The NIH Common Fund, managed by the Office of Strategic Coordination in the Office of the Director, supports cross-cutting, trans-NIH programs that require participation by multiple Institutes and Centers. Common Fund programs are intended to be transformative, catalytic, synergistic, cross-cutting, and unique. This program is funded as a short-term, goal-driven strategic investment, with deliverables intended to catalyze research across multiple biomedical research disciplines. More information can be found at http://www.commonfund.nih.gov.

The genomics era revolutionized medicine and biomedical research by uncovering the genetic basis of thousands of diseases, congenital birth defects, and biological processes. However, genetic studies, which rely on DNA primarily isolated from blood and saliva, fail to fully capture all DNA variation in affected cells, tissues, and organs, yielding an incomplete snapshot of somatic variations and their contribution to health and disease. Variants occur widely throughout the genome and across the lifespan via a variety of genomic and biological mechanisms, creating stochastic, clonal, and dynamic somatic mosaicism. Although small-scale studies show causal roles for somatic variants in development, aging processes, and a number of diseases, the functional consequences of somatic variation are largely unknown.

The purpose of the Somatic Mosaicism across Human Tissues (SMaHT) Network is to propel discovery of new biological processes in human health and disease that are mediated by genomic variation in somatic tissues. The role of somatic variants in human health will be elucidated through: 1) Building a scaffold and foundational datasets that catalog somatic variation across a set of common tissues from a diverse donor pool, 2) developing tools focused on increasing the sensitivity of detection and specificity of the pipelines to detect multiple types of variations, and 3) creating a variant catalog, portal and integrated workbench that facilitates access to the tools, technologies, and data developed by the Network.

The overall goal for phase 1 of the SMaHT Network is to discover biological paradigms mediated by somatic mosaicism. Accomplishing this goal includes:

• Determining the frequency, tissue specificity, and processes involved in cell lineages and cell fate;
• Uncovering the types and extent of somatic variation identified in these tissues; and
• Analyzing data and synthesizing results across these tissues to generate the first systematic and comprehensive “normal” catalog of somatic variation in humans.

Successful completion of this Common Fund Program will provide the biomedical research community with:

• A scaffold and foundational datasets that catalog somatic variation across a set of common tissues from a diverse donor pool
• Improved tools and data analysis pipelines for detection and characterization of somatic variants in human tissues
• An integrated workbench to seamlessly analyze somatic variation alongside the reference genome.

For additional information about how the SMaHT Network is structured, see https://commonfund.nih.gov/smaht.

The SMaHT Network consists of three major initiatives: 1) Somatic Variant Discovery, 2) Technology and Tool Development (TTD projects), and 3) Data Analysis and Organization. Data generated by the Genome Characterization Centers (GCCs) will undergo rigorous QC measures by the Data Analysis Center (DAC), which will use these data to create the Variant Catalog and the SMaHT Workbench. The Technology and Tool Development Initiative will support projects (TTDs) aimed at improving and developing sequencing technology and data analysis. The Organizational Center (OC) will coordinate all activities and ensure there is appropriate communication amongst all projects.

Five initiatives will be issued in FY22 to achieve the goals of this NIH Common Fund program:

• https://grants.nih.gov/grants/guide/rfa-files/RFA-RM-22-009.html The Organizational Center (OC) will coordinate Network activities and establish strong links with related NIH and international programs
• https://grants.nih.gov/grants/guide/rfa-files/RFA-RM-22-010.html The Data Analysis Center (DAC) will integrate the data generated by the Network to build the variant catalog, portal, and workbench
• https://grants.nih.gov/grants/guide/rfa-files/RFA-RM-22-011.html The Technology and Tools Development (TTD) Projects will develop next generation tools focused on significantly improving detection and characterization of somatic variants
• https://grants.nih.gov/grants/guide/rfa-files/RFA-RM-22-012.html The Tissue Procurement Center (TPC) will collect, process, and distribute a set of 10-15 high quality human tissues from a diverse donor cohort
• https://grants.nih.gov/grants/guide/rfa-files/RFA-RM-22-013.html The Genome Characterization Centers (GCC)will use state-of-the-art genomics sequencing technologies to identify all types of somatic variation in tissues from the biorepository

The first phase of the Program was cleared at the May 2021 Council of Councils May 2021 Council of Councils (SMaHT presentation starts at 3:25:16) for five years. If the first phase is successful, there will be a proposal for a second phase to be considered by the Council of Councils.

Announcements and regular updates will be posted on the program website: https://commonfund.nih.gov/SMaHT

General inquiries can be sent to [email protected]. Scientific and Research contacts for individual RFAs are indicated in each announcement. These individuals should be your first contact for questions related to that RFA. In addition, the Common Fund SMaHT Program is administered via a team of NIH program experts. The NIH SMaHT Program Working Group members and their affiliations are listed below and at: https://commonfund.nih.gov/SMaHT/members.

SMaHT focuses on tissues or blood collected from human donors without any underlying pathology or diseases known to significantly impact the morphology, function, or biomolecular profile of the tissue to be analyzed.

We are collecting a common set of at least 15 healthy tissues per donor from a minimum of 150 donors for biobanking and data production. A representative set of tissues from all three germ layers must be collected from each donor. Examples include the following: a) ectoderm-derived tissues/cell-types from brain regions such as hippocampus, cerebral cortex, epidermal layer of exposed and unexposed skin, epithelial layer of oral and nasal cavities, paranasal sinuses, anal canal, etc. b) mesoderm-derived tissues and cell types such as blood, bone marrow, lymphatic tissues, exposed and unexposed skin dermis layer, synovial, smooth muscle, urogenital tissues such as upper vagina and uterus (females) and vas deferens (males); c) endoderm-derived tissues and cell types from ascending and descending colon, trachea or esophagus, lower vagina, spleen, and prostrate; d) reproductive tissues/cells such as ovary, testis, and sperm cells. Additional tissues, including kidney cortex, heart, lung, and liver should be collected when available. Blood samples from each donor should be collected and banked following CLIA-complaint procedures. Applicants should propose a set of representative tissues to reflect several different body systems (and the full range of costs), with rationale for why there is a high probability of complete tissue procurement across 150 donors. However, the final tissue set for this initiative will be finalized after awards are made and result from conversations among the Steering Committee, NIH Staff, and TPC.

SMaHT will use cooperative agreements for each initiative to reach its goal and milestones. All the Principal Investigators (PIs) funded through the Program will work together as a Network, with substantial NIH input.

A cooperative agreement funding mechanism supports discrete, specified, circumscribed projects to be performed by investigators in an area representing their specific interest and competencies. It is used when substantial NIH programmatic involvement is anticipated. In addition to a Program Officer from the administering Institute, each award will be assigned a Project Scientist(s) from NIH who will participate with the Principal Investigators on a Steering Committee. NIH staff will not direct the research but will assist in aligning progress with the goals of the program and promote interaction with other members of the Network. There are several key expectations described in each RFA such as:

• Attendance at SMaHT Network meetings, workshops, and conference calls
• All investigators are under a confidential disclosure agreement regarding all private information within the Network
• Participate in cross-validation of their own and others’ tools/technologies

No. Funding decisions are based on scientific merit and programmatic needs, as defined in the funding announcement, and on the availability of funds.

Academic organizations, small businesses, large businesses, non-profit organizations, and eligible agencies of the Federal Government (e.g. NIH intramural, the FDA) are eligible to apply as described in the “Eligible Applicants” or “Eligibility” section of each announcement.

All applications will be evaluated solely based on the evaluation criteria described in the funding announcement. NIH policies such as Continuous Submission or New Investigator status do not apply to RFAs. There is no preference or disadvantage for organizations beyond the review criteria listed in the relevant announcement.

Yes, but only applications for the TTD Initiative can be submitted by a foreign institution as the primary applicant or as a subcontract to the US-based institution. Justification for inclusion of work to be performed outside the US must be provided in the grant application and if selected for funding, foreign clearance will be required prior to release of a Notice of Award (NoA). Please refer to the eligibility section of each announcement for further information.

Period of performance and budget should be driven by scope and scientific need. Budgets and timelines are expected to vary from project to project.

For a specific RFA there is no prohibition on the number of applications an institution or team may submit, provided the applications are scientifically distinct.

Yes. Team members may span multiple institutions, and it is possible that the full range of expertise needed for a proposal may not exist at one institution. Teams are expected to assemble the expertise across labs, disciplines, institutions needed to achieve the goals of the project and SMaHT.

The Specific Aims for both the UG3 and UH3 should be incorporated into one Specific Aims page. Please indicate which Aims are for the UG3 and UH3 phases. Please use the 12-page Research Strategy Section, Timeline, and Milestones to provide more detail on the UG3 and UH3 phases. When applicable, please provide clear Go/No-Go decisions regarding the transition from UG3 to UH3 phases.

Common Fund Programs are designed to support actively managed, milestone-driven projects that are different from mainstream studies. These projects are expected to work together to address key roadblocks in emerging fields that will transform the way biomedical research is conducted. Applicants must explicitly address how the proposed research will have an impact which cuts across the interests of individual NIH Institutes and Centers and the reviewers will evaluate whether the project proposes an incremental improvement or a significant advancement which will transform the field. Applicants must also provide compelling justification for Common Fund support rather than from an individual NIH Institute or Center.

The SMaHT Network is comprised of SMaHT awardees, NIH staff, External Program Consultants, as well as other scientists and groups agreed upon by the Steering Committee. The purpose of the Network is to foster collaboration across the Network to maximize success of the program. In addition to completing the research goals outlined in their applications, successful applicants will be expected to collaborate across the Network to develop SOPs, data and metadata standards, and data generation metrics. Awardees will also participate in cross-site studies, engage in cross-training, and guide development of data analysis and visualization tools that can be used by the broader scientific community.

The SMAHT Steering Committee (SC) is the governing body for the SMAHT Network. The purpose of the SC is to recommend direction for the SMaHT Network consistent with the program goals; develop Network policies and projects to build synergy and improve communication and collaboration among the projects; and provide a forum for discussing progress, challenges, and opportunities for the Network. The SC includes PDs/PIs of each of the funded awards and NIH WG members. The SC is chaired by two PD/PIs approved by the NIH WG. An Executive Committee (EC) composed of the co-chairs and the NIH Program Team Leads will meet monthly to set the agenda for SC meetings. The SC has established subcommittees to oversee the development and implementation of Network policies including data release, publications, and standards. Possible working groups include:

• Policies
• Communication and Engagement
• Tissues, Technology, and Data Collection
• Data Science
• Tools and Models

As part of the SMaHT Network, NIH staff will engage 5-10 external program consultants (EPCs) not funded as part of the program, but with relevant scientific and Network experience to provide input and advice to the NIH WG. This guidance could include reviewing and evaluating the progress of the entire SMaHT Network or individual awardees, as well as recommending changes in priorities for the SMaHT Network based on scientific advances within and outside of the Network. The EPCs are senior experts who are not directly involved in the activities of the SMaHT Network and who agree to a confidentiality policy and advise on specific issues, as needed. NIH is solely responsible for appointing EPCs for variable durations of service. EPCs are invited to participate in Network meetings and Steering Committees calls and the Annual Investigators’ Meeting. A subset of EPCs may also meet by phone or web at other times of the year, as needed. Annually, the EPCs will provide individual assessments to the NIH of the progress of the Network and will present individual expert recommendations regarding any changes in the SMaHT Network, as necessary. The assessments and recommendations will be provided through the NIH WG to the Director of the Office of Strategic Coordination.

NIH staff has substantial programmatic involvement above and beyond the normal stewardship role in grants, providing technical assistance, advice, and coordination. The roles of NIH are described in each Funding Opportunity Announcement.

The Network is likely to establish an Associate Member Policy to facilitate collaborations with researchers who are not funded directly through the SMaHT program.

NIH intends that the products of the SMaHT Network be broadly available to the research community to establish the foundations for a somatic variation catalog that other programs and the international community will build upon, including methods, tools, reagents, biospecimens, datasets, and software. All funded investigators must facilitate the public release and dissemination of results, data, reagents, technologies, and other products generated through their SMaHT awards in a timely manner and abide by Network and NIH policies. Awardees will be expected to develop policies for public access; data sharing; protocol, tool, and reagent sharing; intellectual property; and software sharing to work collectively with the NIH to harmonize and implement these policies across the Network.

No, a milestone is a defined event, achievement, or important stage that is used to indicate the progress of a project. Milestones should be SMART (Specific, Measurable, Achievable, Realistic, and Timely), and are expected to be:

• Major steps or events (e.g., activities or outcomes) with a clearly defined purpose
• Specific targets that depict progress toward project goals
• Descriptive of what will be done and when it will be completed
• Collectively organized in a logical order (e.g. sequentially, simultaneously, or iteratively)
• Associated with a timeframe (e.g., end of the fiscal year)

Milestones are not specifics aims or broadly aspirational statements of what a project is expected to achieve.

Since this is an actively managed program, investigators should expect that their goals and budgets will be modified during the project period. For example, funds may be withheld each year and released only when Network activities have been proposed and approved. To promote synergy and collaboration among projects in the Network, NIH staff may also work with awardees to amend and refine goals and milestones. As tools and techniques are developed within the Network and other programs, investigators may also be asked to cross-validate these approaches. Investigators can also propose minor changes to the research approach as needed during the course of the project.

Yes. NIH staff may choose to fund a portion of an application based on reviewer feedback. This option may result in a reduction in project budget and/or project period. Projects may also be funded as pilot projects with a reduced budget and duration, with funds being restored for later years if the work is of high programmatic priority and milestones have been met or exceeded.