NIH's new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications for Human Tumor Atlas (HTA) Research Centers. The overall goal of each HTA Research Center is the construction of at least one, and up to three, pilot-scale human tumor atlases describing one of three important transitions in tumorigenesis: the transition from locally invasive to metastatic cancer; the dynamics of patient response to therapy; or the development of resistance to therapy. For the purposes of this FOA, a comprehensive human tumor atlas is defined as the multidimensional molecular, cellular, and morphological mapping of human cancers, complemented with critical spatial information (at the molecular, cellular, and/or tissue level) that facilitate visualization of the structure, composition, and multiscale interactions within the tumor ecosystem.

HTA Research Centers will be part of the Human Tumor Atlas Network (HTAN), which will also include PreCancer Atlas (PCA) Research Centers (solicited under RFA-CA-17-035), a HTAN Data Coordinating Center (HTAN-DCC, solicited under RFA-CA-17-036) and an HTAN Tissue Coordinating Center (anticipated to be solicited in Fiscal Year 2019).

NCI convened the Blue Ribbon Panel (BRP) in 2016 to provide recommendations for achieving the Cancer Moonshot's ambitious goal of making a decade's worth of progress in cancer prevention, diagnosis, and treatment in just 5 years, now called the Beau Biden Cancer MoonshotSM Initiative. The BRP was charged with assessing the state of the science in specific areas and identifying major research opportunities that could uniquely benefit from the support of the Cancer Moonshot and could lead to significant advances in our understanding of cancer and in how to intervene in its initiation and progression. The recommendations focused on areas in which a coordinated effort could profoundly accelerate the pace of progress in the fight against cancer and were not intended to replace existing cancer programs, initiatives, and policies already underway. The BRP final report was approved by the National Cancer Advisory Board and included a recommendation for the Generation of Human Tumor Atlases (BRP Recommendation I). The 21st Century Cures Act was signed into law in December 2016 dedicating new funds to support efforts associated with the Beau Biden Cancer MoonshotSM Initiative, including support for this FOA.

The goals of the HTAN are aligned with opportunities defined by the Blue Ribbon Panel (BRP) of the Beau Biden Cancer MoonshotSM Initiative. While the BRP final report includes a specific recommendation for the Generation of Human Tumor Atlases to facilitate our understanding of important transitions during the course of tumorigenesis and to inform clinical decision-making and treatment options for patients, this FOA establishes a detailed framework for the accomplishment of the BRP goals.

A major hindrance to prevention, early detection, and treatment of cancer is the lack of comprehensive knowledge of the molecular, cellular, and tissue alterations that drive tumor development and progression from its earliest stages. It is now well appreciated that the tumor ecosystem, which is defined by a full suite of cell types including tumor cells, tumor-associated immune, stroma, and vascular cells, and the accompanying patient normal and stem cell populations, evolves during tumor development and treatment. Interactions between evolving cellular and non-cellular components within the tumor ecosystem can facilitate a variety of tumor behaviors including unchecked tumor growth due to positive feedback loops mediated by tumor and stromal cell-associated secreted factors, tumor cell invasion mediated by biophysical cues arising from dysregulated extracellular matrix architectures, or positive patient outcomes, such as tumor resolution via an activated immune system. Mechanistic studies involving isolated cell populations or non-human model systems provide significant insights into the molecular underpinnings of these tumor phenotypes and have led to development of effective therapies in some contexts. However, precision medicine strategies have proven ineffective in many cancer patients due in part to an incomplete understanding of how interactions within the tumor ecosystem promote or suppress tumorigenesis.

Emerging single-cell and in situ technologies are now facilitating the multi-omic characterization of all major cell types (normal, pre-malignant, malignant, stromal, vascular, and immune) and their interactions at sites of tumor initiation, growth, and metastasis. Integration of these data with non-invasive measurements from liquid biopsy techniques and/or a variety of imaging modalities, such as multimodal molecular imaging or high-resolution optical imaging, could result in a multiparameter, multidimensional view of the evolving tumor ecosystem during cancer progression. Recognizing that a concerted, multidisciplinary effort to map human tumors could significantly accelerate scientific discovery and inform clinical decision-making, the Cancer Moonshot BRP recommended construction of dynamic tumor atlases that utilize new and existing data sets to comprehensively characterize the components and interactions within the three-dimensional tumor ecosystem over time. Ultimately, a complete set of human tumor atlases will represent the multidimensional molecular, cellular, and morphological mapping of the structure, composition and interactions within human cancers including dynamic changes that occur during key transitions in cancer, such as the progression of pre-malignant lesions toward malignancy, the initiation of invasive, metastatic disease, and the development of resistance to therapy.

Goal of the Human Tumor Atlas Network:

The NCI intends to support HTA and PCA Research Centers that will function as part of the Human Tumor Atlas Network (HTAN). The HTAN effort builds upon and extends the efforts of The Cancer Genome Atlas (TCGA) which provided genomic and transcriptomic characterization of many tumor types, resulting in an important resource for the scientific and clinical communities while promoting advances in associated technologies and bioinformatic approaches. The HTAN will focus on longitudinal studies of pre-cancer, metastasis, and drug resistance with an emphasis on collecting comprehensive clinical data over time. Furthermore, the tumor atlases generated by the HTAN will facilitate understanding of interactions within multidimensional architecture of the tumor microenvironment, including the role of the immune system, normal cells, and non-cellular components. HTAN will build upon the lessons learned from TCGA, address its limitations, and use evolving state-of-the-art information technology and other emerging technologies to achieve its goal.

The goal of the HTAN is the construction of human tumor atlases that describe the multidimensional cellular, morphological and molecular mapping of human cancers over time for informing future cancer research and, ultimately, clinical decision-making. The human tumor atlases resulting from the HTAN efforts will lend support for evidence-based expansion of the HTAN after completion of the initial 5-year pilot phase.

The HTAN will support two types of atlas-building initiatives spanning the entire continuum of cancer:

• The Human Tumor Atlas (HTA) Research Centers, described in this FOA, that will construct atlases describing the transition from locally invasive to metastatic cancer, dynamic response to therapy, and development of therapeutic resistance.
• The PCA Research Centers (RFA-CA-17-035) that will construct atlases describing how and when premalignant lesions progress to invasive cancer or regress or obtain a state of equilibrium.

The atlas-building initiatives will be supported by:

• An HTAN Data Coordinating Center (HTAN-DCC; RFA-CA-17-036), that will be responsible for data storage, harmonization, distribution, and compilation of the final human tumor atlas collection.
• An HTAN Tissue Coordinating Center (HTAN-TCC; anticipated to be developed in Fiscal Year 2019), that will provide a virtual resource for the investigators to identify and share available biospecimens across the HTAN.

Human tumor atlases developed as part of the HTAN will facilitate future research and generate hypotheses to answer important cancer questions, such as, but not limited to:

• The role of spatial and temporal interactions between tumor cells and the immune system in facilitating tumor progression, regression, or a state of equilibrium, promoting cancer metastasis, enhancing response to traditional, targeted, and/or immuno-therapy.
• Studies focused on clonal evolution, heterogeneity of pre-cancerous lesions and invasive tumors, and changes in the tumor microenvironment in space and time.
• Development of experimental and computational models to better understand the spatial and temporal molecular and cellular dynamic relationships during tumor development and progression.
• Identification of spatial, functional, and/or temporal biomarkers that predict cancer risk, targets for early intervention, and response to therapeutic intervention.
• Identification of new link(s) between molecular genetic alterations and spatial and structural alterations during tumor progression and as a result of treatment with therapeutic agents.
• Identification of spatial, functional, and/or temporal biomarkers that predict cancer risk and/or response to therapeutic intervention.

Objective of HTA Research Centers:

The objective of each HTA Research Center is the construction of multidimensional (i.e. in space and time) tumor atlases containing molecular, cellular, and tissue-level spatial, functional, and/or temporal relationships that are searchable and scalable. Atlases must include molecular and cellular phenotypes as well as spatially reconstructed features of malignant and/or metastatic lesions. Tumor atlases supported under this FOA must focus on one of the following three important transitions in cancer:

• The transition from locally invasive to metastatic cancer, including, but not limited to, atlases characterizing multiple metastatic sites, atlases describing the transition into or out of tumor dormancy, atlases capturing colonization of early disseminated tumor cells at distant sites.
• The dynamic response to therapy, including, but not limited to, atlases describing a positive response to traditional, targeted and/or immuno-therapies, atlases that describe no response, incomplete response, or negative response to traditional, targeted and/or immuno-therapies.
• The development of therapeutic resistance, including atlases describing the transition from responsive to traditional, targeted, and/or immuno-therapy to resistant to that therapy.

Note that atlases describing the transition from pre-malignant to malignant cancer are not supported under this FOA. Investigators interested in atlases describing the initiation of cancer are directed to RFA-CA-17-035 "PreCancer Atlas Research Centers".

High Priority Tumor Atlas(es): The HTA Network aims to build comprehensive tumor atlases through the characterization of tumors representing a diverse patient population, including minority and underserved patients, with a focus on pediatric and adult cancers that are highly metastatic (i.e., ovarian, triple-negative (Estrogen Receptor [ER-]/Progesterone Receptor [PR-]/HER2-) breast, and prostate cancer), promising candidates for immunotherapy (i.e., triple-negative [ER-/PR-/HER2-] breast), microsatellite instability [MSI] positive colorectal, pediatric leukemia), refractory to immunotherapy (i.e., ovarian, breast, colorectal [MSI-]), and high-risk hereditary tumors (colorectal [Lynch Syndrome], ovarian/breast [mutant BRCA1/2]). Parenthetical examples are not meant to limit investigator choice of organ site, but NIH programmatic preference will be given to tumor choices that satisfy the high priority categories listed above. Each Center should focus on no more than three organ specific cancers with the total number of atlases constructed per Center limited to three to ensure comprehensive multi-parameter, multi-dimensional data collection and analysis.

Required Capabilities of the HCA Research Center: Each HTA Research Center will consist of a multidisciplinary team with the expertise required to construct the tumor atlas(es) proposed.

Expertise could include, but is not limited to:

• Clinical expertise, such as clinical oncology, surgery, pathology, molecular pathology, radiology, epidemiology;
• Cancer biology expertise, such as molecular and cellular cancer biology, cancer genetics, cancer immunology, bioengineering;
• Imaging expertise, such as imaging physics, radiomics, quantitation methods, and visualization approaches; and
• Computational expertise, such as bioinformatics, biostatistics, systems biology, imaging physics, data visualization, and mathematical modeling.

Each Research Center must have access to high-quality, well-annotated biospecimens, with NIH programmatic preference to projects that utilize prospective human samples for atlas construction. Additionally, applicants must be able to perform comprehensive characterizations of the composition and architecture of human biospecimens. The nature, types, comprehensiveness, robustness, and quality of these characterizations must be appropriate to allow for the virtual reconstruction of the tumor ecosystem and should ultimately facilitate a better understanding of the molecular, cellular, and/or tissue-level complexities of the specific cancer transition being described within the proposed tumor atlas. Finally, applicants must have demonstrable computational expertise that facilitates data analysis and atlas-building activities, including advanced data visualization.

Structure of the HCA Research Center:

Each HTA Research Center will consist of an Administrative Core and three integrated research units, including: the Biospecimen Acquisition, Processing, and Classification Unit (Biospecimen Unit) responsible for acquiring patient samples representative of the tumor atlas(es) being constructed; the Molecular, Cellular, and Tissue Characterization Unit (Characterization Unit) responsible for collecting multiparameter, multidimensional experimental data to construct comprehensive tumor maps for atlas construction; and the Data Processing, Analysis, and Modeling Unit (Data Analysis Unit) responsible for development of the computational tools necessary to construct the proposed human tumor atlas(es).

Administrative Core

The Administrative Core will be led by the contact PD/PI of the HTA Research Center. Due to the multidisciplinary projects and the focus on collaboration and expertise sharing, the HTA Network Research Centers will require leadership having the ability to synthesize and manage the various approaches needed. Leaders and senior investigators of the team must have relevant expertise in the various aspects of tumor atlas construction, especially clinical oncology, pathology, cancer biology, data analysis, and mathematical/computational modeling. Multi-institution applications are encouraged, if necessary to ensure the necessary expertise.

Responsibilities of the Administrative Core include ensuring that the data collected conform with the agreed practices and principles of the HTAN Standard Operating Procedures (SOPs), Common Data Elements (CDEs) and data sharing plan as approved by the HTAN Steering Committee. The Administrative Core will facilitate communication between the Research Center and the HTAN-DCC and HTAN-TCC and ensure bidirectional exchange of findings and insights with the PCA Research Centers building atlases describing cancer initiation.

Biospecimen Acquisition, Processing, and Classification (Biospecimen) Unit

The primary objective of the Biospecimen Unit is the collection of biospecimens for use in constructing the proposed tumor atlas(es). The types of biospecimens collected and the frequency with which they are collected within the Biospecimen Unit will depend on the purpose of the proposed atlas (i.e., which of the three high-priority transitions in cancer is being addressed). Applicants must have access to high-quality, well-annotated biospecimens, with preference to projects that utilize prospective human samples for atlas construction.

Information pertaining to biospecimen collection, including but not limited to, clinical and epidemiological data and metadata, pathologic analysis, anatomic location (including information about landmarks that might aid in atlas construction), and pre-analytical processing will be made available to the investigators within the Characterization and Data Analysis Units immediately, will also be shared with the members of the HTAN and, eventually, the general scientific public in accordance with appropriate data release standards.

The Unit Lead(s) for the Biospecimen Unit will be expected to participate in HTAN scientific working groups such as those focused on ethical collection and use of human tumor tissue, tumor collection, sample preservation, and clinical/epidemiological data collection.

Molecular, Cellular, and Tissue Characterization (Characterization) Unit

The primary objective of the Characterization Unit is high resolution state-of-the-art molecular, cellular, and tissue-level characterization of biospecimens for the purpose of constructing the specific atlas(es) proposed. The personnel of the Characterization Unit will work closely with those of the Biospecimen Unit to optimize pre-analytical processing of tissue for the variety of imaging and omics assays proposed by the Characterization Unit. Additionally, a close integration is required between the Characterization and Data Analysis Units to ensure adequate collection and sharing of metadata and experimental data for processing, analysis, and atlas-building activities.

The goal of data collection within the Characterization Unit is not to create a cell catalog, but to contribute to a framework for understanding tumorigenesis based on cellular, non-cellular, and extracellular matrix organization. Applications that propose to primarily use dissociative techniques that do not preserve or otherwise inform spatial information or propose to primarily study non-cellular fluids will be of low priority or, if exclusively proposing these techniques without any attempt to reconstruct the multidimensional (3D/4D) tumor ecosystem, non-responsive (see Non-responsive Applications below for a comprehensive list of non-responsive criteria). Rather, it is envisioned that dissociative techniques might be utilized in combination with other in situ analysis techniques in an iterative fashion.

The Characterization Unit needs to be flexible in its design such that new technologies introduced through HTAN collaborative projects, other Cancer Moonshot activities, and/or related atlas-building projects might be quickly tested, validated, and adopted over the course of the award lifetime. The Unit Lead(s) for the Characterization Unit will be expected to participate in HTAN scientific working groups focused on technology development and employment of experimental techniques for multiscale, multiparameter data collection as well as the subsequent analysis and application.

Data Processing, Analysis and Modeling (Data Analysis) Unit

The primary objective of the Data Analysis Unit is the construction and delivery of the virtual human tumor atlas(es) proposed by the HTA Research Center. The Data Analysis Unit will develop workflows that facilitate atlas construction through the generation and subsequent visualization of dynamic multi-dimensional tumor maps from high-content, multiparameter imaging and omics assays conducted by the Characterization Unit on biospecimens procured by the Biospecimen Unit. Importantly, the Data Analysis Unit will design and conduct at least one preliminary study illustrating how the resulting human tumor atlas dataset could be utilized to build a testable, predictive model of cancer.

Personnel from the Data Analysis Unit will work closely with the HTAN Data Coordinating Center and other HTAN investigators to develop and deploy common data elements and interoperable data and analysis formats that facilitate collaboration within and outside the HTAN, allowing seamless integration of the proposed atlas(es) with other atlases to be generated across the HTAN. Ensuring the success of future data-sharing efforts will require close coordination between the Biospecimen, Characterization, and Data Analysis Units. The Unit Lead(s) for the Data Analysis Unit will also be expected to participate in HTAN scientific working groups focused on development and sharing of analysis and visualization tools.

Structure and Coordination of the Human Tumor Atlas Network

Human Tumor Atlas Network (HTAN) overall organization: The HTAN will consist of Human Tumor Atlas (HTA) and Pre-Cancer Atlas (PCA) Research Centers and the HTAN Data Coordinating Center (HTAN-DCC) solicited under three separate FOAs in Fiscal Year 2018. In Fiscal Year 2019, it is anticipated that a HTAN Tissue Coordinating Center (HTAN-TCC) will be added to the Network to provide a virtual resource for investigators to discover and share available biospecimens across the HTAN. The HTAN will function as a collaborative network allowing Research Centers to cross-test ideas, integrate diverse data sets, and validate (or refute) hypotheses derived from analysis of HTAN data. HTA Research Center applicants are encouraged to read the HTAN-DCC (RFA-CA-17-036) and PCA (RFA-CA-17-035) Research Center RFAs for more information.

Governance of the HTAN: All components will be governed by the HTA Network Steering Committee (see Section VI: Terms and Conditions of Cooperative Agreement.) with representatives from the funded HTA and PCA Research Centers, the HTAN-DCC, the HTAN-TCC, and NCI Program staff.

Evaluation of the Program: As the efficiency of the funded research is an important priority for NCI, HTA and PCR Research Centers will be expected to participate in an external evaluation process of the HTAN coordinated by NCI program staff (see Section VI: Terms and Conditions of Cooperative Agreement.)

Cancer Moonshot Public Access and Data Sharing Policy:

Utilizing the provision outlined in the 21st Century Cures Act, NCI has established a data sharing policy for projects that are funded as part of the Beau Biden Cancer MoonshotSM Initiative that requires applicants to submit a Public Access and Data Sharing Plan that: (1) describes their proposed process for making resulting Publications and to the extent possible, the Underlying Primary Data immediately and broadly available to the public upon publication and; (2) if applicable, provides a justification to NCI if such sharing is not possible. NCI will give competitive preference and funding priority to applications that comply with the strategy described here. The data-sharing plan will become a term and condition of award. Data and computational tool sharing by HTAN members will follow FAIR (findable, accessible, interoperable, and reusable) principles as defined here.

Non-responsive Applications:

The following types of projects are outside the scope of this FOA and will be considered non-responsive. (Non-responsive applications will not be reviewed.)

• Projects primarily focused on the pursuit of a biological mechanism through basic research that does not result in a comprehensive tumor atlas.
• Projects proposing atlases constructed through exclusive use of non-human biospecimens.
• Projects proposing atlases based upon one experimental measurement (i.e., applications not based upon multiparameter data).
• Projects that do not propose methods that provide spatial data/information regarding the cellular and/or non-cellular components of the tumor.
• Projects proposing atlases that do not address at least one of the three high-priority transitions in cancer identified within the Research Objectives section above.
• Projects that propose atlases describing the initiation of cancer or the characterization of early, pre-cancerous lesions. Please see RFA-CA-17-035 "PreCancer Atlas Research Centers" for support of those projects.

The following types of applications are non-compliant and will not be reviewed

• Applications not complying with the required component structure for the proposed Research Center.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• o NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

Given the multidisciplinary expertise required for exemplary response to the objectives of the HTA Network, this FOA encourages the use of the multi-PD/PI option.

An investigator designated as a Contact PD/PI of the application under this FOA must not be the designated Contact PD/PI of another application under any HTAN initiative (RFA-CA-17-035 or RFA-CA-17-036).

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct. Institutions submitting an application to this FOA are allowed to submit an application to the companion FOAs RFA-CA-17-035 and RFA-CA-17-036, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

Most applicants will use NIH's ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Shannon Hughes, Ph.D.

National Cancer Institute (NCI)
Telephone: 240-276-6224

Email: NCI_HTAN_HTAU2C@mail.nih.gov

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core (Use for Administrative Core)	6
Functional Unit (use for Biospecimen Unit, Characterization Unit, Data Analysis Unit)	12

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required, maximum of 1
• Biospecimen Unit: required, maximum of 1Characterization Unit: required, maximum of 1
• Data Analysis Unit: required, maximum of 1

When preparing your application in ASSIST, use Component Type 'Overall'.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Project Summary /Abstract: Succinctly describe the human tumor atlas(es) to be generated within the HTA Research Center. State the high-priority transition being described along with the tumor type(s) being pursued.

Project Narrative: State how the atlas(es) constructed within the HTA Research Center will further knowledge in the cancer research field and the potential impact they may have on public health.

Facilities & Other Resources: In addition to the information required in the standard instructions, highlight available facilities and/or services that could contribute to construction of human tumor atlases (e.g., ongoing clinical trials, high content screening, imaging technologies, high-power computation, etc.). Indicate on what basis these resources will be available to the HTAN investigators (e.g., in-lab, freely available, fee-for-service, etc.).

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: State the overall goals for the HTA Research Center. The Specific Aims should be overarching, at a high level, and distinct from the aims of the individual components.

Research Strategy:

In lieu of the standard Research Strategy sub-sections (Significance, Innovation, Approach), use the sub-sections defined below to present a concise overall vision and plan for the proposed HTA Research Center.

Sub-section A: Proposed Human Tumor Atlas(es)

In this sub-section address the following aspects of the HTA Research Center:

• Define the tumor atlas(es) that will be constructed within the HTA Research Center and how they address at least one of the three high-priority transitions in cancer as defined in the Research Objectives section.
• Provide background and rationale for the selection of human tumor atlas(es) and outline the significance and impact provided by the creation of the atlas(es).
• Explain how the choice of tumor type(s) addresses one or more of the highlighted high priority categories as defined in the Research Objectives section.
• If applicable to the type of human tumor atlas(es) proposed, address how health disparity populations or data will be integrated into the proposed studies.
• Succinctly describe the envisioned final structure of the atlas(es) to be created, including the dynamic multidimensional, multiparameter nature of the data and plans for visualization of the data, including the target user base and what additional levels of information the atlas(es) will provide beyond what is available via current publicly accessible big-data efforts.
• Briefly describe how the final atlas might be employed by the scientific, clinical, and lay-person communities. Preview the use case proposed within the Data Processing, Analysis and Modeling Unit that illustrates how the human tumor atlases datasets proposed herein will be utilized to build a predictive model of cancer.

Since the tumor atlases generated by the HTA Research Center are likely to be pilot-scale, this sub-section may briefly highlight how the HTA Research Center will lay the groundwork for longer-term plans, including how the pilot-scale tumor atlas(es) constructed within the HTA Research Center might be expanded to represent larger human populations and extended to include additional types of data.

Sub-section B: Research Center and Team Organization

This sub-section should provide a concise description of the team structure of the Research Center including, at a minimum, the following aspects:

• How the skills of individual team members will translate into the collective capability of the center to accomplish the stated human tumor atlas construction goals.
• How the team brings complementary multidisciplinary scientific expertise required for the integration of multidimensional, multiparametric data to build human tumor atlas(es) to address the key research problems proposed.
• How the diverse expertise of the team members increases the capability for innovation, the ability to anticipate new directions, and the flexibility to redirect research when needed.

Sub-section C: Research Units

In this sub-section provide a brief overview of the structure of each Research Unit (Biospecimen Acquisition, Processing and Classification Unit (Biospecimen Unit); Molecular, Cellular, and Tissue Characterization Unit (Characterization Unit); Data Processing, Analysis, and Modeling Unit (Data Analysis Unit). Provide an overview of the preliminary data included in the application demonstrating the capabilities and expertise included within each Unit.

Sub-section D: Project Milestones

In this subsection describe the following:

• Overall Center Milestones: Define Overall Center Milestones that are well-described, quantitative (if possible and appropriate), and scientifically justified. Discuss the milestones as a means of judging the success of the proposed atlas building activities during the 5 years of support for the pilot-level atlas(es).

Interim Center Milestones: Define a clear set of tentative semi-annual milestones for the Overall HTA Research Center with metrics that will document progress towards the achievement of the Overall Center Milestones. The interim milestones should be connected to the semi-annual milestones that are required for each Research Unit (see the Research Strategy section of the Biospecimen, Characterization, and Data Analysis Units). Quantitative milestones are required to provide clear indicators of a project's continued success or emergent difficulties, and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years.

Sub-section E: Health Disparities

If applicable to the type of research being proposed, address how health disparity populations or data will be integrated into the proposed studies. Highlight, as relevant, any opportunities that, if implemented, can reduce the burden of cancer in the health disparities that currently exist. In this context, efforts are encouraged to address the needs of racially/ethnically diverse populations and those from urban and rural areas who are poor and medically underserved, who continue to suffer disproportionately from certain cancers and have higher morbidity and mortality rates.

Letters of Support: In addition to standard items, applicants must provide letters from the respective leadership official(s) in the institution(s) of the proposed center documenting any specific institutional commitments to the proposed center. Letters should also be included that reflect any additional resources and partnerships that will be employed to achieve the goals of the Research Center.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

• The Data Sharing Plan should be provided only under the Overall component but it should cover all the activities of the Center.
• Applicants should consider pre-existing intellectual property rights associated with the use of existing models/technologies/biospecimens. If proprietary tools/devices are used in building the atlas(es), applicants should clearly state the licensing agreement and are advised to contact NCI and seek assistance as needed from the NCI Technology Transfer Center (https://ttc.nci.nih.gov/) in determining whether such arrangements are appropriate and/or adequate. Specific intellectual property rights are associated with tissue specimens that are collected from participants in clinical trials who are receiving investigational agents provided to NCI under the terms of Cooperative Research and Development Agreements with its pharmaceutical industry partners. If such specimens will be used, contact NCI for guidance from the appropriate staff persons in the Division of Cancer Treatment and Diagnosis.
• Addressing the Cancer Moonshot Open Access Pilot Program: Utilizing the provision outlined in the 21st Century Cures Act, NCI has established a data sharing policy for projects that are funded as part of the Beau Biden Cancer MoonshotSM Initiative that requires applicants to submit a Public Access and Data Sharing Plan that: (1) describes their proposed process for making resulting publications and to the extent possible, the underlying primary data immediately and broadly available to the public upon publication and; (2) if applicable, provides a justification to NCI if such sharing is not possible. NCI will give competitive preference and funding priority to applications that comply with the strategy described here. The data sharing plan will become a term and condition of award.
• Guiding Principles for Cancer Moonshot Biobanking Activities: The goal in developing these guiding principles is to accelerate research by a) increasing the availability of biospecimens for Cancer Moonshot-related and other biomedical research through facilitation of investigator to investigator sharing of biospecimens, and b) increasing the reproducibility of Cancer Moonshot research through improved biospecimen practices and corresponding annotation. These guiding principles also seek to facilitate, where possible, increased engagement of research participants through researchers' communication of aggregate research results and, in some cases, individual genomic findings that may be medically actionable for research participants. NCI will give competitive preference and funding priority to applications that conform to the "Guiding Principles for Cancer Moonshot Biobanking Activities" (http://biospecimens.cancer.gov/programs/cancermoonshot/principles) and are consistent with the "2016 NCI Best Practices for Biospecimen Resources" (https://biospecimens.cancer.gov/bestpractices/).

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application in ASSIST, use Component Type 'Admin Core.'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The HTA Research Center PD/PI (contact PD/PI for applications with multiple PDs/PIs) must serve as the Administrative Core Lead.
• The Administrative Core is expected to have a qualified Center Administrator to manage the day-to-day operations with responsibility for the administrative, budgetary, and operational aspects of the Center. For the Center Administrator, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Center Administrator'.

Budget forms appropriate for the specific component will be included in the application package.

Leadership Effort Commitment: The HTA Research Center contact PD/PI must commit and maintain through the life of the award a minimum of 1.8 person-months of effort. For applications with multiple PDs/PIs, a minimum effort of 1.8 person-months is required for the Contact PD/PI and 1.2 person-months of effort per additional PD/PI is required. The required levels of effort may reflect an aggregate of the effort for the entire Center (listed here under Administrative Core) and the efforts for other Center components, as applicable.

Center Administrator. Based on the complexity of the HTA Research Center, applicants are expected to propose and budget for a Center Administrator to manage day-to-day operations.

Funds for Trans-Network Projects: A minimum of $200,000 in direct costs per year must be allocated to a restricted fund for support of post-award collaborative projects between HTAN Research Centers. These funds should be presented in the Other Direct Costs category under the heading "HTAN Collaborative Project Fund". Funds will be released pending approval by NCI following discussion of proposed projects by the HTAN Steering Committee.

Travel Funds: The budget should include funds to support travel for Network activities, including but not limited to supporting the travel and participation of PD(s)/PI(s) and other HTA Center members in the semi-annual HTAN Steering Committee meeting and annual site visits.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Outline Specific Aims for the Administrative Core

Research Strategy:

In lieu of the standard Research Strategy sub-sections (Significance, Innovation, Approach), use the sub-sections defined below to explain how the effective administrative and organizational capabilities of the Administrative Core will:

• Support all aspects of human tumor atlas construction spanning from tissue acquisition and outreach;
• Foster synergy and integration of the Research Centers;
• Provide efficiency in management of large-scale collaborative research efforts involving multiple institutions (including logistical services and organizational support);
• Coordinate with PCA Research Centers (where applicable) and HTAN activities (SOPs, CDEs, etc.);
• Coordinate attendance at HTAN meetings and teleconferences;

Support planning and evaluation activities.

Sub-section A: Leadership and HTA Research Center Organization

In this sub-section address the major responsibilities of the Administrative Core that are listed above. Outline the organization of the leadership structure and overall HTA Research Center structure (provide respective organizational diagrams). Describe the lines of responsibilities, including, as applicable, the effort distribution across the participating institutions (i.e., institution submitting application and participating institutions on a sub-contractual basis).

Sub-section B: Center logistics and communication

In this sub-section describe the strategies for communication and resource/data/tool exchange between:

• the HTA Research Center leadership (multiple PD(s)/PI(s)) and key personnel within the three Research Units
• the HTA Research Center and the HTAN Data Coordinating Center
• the HTA Research Center and the NCI

State who will be the lead for each level of communication. Provide a strategy for integration of new investigators, technologies, and/or analytical approaches into the Research Center structure and environment.

Sub-section C: Evaluation of Interim Center Milestones

Outline plans for critically evaluating and revising Interim Center Milestones on a regular basis. Describe how these evaluations will be used to prioritize activities to ensure that the main goals of the HTA Research Center will be achieved. Milestones may be revised at the time of the award with approval by NCI Program Officials. Describe what action will be taken, and when, if a milestone is not met or significantly delayed.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type 'Functional Unit'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Biospecimen Unit)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project: Use "Biospecimen Acquisition, Processing and Classification Unit" as the title for this Unit.
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Biospecimen Unit)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Biospecimen Unit)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Biospecimen Unit)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Biospecimen Unit)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Unit Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• For Units with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of 'Other (Specify)' and designate the role under 'Other Project Role Category' as 'Unit Co-Lead' and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Unit Co-Lead' and provide a valid eRA Commons ID in the Credential field.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Unit Leads are expected to include investigators with hands on experience in collection, annotation and characterization of clinical biospecimens, including oncologists and pathologists with medical doctoral degrees and others with molecular pathology expertise. Other key personnel may include, but are not limited to, a research coordinator, surgical nursing staff and/or laboratory technicians.

Budget (Biospecimen Unit)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Biospecimen Unit)

Specific Aims: State the specific aims for the Biospecimen Acquisition, Processing, and Characterization (Biospecimen) Unit and provide a rationale and description of how each aim addresses a specific aspect of the proposed human tumor atlas(es).

Research Strategy: In lieu of the standard Research Strategy subsections (Significance, Innovation, and Approach), describe the activities of the Biospecimen Unit using the sub-sections listed below. However, applications should highlight aspects of the proposed activities of the Biospecimen Unit that speak to the significance and innovation of the approach.

Sub-section A: Overview and Biological Motivation

In this sub-section provide an overview of how the Biospecimen Unit will collect biospecimens that are reflective of the racial/ethnic diversity of the United States for use in constructing the proposed tumor atlas(es). At a minimum, provide the following information within this sub-section:

• An overview of the type, source and frequency of biospecimen collection within the Biospecimen Unit.
• Evidence of access to a source of human samples (i.e., ongoing clinical trial or other approved and accruing cancer-related study) relevant to the proposed tumor atlas immediately upon award.
• A biological and statistical justification for collection frequency, sample type, and volume of biospecimens to be acquired that is motivated by the specific atlas(es) being proposed by the HTA Research Center.
• A description of the use of retrospective human samples, non-human tissues and/or alternative in vivo and/or ex vivo human models. Data contained within the final tumor atlas deliverables of each HTA Research Center is expected to be derived from human clinical biospecimens, preferably prospectively collected. However, it is recognized that biospecimens from retrospective studies, non-human models or in vivo and ex vivo platforms derived from human tumors, such as tumor organoids, patient-derived xenograft models, and other systems that maintain native tumor architecture may be useful during development of standard operating procedures for tissue processing, preservation, and characterization.
• Include details regarding what biospecimens can and will be shared through the HTAN Tissue Coordination Center, a virtual resource of HTAN investigators to begin in Fiscal Year 2019.

Sub-section B: Sample Acquisition Pipeline

In this sub-section provide a comprehensive roadmap for sample acquisition, processing, and characterization, including, but not limited to, information regarding:

• The source of biospecimens, including anatomical location, and how that information will be preserved and shared with the Characterization and Data Analysis Units.
• The use of retrospective and/or prospective human samples. Indicate if longitudinal or cross-sectional sampling strategies will be employed. Provide justification for the sampling strategy with respect to the proposed tumor atlas(es).
• The use of a standardized coordinate framework to preserve tumor lesion location and orientation during collection. The description should include a plan for interoperability of the coordinate system across the HTAN.
• What quality assurance and quality control metrics will be developed and/or employed to ensure high sample quality upon collection, after preservation, and upon pre-analytical processing. In particular, provide parameters that define sample quality, as these may differ between the particular tumor atlas being constructed. The description should include a plan for sharing quality control measures and information derived from such measures across the HTAN.
• What pathology analyses will be performed to characterize the specimen at the time of collection.
• How the tissue will be processed and/or preserved to facilitate the activities of the Characterization Unit, including optimization of pre-analytical processing of tissue for multiple imaging and omics assays.
• The number of samples that can be acquired and processed each year, specifically stating how the accrual rate will contribute the Interim and Overall Milestones described in the Overall Component.
• Possible synergies with other initiatives and how those interactions may affect the sample acquisition pipeline.
• Disparate geographical locations of participating Institutions and how this may or may not influence downstream processing and the activities of the Characterization Unit. Describe and, preferably, demonstrate through presentation of preliminary data strategies to minimize confounding variables during sample collection.

The strongest applications will demonstrate the proposed sample acquisition pipeline through presentation of preliminary data.

Sub-section C: Clinical Data and Metadata

In this sub-section describe plans for collection of appropriate clinical and epidemiological data that will best inform the proposed atlas(es) and future use of the proposed atlas(es). Whenever possible, investigators should collect blood samples from patients for germline DNA analysis. Other possible clinical and epidemiological variables include, but are not limited to, race/ethnicity, treatment and outcomes, smoking history, sun exposure, alcohol use, medications at time of diagnosis and/or sampling, family disease history, body mass index, and other comorbid conditions.

Sub-section D: Informed Consent

In this sub-section provide details about the breadth of informed consent obtained from patients. Biospecimens collected by the Biospecimen Unit will be characterized using the technology platforms proposed by the Characterization Unit, including the potential for new and cutting-edge data collection techniques that will be introduced within the HTAN after award. Therefore, careful attention must be paid to the design of patient consent forms at the time of specimen collection. Consent forms must allow for broad data sharing as required by the Beau Biden Cancer Moonshot Public Access and Data Sharing Policy. Include an approved consent form in the Appendix materials or provide evidence that approval is expected.

Subsection-F: Benchmarks of Unit Progress

Applicants should provide a clear set of tentative semi-annual quantitative benchmarks for the Biospecimen Unit. Outline benchmarks with quantitative metrics that will document progress towards the achievement of the Overall Center Milestones presented in the Overall Component. Applicants should include plans for critically evaluating and revising these benchmarks on a regular basis. Applicants should describe how they will prioritize their activities to ensure that the main goals of the HTA Research Center will be achieved. Benchmarks may be revised at the time of the award with approval by NCI Program Officials. Applicants should also describe what action will be taken, and when, if a milestone is not met or significantly delayed.

Letters of Support: Applications must include letters of support from all collaborating Institutions where biospecimen collection will occur.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Include examples of patient consent forms for biospecimen collection within the Appendix materials for the Biospecimen Unit.

When preparing your application in ASSIST, use Component Type 'Functional Unit'

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Characterization Unit)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project: Use "Molecular, Cellular, and Tissue Characterization Unit" as the title for this Unit.
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Characterization Unit)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Characterization Unit)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Characterization Unit)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Characterization Unit)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Unit Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• For Units with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of 'Other (Specify)' and designate the role under 'Other Project Role Category' as 'Unit Co-Lead' and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Unit Co-Lead' and provide a valid eRA Commons ID in the Credential field.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Unit Leads are expected to include investigators with significant experience leading multidisciplinary teams with hands on experience in collection of multidimensional, multiparameter data sets from tissue samples.

Budget (Characterization Unit)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Characterization Unit)

Specific Aims: State the specific aims of the Molecular, Cellular and Tissue Characterization (Characterization) Unit and provide a rationale and description of how each aim addresses a specific aspect of the proposed human tumor atlas(es).

Research Strategy: In lieu of the standard Research Strategy subsections (Significance, Innovation, and Approach), describe the activities of the Characterization Unit using the sub-sections listed below. However, applications should highlight aspects of the proposed activities of the Characterization Unit that demonstrate the significance and innovation of the approaches.

Sub-section A: Overview and Biological Motivation

In this sub-section, provide a general overview of the various data types that will be collected within the Characterization Unit. It is required that each pilot-scale atlas integrate multiple spatial and temporal levels of data. Describe how the proposed multidimensional (3D/4D), multiparametric data collection will facilitate construction of the targeted human tumor atlas(es).

Molecular, cellular, and tissue characterizations could include, but are not limited to:

• Radiomic analysis of tumor structure/function at the organ or whole tumor level (computed tomography, magnetic resonance imaging, positron emission tomography, ultrasound, photoacoustic, fluorescence, photonic-based imaging methods for solid tumors, etc.) using in vivo data sets as well as high resolution ex vivo data sets (imaging mass spectrometry, multiplexed ion beam imaging, etc.)
• Multidimensional mapping (i.e., in space and time) of tumor structure and molecular content at the tissue or multicellular level (multiplexed immunofluorescence, light sheet microscopy, expansion microscopy, etc.).
• Multiparameter characterization of tumor omics (whole genome/exome sequencing, transcriptome sequencing, epigenomics, metabolomics, proteomics, etc.) in combination with spatial mapping by imaging at the single-cell or near single-cell level (imaging mass spectrometry, multiplexed ion beam imaging, multiparameter fluorescent in situ hybridization, multiplexed immunofluorescence).

Provide a biological justification for collection frequency, data type, and data volume to be acquired that is motivated by the specific atlas(es) proposed by the HTA Research Center. Each measurement to be included within the proposed human tumor atlas(es) should be presented within the Research Strategy of this Unit.

Sub-section B: Proposed Data Collection

In this sub-section provide a comprehensive description of the proposed molecular, cellular and tissue characterization, including, but not limited to:

• Provide a workflow for data collection that describes how multidimensional (3D/4D), multiparameter data will be collected from each biospecimen.
• State the data collection technology(ies)/platform(s) to be employed by the Characterization Unit. Each technology platform is expected to have the following characteristics: a technology platform must be reproducible, quantitative, and sensitive to facilitate comprehensive analysis of the biospecimens collected in the BAPC Unit.
• State if technologies proposed within the application can be considered analytically validated. If not, provide plans and timelines for analytical validation. Note: for the purpose of this FOA, a discovery technology platform is considered analytically validated if it meets the following criteria: 1) has successfully been deployed and validated in at least one other laboratory; 2) is capable of generating reproducible results within and across laboratories using quality control standards typical of the specific field of measurement; and 3) has been published in a peer-reviewed journal.
• Provide a statistical justification for the volume of data to be collected and frequency of data collection across all technology platforms based upon the goals of the tumor atlas(es) being constructed.
• If technology platforms are located across Institutions, provide a plan for how biospecimens collected by the Biospecimen Unit will be divided (or not) for analysis.
• State any non-human models to be utilized in the project (i.e., for technical validation or quality control) and how they will contribute to the construction of the human tumor atlas(es).
• Indicate how the Characterization Unit team will take advantage of the HTA Research Center infrastructure to allow for alternative approaches or perspectives to be quickly employed.

Sub-section C: Preliminary Data

In this sub-section present preliminary data addressing, minimally, the following aspects of the Characterization Unit:

• Demonstrate the current capability within the Characterization Unit using the proposed technology platforms.
• For Units proposing a novel combination/integration of several technology platforms, provide appropriate preliminary data for each individual component as well as the entire combined approach.
• If technology platforms are located across institutions, provide a demonstration of the proposed workflow.

Sub-section D: Quality Assurance/Quality Control

In this sub-section describe a strategy to monitor and ensure the quality of instrument performance and data generated across the HTA Research Center. Applications should describe typical error rates for the proposed technology platforms to ensure data quality. Include preliminary plans for coordinating data collection quality across the HTAN.

Subsection-F: Benchmarks of Unit Progress

Applicants should provide a clear set of tentative semi-annual quantitative benchmarks for the Characterization Unit. Outline benchmarks with quantitative metrics that will document progress towards the achievement of the Overall Center Milestones presented in the Overall Component. Applicants should include plans for critically evaluating and revising these benchmarks on a regular basis. Applicants should describe how they will prioritize their activities to ensure that the main goals of the HTA Research Center will be achieved. Benchmarks may be revised at the time of the award with approval by NCI Program Officials. Applicants should also describe what action will be taken, and when, if a milestone is not met or significantly delayed.

Letters of Support: Letters of support should be included from collaborators whose technologies are new to the HTA Research Center and are not part of the investigative team. If the application includes discounts or other special consideration from vendors, letters of support stating that commitment should be included in this Unit.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type 'Functional Unit'.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Data Analysis Unit)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project: Use "Data Processing, Analysis and Modeling Unit" as the title for this Unit.
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Analysis Unit)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data Analysis Unit)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Analysis Unit)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Data Analysis Unit)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Unit Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• For Units with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of 'Other (Specify)' and designate the role under 'Other Project Role Category' as 'Unit Co-Lead' and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Unit Co-Lead' and provide a valid eRA Commons ID in the Credential field.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Unit Leads are expected to include investigators with significant experience leading multidisciplinary teams with hands on experience in analysis of multidimensional, multiparameter data sets from tissue samples.
• The Unit must have senior/key investigators with expertise in biostatistics, data analysis, data processing, bioinformatics, and computational and mathematical modeling.

Budget (Data Analysis Unit)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Data Analysis Unit)

Specific Aims: State the specific aims of the Data Processing, Analysis, and Modeling (Data Analysis) Unit and provide an overview of the final tumor atlas(es) to be delivered by the HTA Research Center.

Research Strategy: In lieu of the standard Research Strategy subsections (Significance, Innovation, and Approach), describe the activities of the Data Analysis Unit using the sub-sections listed below. However, applications should highlight aspects of the proposed activities of the Data Analysis Unit that speak to the significance and innovation of the approaches.

Sub-section A: Biological Motivation and Proposed Atlas Use Case

In this sub-section provide a brief overview of the various data processing, analysis and modeling techniques that will be utilized within the Data Analysis unit, concentrating on type of biological insight that can be gained through employment of those techniques. Explain how the various analytical and computational techniques will contribute to construction and use of the proposed tumor atlas(es).

Provide plans for completion of at least one use case example that will demonstrate how the resulting human tumor atlas dataset can be utilized to build a predictive computational model of cancer. Describe the clinical or biological insight that will be gained from the modeling effort.

Sub-section B: Biostatistics

In this sub-section, describe the type of biostatistical analyses to be performed by the Data Analysis Unit for use by both investigators within the Data Analysis Unit and within the Biospecimen and Characterization Units. Appropriate information includes, but is not limited to;

• A clear statement on how statistical power is defined in multiple samples and what sample size is required to achieve this power. Examples of power definition: (a) the probability to detect at least one of possible true nonzero effects; (b) the probability to detect all nonzero effects; and (c) true discovery rate, etc.
• Resulting power analyses to determine biospecimen collection, frequency of sample and data collection, and volume of data collection across data types.
• A discussion of the overall statistical power of the proposed tumor atlas(es) for use in answering biological and/or clinical questions.
• State the limitations of the proposed work.

Sub-section C: Data Processing

In this sub-section describe and demonstrate any existing or proposed data processing pipelines to be employed within the HTA Research Center, specifically with regards to imaging and/or omics data collection. State how these pipelines might be scaled to meet the demands of increased throughput within the HTA Research Center or across the HTAN. State the degree to which the resulting processed data is interoperable and meets the qualifications for FAIR data sharing standards. If standard data processing pipelines are not being employed within the Center, provide justification for the use of in-house pipelines and provide examples of downstream analyses utilizing the output of the data processing pipeline (to demonstrate interoperability).

Sub-section D: Data Analysis

In this sub-section describe and demonstrate the computational approaches to be employed within the Data Analysis Unit that will result in the generation of dynamic multi-dimensional tumor maps from high-content, multi-parameter imaging and omics assays conducted by the Characterization Unit. Approaches to include within this sub-section could include and are not limited to:

• bioinformatic analysis of bulk and/or single- or near single-cell multi-parameter -omics data;
• integrated analysis of disparate omics and imaging data types;
• advanced image analysis;
• radiomics analysis;
• systems biology approaches to connect disparate data at multiple time and/or length scales.

Sub-section E: Atlas Construction

In this sub-section, describe and demonstrate plans to aggregate and integrate data and metadata from the broad range of experimental and computational approaches outlined throughout the application into a tumor atlas utilizing the tumor maps described in the previous section. At a minimum, include the following information:

• Describe how dynamic spatial relationships (3D/4D) will be reconstructed or maintained within the proposed tumor atlas(es) through employment of visualization and image analysis approaches.
• Address how anatomical relationships will be maintained within the tumor atlas(es). The importance of precision registration between in vivo and ex vivo data sets may vary in importance for clinical predictions depending on the atlas(es) proposed. If applicable, a theoretical discussion concerning the importance of in vivo to ex vivo registration methodology and how it might subsequently be realized/applied in a clinical environment should be included.
• Describe the different levels of ontologies that will be utilized to describe information within the atlas(es).
• Propose a forward-looking, standardized workflow for integrating various multidimensional, multiparameter tumor maps into a scalable and searchable tumor atlas.
• Provide plans to develop and/or adapt computational tools for searching, cross-validation, and data visualization.

Sub-section F: Network-wide Collaboration

In this sub-section describe plans to collaborate with the HTAN Data Coordinating Center and other HTAN Research Centers in developing common data formats and interoperable tools and procedures allowing seamless integration and presentation of the atlases across the entire HTAN. Additionally, describe how analysis workflows or pipelines will facilitate consistent use of the algorithms by numerous experimental labs.

Demonstrate through evidence of collaboration and/or open source algorithm and computational tool development the flexibility of the Data Analysis Unit to incorporate disparate data types generated by other members of the HTAN. Analytical flexibility is an important aspect of the Data Analysis Unit because the HTAN has not yet formed and the breadth of data types across the Network is currently unknown.

Subsection G: Benchmarks of Unit Progress

Applicants should provide a clear set of tentative semi-annual quantitative benchmarks for the Data Analysis Unit. Outline benchmarks with quantitative metrics that will document progress towards the achievement of the Overall Center Milestones presented in the Overall Component. Applicants should include plans for critically evaluating and revising these benchmarks on a regular basis. Applicants should describe how they will prioritize their activities to ensure that the main goals of the HTA Research Center will be achieved. Benchmarks may be revised at the time of the award with approval by NCI Program Officials. Applicants should also describe what action will be taken, and when, if a milestone is not met or significantly delayed.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this FOA, note the following:

Reviewers will provide an overall impact score for the entire HTA Research Center (Overall component). In addition, assigned reviewers will provide individual "criterion scores" for the Overall criteria but not for the other components.

Biospecimen Unit, Characterization Unit, and Data Analysis Unit will be evaluated by each reviewer but each will receive only one overall numerical score and will not receive individual criterion scores.

Administrative Core will be evaluated by each reviewer but will receive only one overall adjectival rating and will not receive individual criterion scores.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Research Center to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the Research Center proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a Research Center that by its nature is not innovative may be essential to advance a field.

Does the Research Center address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the Research Center are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: How well will the proposed human tumor atlas(es) describe an important cancer transition within the high priority tumor categories defined within the FOA (highly metastatic, promising candidates for immunotherapy, refractory to immunotherapy and high-risk hereditary tumors)? How much potential do the proposed human tumor atlas(es) proposed have to be useful to the diverse population of the United States, including minority and underserved population? To what degree might the proposed pilot-scale tumor atlas(es) enhance our understanding of mechanisms underlying cancer metastasis and/or treatment decision for cancer patients?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Research Center? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Do the Research Center PD(s)/PI(s) and other key personnel have the necessary understanding of the design, administration, and analysis of multi-institutional basic and clinical research? How well do the proposed interactions and collaborations between the HTA Research Center PD(s)/PI(s), Unit Leads, and other key personnel unite the components and advance the atlas building efforts of the Research Center? Do the PD(s)/PI(s) named in the Administrative Core have the appropriate expertise and previous experience to lead a multi-institutional, multi-disciplinary research team?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA: Does the proposed human tumor atlas(es) employ novel concepts, approaches, and/or methods for atlas construction? Does the overall plan for the proposed human tumor atlas(es) incorporate novel strategies for integrating large-scale molecular, cellular, non-cellular, and clinical datasets?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Research Center? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the Research Center involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA: Have the investigators presented adequate plans to include a population representative of the diverse population of the United States? How well do the preliminary data demonstrate the capabilities of the HTA Research Center for their proposed atlas-building efforts? How are the overall and Interim Center Benchmarks designed to ensure successful tumor atlas construction while providing the flexibility required to incorporate new and/or improved technologies and analytical approaches? How acceptable are the plans for addressing the NCI Cancer Moonshot Public Access and Data Sharing Policy?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA: Is there evidence for sufficient institutional support for the HCA Research Center? Will the scientific environment at the participating institutions stimulate multidisciplinary research collaborations?

Integration

Will the proposed HTA Research Center be a truly integrated entity, rather than a collection of unrelated research ventures and support services? How well does the HTA Research Center organization promote scientific integration, synergy, and a cohesive research goal?

Reviewers will provide only one overall adjectival rating for the Administrative Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the Research Center?
• How well will the structure of the Administrative Core promote communication between the various Research Center components?

Reviewers will provide only one overall numerical score for the Biospecimen Unit (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• Are the Unit Leads, collaborators, and other researchers well suited to the goals of the Biospecimen Unit?
• Is the biospecimen collection roadmap proposed based on strong scientific rationale?
• Is atlas construction based upon data from prospective human biospecimens?
• Do the applicants present a sound plan for high quality biospecimen collection, processing, and storage, and for obtaining high quality clinical and epidemiological information linked to biospecimens?
• How will the proposed quality assurance and quality control plans facilitate distribution of high quality biospecimens to the Characterization Unit?
• If the investigators propose a new study to procure biospecimens, will the accrual of samples support atlas-building activities within the proposed timeframe and will particularly risky aspects of the study be managed?
• Based on sample consent forms provided, will the applicants strategy for this aspect be optimal for the goals of biospecimen collection?
• Are potential problems, alternative strategies, and benchmarks for success presented?

Reviewers will provide only one overall numerical score for the Characterization Unit (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• Are the Unit Leads, collaborators, and other researchers well suited to the goals of the Characterization Unit?
• Is there a strong scientific premise for the multidimensional, multiparameter data collection proposed?
• How well do the preliminary data demonstrate the capabilities of the Characterization Unit for the proposed molecular, cellular and tissue-level characterization proposed?
• How will the proposed quality assurance and quality control plans facilitate successful molecular, cellular, and tissue level characterization of biospecimens?
• If the investigators propose technologies for biospecimen characterization that have not been analytically validated (as defined within the FOA), will the technologies be fully validated and capable of contributing data to the proposed tumor atlas within the proposed timeframe?
• Will particularly risky aspects of the study, such as biospecimen characterization that occurs across institutions, the employment of new technologies, or the integration of disparate technologies, be managed?
• Are potential problems, alternative strategies, and benchmarks for success presented?

Reviewers will provide only one overall numerical score for the Data Analysis Unit (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• Are the Unit Leads, collaborators, and other researchers well suited to the goals of the Data Analysis Unit?
• How does the proposed human tumor atlas demonstration use case provide a novel example of how the resulting human tumor atlas dataset can be utilized to build a predictive computational model of cancer?
• Are statistical analyses, procedures, and policies adequate, appropriate, and consistent with accepted standards?
• Is there a strong scientific premise for the range of data processing, analysis, and computational modeling proposed?
• How well do the preliminary data demonstrate the range of data processing, analysis, computational modeling, and visualization approaches proposed, including any data processing, analysis and visualization algorithms that are not field standards?
• How well do the preliminary data demonstrate the flexibility of the Data Analysis Unit for integrating new and unanticipated data streams?
• How well do the plans of the Data Analysis Unit ensure that data and algorithms are interoperable and meet the qualifications for FAIR data-sharing standards?
• Will particularly risky aspects of the study be managed?
• Are potential problems, alternative strategies, and benchmarks for success presented?

As applicable for the Research Center proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed Research Center involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the Research Center proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the Center for Scientific Review in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Compliance with Beau Biden Cancer Moonshot Open Access and Data Sharing Policy

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee's business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Awardee-selected projects that involve clinical trials or studies involving greater than minimal risk to human subjects require prior approval by NIH prior to initiation.

• The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH's Instructions for Preparing the Human Subjects Section of the Research Plan.
• The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Overseeing the scientific research in the Research Center, analyzing and interpreting research data, reporting results to the scientific community, and disseminating approaches, methods, models, software, and tools broadly.
• Committing and maintaining throughout the life of the HTA Research Center a minimum of 1.8 person-months of effort per year for the investigator designated as the contact PD/PI.
• Committing and maintaining throughout the life of the HTA Research Center a minimum of 1.2 person-months of effort per year for any investigator designated as a non-contact PD/PI of the Research Center.
• Agreeing to be an active participant in the HTAN, including attending the semi-annual Steering Committee Meeting, participating in other network sponsored meetings and workshops, and participating in collaborative activities.
• Serving on the HTAN Steering Committee. The HTAN Research Center PD/PI (contact PD/PI for applications with multiple PD(s)/PI(s)) is required to serve as a member of the Steering Committee.
• Abiding by the governance of the HTAN and all program policies agreed upon by the HTAN Steering Committee and approved by NCI Program Officials to the extent consistent with the applicable rules and regulations.
• Reporting progress to the NCI Program Officials on all HTAN Research Center research and outreach activities annually. The PD(s)/PI(s) may be expected to provide additional information, outside the scope of the standard reporting requirement, as needed and requested by program staff members.
• Being prepared for the annual site visits of NCI Program staff members and participation in the NCI-coordinated evaluation of the HTAN program. The Administrative Core should coordinate participation in Research Center program evaluation activities, including generation of progress reports and logistics of site visits.
• Leveraging, where feasible, technology from related NCI-sponsored informatics initiatives, for example the NCI Informatics Technology for Cancer Research (ITCR) program, which supports the development of informatics algorithms, tools, and resources across the continuum of cancer research.
• Coordinating with and leveraging, where feasible, the technology of the NCI Cancer Research Data Commons, a program that will provide infrastructure to make diverse cancer research data broadly available and to maximize their reuse and impact.
• Ensuring that data are deposited in a timely manner to the HTAN Data Coordinating Center, and that models, software, and other tools and resources developed as part of this Research Center are made publicly available according to HTAN policies and in accordance with the Beau Biden Cancer Moonshot Public Access and Data Sharing Policy. Additionally, all HTAN Research Centers will be required to utilize the resources within the HTAN Data Coordinating Center, including common data elements and metadata dictionaries developed in collaboration with HTAN investigators. The HTAN Data Coordinating Center will be funded under the companion FOA RFA-CA-17-036.
• Ensuring that results of the Research Units and the resulting human tumor atlas(es) are published in a timely manner.
• Organizing scientific working groups to facilitate collaborative projects and cross-testing of experimental and analytical concepts.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. Participating HTA Research Center members are also encouraged to organize and participate in other HTAN meetings and workshops, organize collaborative activities, and promote Trans-Network collaborations, and organize and participate in scientific and programmatic working groups.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

One or more designated NCI Program staff members will have substantial involvement as Project Scientist(s) for the HTAN.

Additionally, an NCI Program Director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Program Officials may also have substantial programmatic involvement (as Project Scientists).

In carrying out its stewardship of Beau Biden Cancer Moonshot initiatives, the National Cancer Institute (NCI) will monitor and evaluate progress to meet the expectations set forth by Congress in the 21st Century Cures Act.

The specific roles of the substantially involved NCI staff members include the following activities:

• Serving as non-voting members of the HTAN Steering Committee.
• Assisting the Steering Committee, the HTAN Data Coordinating Center, and individual U2C awardees in avoiding unwarranted duplications of effort across the HTAN.
• Facilitating collaborative research efforts that involve multiple HTAN Research Centers and would be suitable for consideration as a trans-HTAN collaborative project to be funded by restricted Research Center funds.
• Assisting the awardees as a resource in facilitating their broader interactions with other NCI and NIH programs to disseminate results, tools, and models from the HTAN and take advantage of existing NIH/NCI resources and infrastructures. This will specifically include acting as a liaison between the HTAN and other atlas-building programs.
• Ensuring that the HTAN Data Coordinating Center data- and tool-sharing infrastructure is provided to HTAN members in a reasonable and expeditious way.
• Evaluating the effectiveness and facilitating consortium-wide adoption data- and tool-sharing and interoperability practices.
• Monitoring the operations of the HTAN awardees and making recommendations on overall project directions and allocations of HTA Research Center funds.
• Reviewing the progress of the HTAN awardees (including HTAN Data Coordinating Center), conducting periodic site visits, and taking other actions as needed.
• Participating in organizing semi-annual HTAN meetings, specialized workshops, and webinars of the network.

Areas of Joint Responsibility include:

Steering Committee: The Steering Committee will be the main governing body for the HTAN. The Steering Committee will be composed of one representative (contact PD/PI or other senior level investigator) from each HTAN awardee, i.e., from HTA Research Centers, PCA Research Centers, and HTAN Data Coordinating Center and HTAN Tissue Coordinating Center who will have one vote each.

NIH/NCI program staff members will participate in HTAN Steering Committee meetings as non-voting members.

If needed, other government staff members may also participate in HTAN Steering Committee meetings as non-voting members.

Two PD(s)/PI(s), representing two different HTAN awards, will be selected to serve as chairpersons of the Steering Committee starting at the first meeting of the Steering Committee following award issuance. All HTAN Steering Committee decisions and recommendations that require voting will be based on a majority vote.

The HTAN Steering Committee will meet monthly by videoconference and in-person at the HTAN semi-annual Steering Committee Meeting and as needed.

The HTAN Steering Committee will:

• Identify scientific and policy issues that need to be, or can benefit by being, addressed at the Network level and develop recommendations to NIH/NCI Program Officials for addressing such issues.
• Review progress of the HTAN toward meeting the overall Network goals.
• Ensure that all HTAN members utilize the resources developed by the HTAN-DCC and HTAN-TCC.
• Discuss and prioritize the collaborative projects to be supported by the restricted "HTAN Collaborative Project" funds within each Research Center.
• Coordinate dissemination of Network output to the broader cancer research community.
• Ensure that the Network takes advantage of existing NCI and NIH resources and programs.
• Establish, as necessary, subcommittees to ensure progress of the individual Centers and the Network.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-945-7573

Shannon Hughes, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6224
Email: NCI_HTAN_HTAU2C@mail.nih.gov

Tracy Lively, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5944
Email: NCI_HTAN_HTAU2C@mail.nih.gov

Lambratu Rahman Sesay, Ph.D.
Center for Scientific Review, NIH
Telephone: 301-905-8294
Email: rahmanl@csr.nih.gov

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: wolfreyc@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.