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 Pre-Cancer Atlas (PCA) Research Centers. The goal of the PCA Research Centers is to construct comprehensive, dynamic, high-resolution, multidimensional, multiparametric, temporal and scalable atlases of pre-cancerous lesions and their surrounding microenvironment for select organ sites, including high-priority cancers that disproportionally affect minority and underserved patients. The data generated can be interrogated to understand events that drive transition of pre-malignant to malignant state as a function of time, find molecular markers of risk and early detection, identify targets to intercept and prevent development of cancer and for predictive modeling to chart the potential trajectories of tumor development and progression that researchers and clinicians can consult for research purposes or clinical decision making. Each PCA Research Center will lead the construction of at least one human pre-cancer atlas.

The PCA Research Centers will be part of the Human Tumor Atlas Network (HTAN), which will also include the Human Tumor Atlas (HTA) Research Centers (solicited under companion RFA-CA-17-034), an HTAN Data Coordinating Center (HTAN-DCC; solicited under companion RFA-CA-17-036), and an HTAN Tissue Coordinating Center (anticipated to be developed in Fiscal Year 2019).

Key definitions for the purposes of this FOA:

Pre-cancer: Pre-cancers can be defined as the following: a condition that may (or is likely to) become cancer, pre-malignant lesions where there is a clear evidence of association with increased risk of invasive cancer, chronological evolution of the lesions result in progression to invasive cancer or regression, lesions differ from normal cells and share molecular and phenotypic features with invasive cancer, invasive cancer originates from the pre-malignant lesion.

Pre-Cancer Atlas: A human pre-cancer atlas is defined as a multidimensional cellular, morphological and molecular mapping of human pre-malignant tumors, complemented with critical spatial information (at cellular and/or molecular level) that facilitate visualization of the structure, composition, and multiscale interactions within the tumor ecosystem over time resulting in progression or regression of the tumors.

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 by specifically focusing on a concerted, multidisciplinary effort to construct pre-cancer atlases for select organ sites.

A major hindrance to advancement in early detection and prevention of cancer is the lack of comprehensive knowledge of molecular, cellular and tissue alterations that drive tumor development and progression at its earliest stages. Pre-malignant lesions are states of abnormal tissue that often precede the development of malignancy. These lesions can be found in diagnostic biopsies and are frequently detected by circulating macromolecules, exosomes and aberrant cells in blood and other body fluids of potential cancer patients, as well as in biosamples obtained during screening procedures in patients at increased risk of cancer. Pre-cancer and in situ neoplasia comprise an array of diverse phenotypes within each organ site. Some of these lesions are observed in imaging as ill-defined incidental findings that can progress to invasive carcinoma, while many will remain stable or even regress. Although histologic features of these lesions have been characterized for many cancers, comprehensive multi-omic (e.g., genomic, transcriptomic and epigenomic) profiles and functional relationships of the tumor microenvironment including the immune milieu are not well-defined, making it difficult to develop risk stratification, precision prevention and therapeutic intervention strategies. In contrast to late-stage cancer, few studies have been performed to comprehensively profile the molecular and cellular alterations in pre-cancers and accompanying tissue microenvironment. Furthermore, systematic efforts to longitudinally collect and perform multi-omic and immune profiling of pre-malignant lesions as they progress towards malignancy or regress are lacking.

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) at sites of tumor initiation, growth, and metastasis. Integration of these data with non-invasive measurements based on multimodal molecular imaging or high-resolution optical imaging, could result in a multiparametric, multidimensional view of the evolving tumor ecosystem during cancer initiation and progression. It is now well acknowledged that the tumor ecosystem, which is defined by a full suite of cell types including tumor cells, tumor-associated immune, stroma, and vascular cells, evolves during tumor development and progression. 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 insight into the molecular underpinnings of these tumor phenotypes and have led to development of effective therapies in some contexts. However, to develop effective precision prevention strategies, an understanding of how interactions within the tumor ecosystem promote or suppress tumorigenesis, is needed. It is expected that the pre-cancer atlases will represent the multidimensional cellular, morphological and molecular mapping of the structure, composition and interactions within human pre-cancers as a function of time and space that can be visualized, describe the dynamic changes that drive progression of pre-malignant lesions toward malignancy, discover new biomarkers, and identify targets for preventive interventions.

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 PCA Research Centers, described in this FOA, that will construct atlases describing how and when pre-malignant lesions progress to invasive cancer or regress.
• The HTA Research Centers (RFA-CA-17-034), that will construct atlases describing the transition from locally invasive to metastatic cancer, dynamic response to therapy, and development of therapeutic resistance.

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 (HTA and PCA Research Centers) will facilitate future research and generate hypotheses to answer important cancer questions. The atlas construction includes, but are not limited to:

• The role of spatial and temporal interactions between tumor cells and the immune system in facilitating progression or regression of pre-malignant lesions, enhancing response to traditional, targeted and/or immunotherapy.
• Studies focused on clonal evolution, heterogeneity of pre-cancerous lesions and invasive tumors and changes in the tumor microenvironment in space and time.
• The principles governing the dynamics of somatic mutations, copy number changes, other molecular changes that affect cellular fitness and immunity and contribute to tumor initiation and progression.
• Development of experimental and computational models to better understand the spatial and temporal molecular and cellular dynamic relationships during tumor development.
• Identification of new link(s) between molecular genetic alterations and spatial and structural alterations during transition from pre-malignant to malignant state, tumor progression and as a result of treatment with therapeutic agents.
• Identification of spatial, functional and/or temporal biomarkers that predict cancer risk, targets for early intervention and response to therapeutic intervention.

Objective of the PCA Research Center

Through this FOA, the NCI will support up to three PCA Research Centers. Each PCA Research Center undertakes comprehensive molecular, cellular, and tissue characterization of human pre-malignant lesions with spatial resolution to construct comprehensive, dynamic, high-resolution, multidimensional, multiparametric, multiscale, temporal, and scalable atlases of pre-cancerous lesions and their surrounding microenvironment for select organ sites, including cancers that disproportionally affect minority and underserved patients. The atlases will provide a deeper understanding of the transition of pre-malignant to malignant cancer and identify markers for early detection and preventive interventions. The rationale for the selection of organ site(s) must be based on the following four criteria:

• Impact on Public Health: This is determined by the public health burden, prevalence of the tumor, nature of the clinical question to be addressed, health disparities in a variety of racially and ethnically diverse populations, and care settings. In the long term, a successful atlas will have a substantial role in assisting clinical decision making as well as its use by the scientific and clinical communities.
• Access to Technologies and Biospecimens: Retrospective samples from existing cohorts that are stored using different sample preservation methods could be used to broadly test emerging technologies (e.g., single cell and/or single nucleus analysis) that will be used for atlas construction, and the final atlas-building effort should use uniformly collected and extensively annotated, longitudinal biospecimens. Therefore, access to state-of-the-art technologies and extremely well-characterized and well-annotated biospecimens (cross-sectional and longitudinal) is important. Also, samples must be of high quality, quantity (for a variety of assays) and purity.
• Feasibility of Atlas Construction: The feasibility of atlas construction is based on the available cohorts, number of available biospecimens, rate of progression to cancer and the available tools and technologies.
• Synergistic Partnerships for Maximizing Resources: Partnership with ongoing initiatives in this area (federal, foundation, industry, etc.) is preferred for access to cohorts, technologies and any other resources deemed necessary for atlas construction.

Because of limited information on how to characterize pre-cancer lesions for atlas building purposes, the pre-cancer atlas should be built using a hybrid study design consisting of the following steps:

Step 1: Use retrospective biospecimens from existing cohorts to broadly test and standardize emerging state-of-the-art technologies and lock down promising technologies to be used in Step 2.

Step 2: Apply the selected promising technologies on prospectively collected longitudinal biospecimens with uniform clinical/imaging annotation to build the atlas.

The overarching goal of the PCA Research Centers is to begin assembling and linking the comprehensive datasets generated by the Centers for subsequent integration into an atlas and analytical exploration. The results of the studies conducted by the PCA Research Centers should have the potential to reveal significant insights into cancer biology, tumor initiation and progression, and the longitudinal trajectory of pre-cancerous to cancerous state. While the visualization and image analytics associated with these datasets represent a virgin territory, they offer the possibility to obtain "ground truth" assessments by integrating the abstracted data from all known areas of current cancer research. Investigators should be able to query the atlases in order to identify and understand hallmark events that drive oncogenesis, find molecular markers of early detection and identify targets to intercept and prevent development of cancer. Once the pilot atlases are built, they can be compared across organ sites to identify shared and unique etiological and pathological components. It is hoped that these pilot-level atlases can lend support for evidence-based expansion of the pre-cancer atlas(es) after completion of the pilot phase.

The collected tissue, digital imaging, clinical annotation, and generated data, all linked through the HTAN, will also provide a national resource for subsequent exploration and discovery of novel spatial, functional, and temporal interrelationships associated with cancer development and progression.

Note that atlases describing the transition from locally invasive to metastatic cancer, dynamic response to therapy, and development of therapeutic resistance are not supported under this FOA. Investigators interested in these atlases are directed to RFA-CA-17-034 "HTA Research Centers".

Required Capabilities of the PCA Research Center

Each PCA Research Center will consist of a multidisciplinary, collaborative team with expertise required to construct the pre-cancer atlas.

Expertise should include, but is not limited to:

• Clinical expertise, such as clinical oncology, cancer screening, 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;
• 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 pre-malignant biospecimens, with NIH programmatic emphasis to projects that utilize prospective human samples for atlas construction, as well as the technology and instrumentation for performing quantitative analytical assessments. Additionally, the team must have capability 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 complexity of the specific cancer transition being described within the proposed pre-cancer atlas. Finally, applicants must have demonstrable computational expertise that facilitates data analysis and atlas building activities, including advanced data visualization.

Structure of the PCA Research Center

Each PCA Research Center will consist of an Administrative Core and three highly integrated research units Biospecimen Acquisition, Processing, and Classification Unit (Biospecimen Unit); Molecular, Cellular, and Tissue Characterization Unit (Characterization Unit); and Data Processing, Analysis, and Modeling Unit (Data Analysis Unit).

Administrative Core

The Administrative Core will be led by the contact PD/PI of the PCA Research Center. Multi-PD/PI and multi-institution applications are encouraged because of the multidisciplinary nature of the projects. The primary role is to work with the HTAN Coordinating Centers to provide logistical and organizational support. It will ensure that the data collected on pre-cancerous lesions 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. It will also provide support to the HTAN-DCC by gathering all multiplatform data sources across the PCA Research Centers for data sharing and data integration purposes and to the HTAN-TCC (when it develops). The Administrative Core will also ensure bidirectional exchange of findings and insights with the HTA Research Centers focused on the more advanced invasive tumors. More application-related details are provided in Section IV. Application and Submission Information of this FOA.

Biospecimen Acquisition, Processing, and Classification Unit (Biospecimen Unit)

The Biospecimen Unit will be responsible for collection of biospecimens, e.g., biopsy, blood, serum, plasma and any other cross-sectional and prospective, longitudinal specimens deemed necessary to support the construction of the proposed atlas(es). The selection of model organ sites for pre-cancer atlas building purposes will be based on four stringent criteria described in a latter section of the FOA [PHS 398 Research Plan]). The unit should be staffed by clinician(s), surgeon(s), a research coordinator, and pathologist(s) to classify/stage/grade specimens per World Health Organization (WHO), American Joint Committee on Cancer (AJCC), Union for International Cancer Control (UICC), and/or American College of Physicians (ACP) guidelines. The Research Center should have expertise in preparing and optimizing pre-analytical processing of tissue specimens for extensive characterization of the lesions. The pilot-level pre-cancer atlases should be built based on data from prospective, longitudinal, well-annotated clinical biospecimens representative of the racial/ethnic diversity of the United States (U.S.) population. The PCA Biospecimen Unit will work with other HTAN Biospecimen units to develop appropriate SOPs and CDEs for specimen collection and processing to reduce biases and allow comparison of independent data sets among the HTA/PCA Research Centers. More application-related details are provided in Section IV. Application and Submission Information of this FOA.

Molecular, Cellular, and Tissue Characterization Unit (Characterization Unit)

The Characterization Unit will be responsible for conducting state-of-the-art molecular, cellular, non-cellular and tissue characterization for selected organ site(s) using biospecimens procured by the Biospecimen Unit and must include multidimensional/multiparametric characterization. The goal is to not create a cellular and molecular catalog, but to contribute to a framework that provides an understanding of transition from pre-malignant to malignant cancer. The Characterization Unit will include, as appropriate, experts in the areas mentioned above under "Required Capabilities of the PCA Research Center". The personnel associated with 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 tight integration is required between the Characterization Unit and the Data Analysis Unit to ensure adequate collection and sharing of metadata and experimental data for processing, analysis, and atlas-building activities. More application-related details are provided in Section IV. Application and Submission Information of this FOA.

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 Unit (Data Analysis Unit)

The Data Analysis Unit will be responsible for integrating and modeling the data generated by the Characterization Unit to visualize high-resolution structural, functional and temporal relationships as a dynamic, multidimensional, multiparametric atlas in a searchable and scalable format. Importantly, analysis workflows or pipelines should enable consistent use of the algorithms by numerous experimental labs. This Unit will have advanced computational biology capabilities including statistical and mathematical analysis, as well as the ability to develop new methods/tools/models for data integration research relevant to the pre-cancer atlas. Finally, the Data Analysis Unit will conduct at least one preliminary study that illustrates how the resulting human tumor atlas dataset could be utilized to build a predictive model of cancer. More application-related details are provided in Section IV. Application and Submission Information of this FOA.

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. The PCA Research Center applicants are encouraged to read the HTA Research Center (RFA-CA-17-034) and HTAN-DCC (RFA-CA-17-036) RFAs for more information.

Governance of the HTAN: All components will be governed by the HTAN 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 PCA 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 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 pre-cancer atlas.
• Projects proposing atlases constructed through exclusive use of non-human biospecimens.
• Projects that propose atlases for advanced cancers or recurrences and are not focused on pre-cancers. (Please see RFA-CA-17-034 "HTA Research Centers" for support of advanced cancer projects.)
• Projects proposing atlases of organ sites that are not based on the four stringent criteria (impact on public health, access to technologies and biospecimens, feasibility of atlas construction and synergistic partnerships for maximizing resources) mentioned in the Research Objectives section above and described in details in a latter part of the FOA (PHS 398 Research Plan).
• Projects proposing atlases based upon one experimental measurement (i.e. applications not based upon multiparametric data).
• Projects that do not propose methods that provide multidimensional data/information regarding the cellular and/or non-cellular components of the tumor.

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

• Projects that do not propose all components of the PCA Research Center.

See Section VIII. Other Informationfor 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.
• 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 PCA Research Centers, 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 companion HTAN initiative (RFA_CA-17-034 and 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-17-034 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:

Sharmistha Ghosh-Janjigian, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7122
Email: NCI_HTAN_PCAU2C@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 1
• Characterization 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 pre-malignant tumor atlases to be generated within the PCA Research Center. State the tumor type(s) selected for the study.

Project Narrative: State how the outcomes of the PCA 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 can be leveraged for construction of the human pre-malignant tumor atlases (e.g., ongoing prospective/longitudinal collection of pre-malignant lesions, well-annotated existing cohorts [cross-sectional and/or longitudinal], experimental and/or computational platforms etc.). Specify 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: Outline the overall vision and goals for the proposed PCA Research Center for the funding period, distinct from the aims of the individual functional units. 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 PCA Research Center.

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

Define the pre-cancer atlas(es) that will be constructed within the PCA Research Center. Provide a brief description of the proposed project, rationale for the selected organ site(s) (based on the four criteria described in Section I Research Objectives and Main Requirements as well as outlined below), and as background information, describe the current state-of-the-science regarding mapping pre-malignant lesions and include preliminary findings as they relate to the proposed projects. Also, describe the gaps and/or challenges in building pre-cancer atlas(es). Describe the significance and innovation in the context of visualization of a dynamic, multidimensional, multiparametric, multiscale, temporal, searchable and scalable atlas. Describe the PCA Research Center's vision of the final structure of the pre-cancer atlas and define its success through implementation in a multidimensional format, include 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. Describe how the atlas can help develop risk stratification, precision prevention and therapeutic intervention strategies. Since the pre-cancer atlas(es) are likely to be feasibility/pilot-level atlas(es), applicants should briefly highlight how the PCA Research Center will lay the groundwork for longer-term plans, including how the pilot-level atlas(es) could be expanded to represent larger human populations and extended to include additional types of data.

Provide a rationale for the selection of organ site(s) based on the following four criteria:

• Impact on Public Health:

Describe the public health burden, tumor prevalence, the clinical question to be addressed, including health disparities by focusing on a variety of populations (e.g., racially and ethnically diverse populations) and care settings, as and when possible. Outline a vision of how the pre-cancer atlas may be used to assist clinical decision making and be employed by the scientific and clinical communities in the long term.

• Access to Technologies and Biospecimens:

Outline what retrospective samples and what sample preservation methods will be used from existing cohorts to broadly test emerging technologies, and what validated/standardized technologies will be used on what prospective, longitudinal biospecimens for atlas construction.

• Feasibility of Atlas Construction:

Justify feasibility of atlas with the available cohort, biospecimens, rate of progression to cancer and any other aspect deemed important in this regard.

• Synergistic Partnerships for Maximizing Resources:

Describe partnerships with any ongoing initiatives in this area (federal, foundation, industry etc.) and how that will maximize the successful construction of the atlas.

Explain how you plan to adopt the required two-step hybrid study design defined in Section I. Describe the biospecimens that will be used to test and standardize state-of-the-art technologies and the process of selection of the most promising technologies in Step 1, and the application of the technologies on well-annotated longitudinal biospecimens for atlas construction in Step 2.

If more than one atlas is proposed, provide the above information in separate blocks for each atlas/each organ site.

Sub-section B: Research Center Organization and Team Integration

Provide a concise description of the team structure of the PCA Research Center and explain 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, i.e., how the team brings complementary multidisciplinary scientific expertise required for the integration of multidimensional, multiparametric data to build the atlases to address the key research problems proposed; highlight 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; applicant's vision of integration of the components into a Research Center as an entity that would be greater than the sum of its individual parts in terms of ability to advance fundamental understanding of cancer initiation and progression through construction of the proposed human pre-cancer atlas(es); collective experience and capabilities in areas pertinent to leading, coordinating, managing and understanding the various needs of the team and the projects; and how the elements of the Research Center, including key personnel, will interact to realize this vision. Provide a strategy for integration of new investigators, technologies, and/or analytical approaches into the Research Center structure and environment. Without repeating information in other sections, explain how any ongoing grant-supported, institutional, and/or private sector resources can augment or complement resources for which funding from this FOA is sought.

Sub-section C: Research Units

Provide a succinct outline of the structure of each Research Unit (Biospecimen Acquisition, Processing and Classification Unit (Biospecimen Unit); Cellular, and Tissue Characterization Unit (Characterization Unit); Data Processing, Analysis, and Modeling Unit (Data Analysis Unit) based on the requirements described in the "PCA Research Center Capabilities" section earlier. Describe the workflow from sample acquisition to pathology examination, the acquisition of experimental data from molecular, subcellular, cellular to the tissue levels, including imaging analysis, all the way to data aggregation, analysis and modeling.

Sub-section D: Project Management Plan

In this sub-section, describe the following:

• Overall Center Milestones: Describe the timeline for the overall project/building the atlas with brief descriptions of how the goals of each of the proposed specific aims will be achieved annually. Specific aims themselves may not be regarded as milestones (unless they include quantitative endpoints). The overall milestones must be well-described, quantitative, and scientifically justified. Discuss the milestones as a means of judging the success of the proposed projects during the 5-year support.
• Interim Center Milestones: Define a clear set of tentative semi-annual milestones for the PCA 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 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. 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.
• 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; (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/).

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 PCA 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 PCA 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 PCA Research Center, applicants are expected to propose and budget for a Center Administrator to manage day-to-day operations.

Set-Aside Funds for Trans-Network Projects: A minimum of $200,000 per year (direct costs) 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 PCA Research 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 pre-cancer 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);
• Provide coordination among PCA Research Centers and with HTA Research Centers (agreed upon practices and principles, SOPs, CDEs, etc.), including management of set-aside funds;
• Provide coordination of HTAN meetings and teleconferences;
• Support planning and evaluation activities;
• Provide support to HTAN-DCC for data aggregation and integration from multiplatform data sources by generating a linked compendium of all data sources gathered across the Network;
• Ensure bidirectional exchange of findings and insights between the PCA and the HTA Research Centers.

Applicants must also review Section I. Funding Opportunity Description for expectations from the Administrative Core.

Sub-section A. Leadership and PCA Research Center Organization

Address the major responsibilities of the Administrative Core that are listed above. Outline the organization of the leadership structure and overall PCA 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

Describe the strategies for communication between:

• PCA Research Center leadership (multiple PD(s)/PI(s)) and key Research Center investigators within PCA Research Center and across the HTAN;
• PCA Research Center and the HTAN Data Coordinating Center;
• PCA Research Center and the NCI.

State who will be the lead for each level of communication.

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.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• 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.
• Unit Leads are expected to include investigators with hands on experience in collection, annotation and characterization of clinical biospecimens. The Unit should be staffed with clinician(s), surgeon(s), pathologist(s) and personnel with expertise in molecular pathology. 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: Outline specific aims for the Biospecimen Acquisition, Processing, and Characterization Unit (Biospecimen Unit) and provide a rationale and description of how each aim addresses a specific aspect of the proposed human pre-cancer 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.

If proposing more than one human pre-cancer atlas within the application, applicants can duplicate the sub-sections as needed.

Sub-section A: Biological Rationale

Explain how the Biospecimen Unit will conduct collection of biospecimens necessary to support the construction of the proposed atlas(es). The description should address all expectations for the Biospecimen Unit stated in Section I. Specify the specimen types selected for construction of the proposed pre-cancer atlas. Provide a biological and statistical justification for collection frequency, sample type, and volume to be acquired that is motivated by the specific atlas being proposed by the PCA Research Center.

Sub-section B: Sample Acquisition, Processing and Characterization

The Biospecimen Unit is responsible for the first step towards building the precancer atlas and ensure success of other Units. The biospecimen science and biobanking practices play critical roles in sample collection and processing to ensure integrity of macromolecules, aid experimental design, and to generate more accurate and reproducible data. Erroneous information will be generated if the selection process for tissue is not managed well and inadequate amounts of sample are used to represent selected regions for morphologic and molecular/cellular analysis or an admixture of different cell types are used. Failure to adhere to rigid protocols for analyzing genomic, proteomic, epigenomic or other 'omic' profiles will result in biases and also lead to inaccurate or misleading analytical interpretation. Genetic/genomic observers often inaccurately assume that the used probe and associated data points are correct (i.e., reflect cellular biology and the tissue level) without examining the sample for viability (e.g., amount of necrosis, percentage of normal and tumor histology, tumor heterogeneity such as benign versus atypical versus neoplastic tumor tissue, or epithelial and stromal tissue ratios). Similarly, quantitative RNA assays, tissue-based protein measurements or other molecular assays are likely to be affected by sample age, sample processing and storage time. The Biospecimen Unit should define and follow best practice guidelines for sample collection, processing and storage (e.g., NCI Biorepositories and Biospecimen Research Branch's Best Practices). Quality assurance (QA) practices from tissue collection to molecular phenotyping are critical to implementing the pre-cancer atlas.

Provide a comprehensive roadmap for sample acquisition, processing, sample integrity, and characterization, including, but not limited to, the following:

• Describe acquisition of samples that are based on strong biospecimen science and biobanking practices.
• Describe the source of biospecimens, extensive annotation including anatomical location, and how all information will be preserved and shared with the Characterization and Data Analysis Units.
• Provide justification for sampling strategy (germline/somatic, retrospective/prospective, cross-sectional/longitudinal) with respect to the hybrid study design described in the Overall section. Whenever possible, investigators should include plans for collection of blood samples for germline DNA analysis.
• Describe the number and types of specimens that will be used and how those specimens will be acquired.
• Provide methods of sample collection, handling, preservation, processing, storage, rejection criteria and any other relevant points.
• Describe how tissue specimens to be used for pre-cancer atlas will be evaluated to ensure that morphologic and molecular characterizations match.
• Describe plans to work with Characterization Unit for standardization and optimization of pre-analytical variables.
• Describe how protocols and standards will be established to ensure molecular integrity and take quality control (QC) and QA considerations for providing reliable and accurate measures of biospecimen integrity.
• Describe how the biospecimens submitted to the Characterization Unit will be verified by a trained pathologist(s) to ensure that the samples meet the protocol guideline standards. Include parameters describing to what extent they are histologically homogeneous and what needs to be done if deviations from guideline standards occur.
• Describe how the Unit plans to work with other HTAN Biospecimen Units to develop appropriate SOPs and CDEs for specimen collection and processing.

If available, provide preliminary data demonstrating the various aspects of the proposed sample acquisition pipeline (programmatic priority may be given to applications with strong preliminary data for these aspects).

Sub-section C: Specimen Collection

Applicants must document their ability to recruit patients, procure specimens prospectively, collect epidemiological and clinical data using previously developed CDEs, for example, by the cancer Data Standards Registry and Repository (caDSR) or by the Early Detection Research Network (EDRN), and to process, track, and store specimens.

Describe in detail any proposed retrospective and/or prospective specimen collections, either new or ongoing, that will be used for PCA Research Center activities. Detailed specimen annotation is a requirement. The description should include information on the types of patients and control subjects to be accrued, clinical information to be collected, and types of specimens to be collected. Samples should be representative of the wide racial/ethnic diversity of the U.S. population. Active prospective collections can be proposed for studies proposed in this application and in collaboration with NCTN Clinical Trials Groups or any ongoing trials that provide a unique opportunity for prospective longitudinal collection of cancers (under the purview of the proposed Center) to ensure the success of the collaborative PCA/HTA research projects.

If the applicants already have existing biospecimen repositories that they are willing to make available for consortium collaborative studies, they should describe the purpose of the study(ies) from which samples are being made available and the extent of the clinical information collected. Sites with adequate existing repositories that will be available to the PCA/HTA Research Center investigators should furnish a list of types and number of specimens by organ site and provide information on histopathological stage and clinical grade, mode of detection, and the availability and length of follow-up data. A number of such resources could be also accessed through http://epi.grants.cancer.gov/biospecimens.html.

Applicants should describe the QA/QC procedures. The procedures and the documentation should include confirmation of pathology and radiology reports and inter-laboratory comparisons of test results and procedures. The applicants must discuss their experience with quality control issues and other considerations that may arise in multi-institutional studies. All new specimen collections and storage should follow the guidelines provided in NCI Biorepositories and Biospecimen Research Branch's Best Practices.

Sub-section D: Clinical Data and Metadata

Applications should include plans to collect appropriate epidemiological and clinical data that would best inform the atlas and interpretation of data from the atlas. The clinical and epidemiological variables include, but are not limited to, age, gender, race/ethnicity, exposure to risk factors, family disease history, method of diagnosis (screen-detected, symptom-detected, incidental etc.), histopathology etc.

Sub-section E: 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 semi-annual, quantitative benchmarks for each specific aim. Outline benchmarks with quantitative metrics that will document progress towards the achievement of the overall Center milestones. 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 PCA 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 commitment for resources and/or technology made available by the proposed collaborators.

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.
• 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. The Unit should include, but is not limited to, personnel with expertise pathology, molecular biology (omics), genetics, cell biology, immunology, imaging, imaging physics, bioengineering, quantitation and visualization approaches, etc.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

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: Outline specific aims for the Molecular, Cellular, and Tissue Characterization Unit (Characterization Unit) and provide a rationale and description of how each aim addresses a specific aspect of the proposed human pre-cancer 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 speak to the significance and innovation of the approach.

If proposing more than one human tumor atlas within the application, applicants can duplicate the sub-sections as needed.

Sub-section A: Biological Rationale

Explain how the Characterization Unit will approach conducting a multidimensional and multiparametric characterization of molecular, cellular, non-cellular and tissue components of pre-malignant lesions for selected organ site(s) using biospecimens procured by the Biospecimen Unit and state-of-the-art technologies. The description should address all expectations for the Characterization Unit stated in Section I.

Recent technological advances (e.g., next-generation sequencing [NGS], single-cell analysis, digital pathology etc.) can now yield high-resolution, large-scale, multidimensional information that can be collected, analyzed and visualized to discover/identify relationships associated with disease progression. Applicant must justify how the proposed pre-cancer characterization is crucial for understanding the transition of pre-cancers to malignant cancers in the select organ site(s). Also, describe how the different molecular, cellular and tissue maps will contribute toward constructing the proposed atlas(es).

Sub-section B: Molecular, Cellular and Tissue Characterization

The molecular characterization of tumors using multiple, high-throughput molecular platforms including NGS approaches for DNA and RNA sequencing, copy number variation, single nucleotide polymorphism (SNP) profiling, genome-wide DNA methylation profiling, microRNA profiling, proteomic profiling, etc. are quickly becoming an integral part of clinical decision making. However, each of these methods poses unique challenges. For example, cancer genomic profiling involves significant challenges including DNA quality and quantity, tumor heterogeneity, and the need to detect a wide variety of complex genetic mutations. Evaluation of RNA templates is increasingly important, as many tissue types, including formalin-fixed, paraffin-embedded (FFPE) materials, have been adapted to NGS platforms and technologies. The higher sensitivity of recent platform measures may accentuate the disparate reporting of findings and limit the analytical confidence. Molecular techniques have been plagued with reproducibility challenges, including the fact that parallel studies frequently identify different gene sets because of variations in sample processing, reagents, array platform, endpoints of interest, computational analysis method or software. In addition, cells in the microenvironment may affect heterogeneity of pre-malignant lesions and their progression to malignancy or regression. Although the importance of tissue context is clear, capturing such information in a rigorous and reproducible manner has been difficult or not possible thus far. It is expected that the applicants will take necessary measures to address the challenges and a plan for addressing potential pitfalls and challenges in the approach must be provided.

Because histopathological examination remains the gold standard for clinical diagnostics, applicants must describe plans for having the samples evaluated/verified by a trained pathologist(s)/molecular pathologist(s). The Characterization Unit should work closely with Biospecimen Unit regarding standardization, optimization and preservation of sample integrity submitted for molecular, cellular and tissue characterization. Appropriate controls must be used for all assays.

Applicants must provide a comprehensive roadmap for molecular, cellular and tissue characterization, including, but not limited to, the following:

• Describe how the molecular and cellular characterization plan can help develop an atlas that will provide an understanding of how pre-malignant lesions progress to cancer or regress, and enhance risk stratification, precision prevention and therapeutic intervention strategies.
• Describe how a multidimensional, multiparametric, multiscale, temporal characterization of the phenotype pre-cancer lesions, which includes the pre-malignant tumor itself and its surrounding ecosystem (immune cells, non-tumor cells, microbiome, acellular matrix and the tissue context), as well as spatial resolution, will be conducted.
• Describe how the Characterization Unit has the capability to address the challenges of assay design/analysis of pre-cancer lesions, and often very limited sample size, to reliably identify copy number alterations, actionable variants and other molecular alterations.
• Describe the best practices for the selected molecular analyses with least variability due to external and internal confounders (e.g., wired-in biases due to sample processing, batch effects, experimental reagents, study design, etc.). These will presumably have greater effect on analysis of RNA and labile proteins compared with DNA.
• Describe QA/QC considerations; describe a strategy to monitor and ensure the quality of instrument performance and data generated across the PCA Research Center. Applications should describe typical error rates for the proposed technology platforms to ensure data quality.
• Describe plans to work with Biospecimen Unit for standardization and optimization of pre-analytical variables. Applicants must consider all pre-analytics while designing their experiments and describe how this will be done.
• Describe plans for successful completion of Step 1 of the hybrid study design (see Overall), before progressing to Step 2.
• Applicants must follow the documented sources of variability by improved standardized procedures to ensure that appropriate samples are being analyzed when molecular and imaging techniques are employed. Describe how this will be done.
• Describe plans to establish a tight integration between the Characterization Unit and the Data Analysis Unit to ensure adequate collection and sharing of metadata and experimental data for processing, analysis, and atlas-building activities.
• Include preliminary plans for coordinating data collection quality across the HTAN.
• Indicate how the Characterization Unit team will take advantage of the HTAN infrastructure to allow for alternative approaches or perspectives to be quickly employed.

Sub-section C: Preliminary Data

Use this sub-section to 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 projects 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.

Subsection-D: Benchmarks of Unit Progress

Applicants should provide a clear set of semi-annual, quantitative benchmarks for each specific aim. Outline benchmarks with quantitative metrics that will document progress towards the achievement of the overall Center milestones. 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 PCA 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 commitment for resources and/or technology made available by the proposed collaborators.

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.

Unit Leads are expected to include investigators with significant hands on experience in analysis of large-scale, 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.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

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: Outline specific aims for the Data Processing, Analysis, and Modeling Unit (Data Analysis Unit) and provide an overview of the final pre-cancer atlas(es) to be delivered by the PCA 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.

If proposing more than one human tumor atlas within the application, applicants can duplicate the sub-sections as needed.

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

Provide an overview of the various data processing, analysis, integration and modeling techniques that will be utilized within the Data Analysis unit to construct the dynamic, multidimensional, multiparametric pre-cancer atlas(es) that is searchable and scalable, and concentrating on the type of biological insight that can be gained through employment of those techniques. The description should address all expectations for the Data Analysis Unit as outlined in Section I.

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. Demonstrate the utility of the atlas(es) for developing risk stratification, precision prevention and/or therapeutic intervention strategies. Describe the clinical or biological insight that will be gained from the modeling effort and in understanding how pre-malignant lesions progress to malignancy or regress. Provide predictive accuracy of the modeling approach.

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.
• For case-control designs, provide clear definitions of whether matching is involved and what cofounders are adjusted for and why.
• 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 and Analysis

Describe how the Data Analysis Unit will conduct the following functions:

• Describe development of rigorous study design and study protocols applicable to multicenter collaborative studies (including robust data collection and quality control procedures) and strategy for management of data (statistical and computational analysis support, study design, informatics infrastructure).
• Describe and demonstrate any existing or proposed data processing pipelines to be employed within the PCA 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 PCA 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 field standard 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 pipeline (to demonstrate interoperability).
• Approaches for data analysis could include, but are not limited to: bioinformatic analysis of bulk and/or single- or near single-cell multiparameter -omics data, integrated analysis of disparate omics and imaging data types, advanced image analysis, radiomics analysis, other systems biology approaches to connect disparate data at multiple time and/or length scales.
• Describe how dynamic, multidimensional relationships will be reconstructed or maintained through the proposed analyses.

Provide a solid plan for visualization and image analytics approaches, which includes, but are not limited to, the following:

• Plans for registering data;
• Use of innovative algorithms for efficient large scale image recognition and reconstruction of high dimensional data based on digitized images (i.e. Very Deep Convolutional Neural Networks, Cellular Neural Networks, Swarm Optimization, Stochastic Optimization [James C. Spall algorithm]);
• Use of spatial statistics for quantification of individual images and arranging them into time-dependent sequences (i.e. autoregressive time series analysis);
• Plans for calculating association of time-dependent statistical characterizations extracted from sequences of images with other concurrent characterization gleaned from omics analyses, clinical data and demographics;
• Use of software for making case histories and flat images available to scientific community (i.e. standard tools of Google BigQuery).

Sub-section D: Atlas Construction

The ability to collect complex interactions in space and time at single-cell resolution and use computational methods for large scale analysis of digitized images, intracellular dynamics, comprehensive molecular data, epidemiological, pathological, and other medical record information, metadata and all clinical annotations will be the foundation to build pre-cancer atlases in a format that is searchable and scalable and can be integrated with atlases generated by the HTA Research Centers following a harmonized, standardized protocol. The atlas should enable improved risk assessments and clinical management decisions. The applicant must provide a comprehensive roadmap to atlas construction, including, but not limited to, the following:

• Describe and demonstrate plans to aggregate and integrate multiparameter data and metadata from the broad range of experimental and computational approaches outlined throughout the application and creating a displayable pre-cancer atlas that describes the progression of pre-malignancy. This should include description of how dynamic spatial relationships will be constructed.
• High-throughput sequencing, large-scale data generation projects, and web-based cloud computing are changing how computational biology is performed, who performs it, and what biological insights it can deliver. Describe how the Data Analysis Unit will deploy sophisticated computational resources (e.g., tools for integrative computational analysis of large-scale datasets) to laboratory data tailored toward building the multidimensional atlas which will depict changes in molecular, cellular and non-cellular data over time.
• Describe how to test the performance of the atlas and how it could be interrogated.
• Describe the different levels of ontologies that will be utilized to describe information with the atlas.
• 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 E: 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 as aspect of the Data Analysis because the HTAN has not yet formed and the breadth of data types across the Network is currently unknown.

Subsection-F: Benchmarks of Unit Progress

Applicants should provide a clear set of semi-annual, quantitative benchmarks for each specific aim. Outline benchmarks with quantitative metrics that will document progress towards the achievement of the overall Center milestones. 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 PCA 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 commitment for resources and/or technology made available by the proposed collaborators.

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 components of participating organizations, 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.

Administrative Core will be evaluated by each reviewer but will receive only one overall adjectival rating.

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 strong is the evidence in the human pilot-level atlas for future expansion of the pre-cancer atlas(es)? What is the potential of the pre-cancer atlas(es), as proposed, to be adopted into routine clinical practice and help advance cancer early detection and precision prevention in the long run? Are novel markers and chemoprevention targets identified? Does the pre-cancer atlas(es) have potential to be useful to the diverse population of the U.S.?

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 investigators demonstrate significant experience with coordinating collaborative clinical research? How strong are the backgrounds, expertise, and commitments of the PD(s)/PI(s) and other key personnel? Are they sufficient for the proposed scope of activities and in line with the overall goals of the PCA Research Centers and the HTAN? Do the research experience and qualifications of the PDs/PIs, coinvestigators and other personnel demonstrate a strong understanding of the design, administration, and analysis of multi-institutional clinical research? Do the investigators have extensive expertise in human cancer biospecimen collection, handling, annotation, characterization and analysis of big data and data modeling? Has the applicant adequately addressed the institutional patent policy, if applicable? Are the PD(s)/PI(s) and other personnel well suited to their roles in the atlas building effort? Do the investigators have complementary and integrated expertise necessary for construction of pre-cancer atlas(es)?

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: Will the proposed pre-cancer atlas(es) be constructed using novel strategies for integrating and visualizing large-scale molecular, cellular, non-cellular and clinical datasets and/or predictive modeling?

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: How well do the preliminary data demonstrate the capabilities of the PCA Research Center for their proposed atlas building efforts? Is the rationale for the proposed organ site(s) based on the four criteria (impact on public health, access to technologies and biospecimens, feasibility of atlas construction, and synergistic partnerships for maximizing resources) outlined in the FOA? Is the proposed two-step hybrid design adequate for atlas construction? How valid and useful are the identified promising technologies in Step 1 of the hybrid design? How sound is the plan for patient recruitment, retention, and follow up, for high quality specimen collection, processing, and storage, and for obtaining high quality clinical and epidemiological information linked to specimens? Do appropriate quality assurance and quality control measures exist for technological platforms as well as biospecimens? How strong/adequate are the statistical study design and power calculations? Are institutional data management and statistical analyses, procedures, and policies adequate, appropriate, and consistent with accepted standards? How strong is the proposed atlas(-es)? Given the performance of the atlas(es) proposed that may be expected, what is the potential of the atlas(-es) to meaningfully contribute to/enhance cancer prevention and early detection efforts? Is there an adequate Project Management Plan that has the potential to lead to a successful atlas construction? Does the application contain acceptable plans for addressing the NCI Cancer Moonshot Public Access and Data Sharing Policy? If health disparity is one of aspects being addressed, are the plans adequate in terms of including data from appropriate subpopulations?

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 PCA Research Center? Will the scientific environment at the participating institutions stimulate multidisciplinary research collaborations? Are there any proposed partnerships with other endeavors toward mapping human tumors?

Integration

Will the proposed PCA Research Center be a truly integrated entity, rather than a collection of unrelated research ventures and support services? How well does the PCA Research Center organization promote scientific and administrative integration, synergy and a cohesive research goal? How well do the proposed interactions and collaborations between the PCA 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 applicants state their willingness to collaborate and share samples, data, software, and other resources within the PCA Research Centers and across the Network?

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:

• Is there adequate evidence for managerial and collaborative team-work experience of the proposed leadership? How strong are the leadership structure and activities of the proposed PCA Research Center in terms of facilitating: achievement of the overall goals of the PCA Research Center; integration of multiple institutions participating in a given pre-cancer atlas project; effective interaction, coordination and collaboration across HTAN?

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?
• How strong are the biospecimen science and biobanking practices? 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?
• Are there adequate QA/QC measures to address all pre-analytical variables?
• Are there plans for coordination with other Units for defining pre-cancers, phenotypic characterization and clinical annotation?
• How likely is it to develop a successful pre-cancer atlas based on the type and quality of the biospecimens procured by this Unit?
• If the investigators have proposed prospective collection of biospecimens, will the accrual of samples support atlas building activities within the proposed timeframe of the funding period?
• 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?
• How strong is the plan for histopathological examination?
• How comprehensive is the molecular, cellular and tissue characterization plan?
• How well is the two-step hybrid study design developed? Is there adequate evidence for technology validation before progressing to Step 2 with prospective biospecimens?
• 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?
• 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 strong is the proposed pre-cancer atlas(es)? How strong are the scalability and searchability features of the atlas(es)? Are the plans for assessing atlas(es) performance sufficiently rigorous?
• 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 how premalignant lesions progress to 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?
• How well will particularly risky aspects of the study be managed?
• How well 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 PCA 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 PCA Research Center a minimum of 1.2 person-months of effort per year for any investigator designated as a multi-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 as requested.
• 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 progress reports and 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 PCA 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 chairperons 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

Sudhir Srivastava, Ph.D., M.P.H. (For inquiries on atlas construction)
Division of Cancer Prevention, NCI
Telephone: 240-276-7028
Email: NCI_HTAN_PCAU2C@mail.nih.gov

Sharmistha Ghosh-Janjigian, Ph.D. (For inquiries specific to the FOA)
Division of Cancer Prevention, NCI
Telephone: 240-276-7122
Email: NCI_HTAN_PCAU2C@mail.nih.gov

Jacob Kagan, Ph.D. (For inquiries on technology)
Division of Cancer Prevention, NCI
Telephone: 240-276-7027
Email: NCI_HTAN_PCAU2C@mail.nih.gov

Richard Mazurchuk, Ph.D. (For inquiries on imaging and data visualization)
Division of Cancer Prevention, NCI
Telephone: 240-276-7126
Email: NCI_HTAN_PCAU2C@mail.nih.gov

Asad Umar, Ph.D., D.V.M. (For inquiries on clinical aspects)
Division of Cancer Prevention, NCI
Telephone: 240-276-7070
Email: NCI_HTAN_PCAU2C@mail.nih.gov

Lambratu Rahman Sesay, Ph.D.
Scientific Review Officer
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.