical Trials,” which are intended to lead to the development of more quantitative and reliable outcome measures. As with all our targeted RFAs, we do not encourage re-submissions from this targeted RFA to our annual RFA, unless an applicant has been encouraged by a member of the SFARI science team to submit a revision.

We realize that clinical studies can be expensive, and thus, we will consider clinical and translational proposals with budgets up to $350,000 per year submitted in response to the annual RFA. This grant mechanism is not intended to support large, randomized clinical trials of medications.

Cohorts:

We often receive applications proposing clever new ways of measuring various genetic, biochemical, psychophysical or neuroimaging parameters in individuals with ASD. Given that ASD is a behavioral diagnosis, we strongly encourage efforts to forge links between the behavior and the biology.

The trouble is, the first step for many of these investigators is to assemble a sufficiently large and diverse cohort of subjects. We’ve learned from assembling the SSC and Simons VIP cohorts, as well as from experiences of previous grants, that recruitment and retention is far more difficult and costly than many researchers anticipate. 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 encourage investigators to use well-characterized cohorts, such as the SSC and the Simons VIP, in which multiple types of data (medical history, psychometric testing, genetic, brain imaging, etc.) can be layered to create a coherent picture and, importantly, be shared with the community to accelerate research. In addition, biospecimens are available for the SSC and Simons VIP, which can be used to elucidate the changes in molecular signaling that might be the link between genetics and phenotype. Some families that were recruited to the SSC ended up not being eligible for inclusion because of some of the criteria, such as having another family member with a psychiatric illness. In cases where biospecimens were collected before the exclusion was flagged (and some other circumstances), these specimens are now available in an ancillary collection that approved researchers can access via SFARI Base.

One more thought on cohorts: Genetic discovery is moving fast, and the potential for connecting genotype with phenotype seems especially promising. Our view is that it is no longer sensible to study individuals with ASD without knowing something about their genetic background or, at a minimum, including the collection of biospecimens for future studies and analyses. We will work with investigators who need advice about logistics on this subject.

Reproducibility:

Proposals that focus on reproducing previous results are often at a disadvantage in review panels because, almost by definition, they don’t bring new ideas. But we are aware of the critical importance of replication, especially for potential clinical interventions. And if studies cannot be replicated, the ‘negative’ findings need to be swiftly communicated to the research community. In short, we will consider requests that involve replicating and expanding key findings.

Data sharing:

We expect SFARI investigators to share renewable reagents and data developed using SFARI funds with other qualified investigators; a positive funding decision will depend on the quality of the data-sharing plan. (For more information, see section 17 of our Policies and Procedures document). In the case of several projects for which early release of data is critical, we make funding contingent on pre-publication sharing of results with other SFARI investigators. In these cases, we add important safeguards to ensure that the researchers are protected in various ways and can’t be scooped on their own data. In a News & Opinion Viewpoint published on SFARI.org, Randy Buckner articulates the critical need to share data and how best to balance this need with protecting investigators’ intellectual contributions.

The LOI stage:

All applicants are required to submit an LOI. These are short (three-page) statements that are intended to save time — for applicants and SFARI science team members — compared with the effort required for full applications.

Applicants should familiarize themselves with the two types of annual awards that we offer, Pilot Awards and Research Awards, and should carefully consider which option is more appropriate given the state of their science and the extent of preliminary data.

At the LOI stage, we read applications primarily with an eye toward whether they are in line with SFARI’s mission and whether and how they complement our existing portfolio of awards.

Each LOI is read by at least two members of the SFARI science team, which includes our Director, Louis Reichardt, plus Marta Benedetti, Wendy Chung, Alice Luo Clayton, Pam Feliciano, Alan Packer, Julia Sommer, John Spiro and Steve Zukin, with additional advice from our former Scientific Director Gerald Fischbach. We seek advice from outside experts as needed, but by making this first-level decision in-house, we are able to streamline the process significantly.

The full application stage:

If an LOI passes the internal review stage described above, the investigator will be invited to submit a “full application,” a six-page proposal detailing planned experiments. Full applications are sent out for peer review. Our referees are a diverse group of scientists who evaluate the scientific merits of a proposal (including the study plan, investigators’ track records, quality of preliminary data, data-sharing plan and budget). Some referees have been with us for many years, but each year we also rotate a number of the peer-reviewers to ensure that the scientific expertise of the panel fits well with the scope of the current proposals. In the past few years, we’ve included some SFARI investigators. After an initial electronic pre-review, in which referees submit written comments (proposals that do poorly at this initial stage are triaged without full discussion), we hold a two-day meeting to discuss the grants in-person. At that meeting, referees present grant proposals, and together with the SFARI science team, debate strengths and weaknesses and then rank scores for each proposal. Conceptually related proposals are discussed in batches in order to facilitate direct comparisons.

We don’t divide the committee into subgroups by expertise. All members are present for discussion of all proposals — except, of course, when potential conflicts of interest exist. This approach may be more time consuming than that of a specialized subcommittee, but it offers a check against overspecialization unduly influencing decisions.

The referees and SFARI science team both have substantial flexibility in suggesting changes to the scope, experimental design and budget of a grant application. The feedback that we get from referees about this flexibility has been very positive compared with other types of review committees that are less interactive.

We try to give investigators we do not fund a summary of the reasons for the decision. However, we ask applicants to keep in mind that referees are not asked to prepare formal remarks for the applicants, and it can be challenging to summarize the verbal discussions.

Returning investigators and percent effort:

We try to balance the needs of new investigators with continuation applications from current investigators. We have always been enthusiastic about bringing in investigators who have a strong track record in another research area and can offer a fresh approach to autism research.

In general, we prioritize new grant applications and only in rare cases provide limited funding for renewal of three-year Research Awards. After three years of support, grantees are encouraged to seek continued funding from the National Institutes of Health and other agencies; when justified by exceptional progress, we will consider limited transitional funding. We will continue to welcome former grantees’ attendance at SFARI-sponsored meetings, workshops and other activities. We do encourage recipients of SFARI Pilot or Explorer Awards who have achieved success in their initial studies to apply for three-year Research Awards.

We seek applications from independent investigators who can devote a substantial portion of time to their SFARI project. Although we do not require a minimum Principal Investigator effort, we expect the investigator to commit to a level of effort that reflects a leading role in the project.

A note about budgets:

Proposals are judged to some degree on whether the budgets are reasonable given the potential risks and rewards of the research (larger budgets raise the bar for funding and are subject to heightened scrutiny) and whether there is funding from other sources. At the full application stage, we are especially vigilant about how specific aims overlap with other current or pending grants. We also work with successful applicants to adjust budgets after the review process.

Explorer Awards:

In addition to our annual RFA cycle described above, we also have SFARI Explorer Awards. Unlike Pilot Awards granted through the annual RFA, applications for Explorer Awards are accepted throughout the year on a rolling basis, are for a duration of one year only, and are capped at $50,000 in direct costs.

Explorer Awards are intended to provide resources to support exploratory and high-risk/high-reward experiments that strengthen hypotheses and lead to competitive applications for larger-scale funding from SFARI or other organizations. We review the applications internally with a response time as short as 30 days. What distinguishes both Explorer and Pilot Awards from Research Awards is that they place less emphasis on preliminary data.

We always welcome feedback about our decision-making process. The more specific the feedback, the better. “I can’t believe my grant didn’t get funded; you guys make lousy decisions”, is less helpful than a reasoned critique of some of the criteria we have outlined above. We use your feedback to improve our review process. You should not expect that we will change our decision on your proposal as a result of your feedback.

Also, please keep in mind that a negative decision this round is not a broad judgment about the quality of work emerging from a lab, or a blanket statement about the potential for future SFARI funding. It’s simply that the abundance of high-quality grants and a finite budget force us to make tough decisions.
 

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