Required Application Instructions

It is critical that applicants follow the 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). 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

A critical unmet need in the management of malignancies (e.g., breast, prostate, lung, and pancreas cancers, and melanoma) are minimally invasive methods that predict whether a screen-detected lesion is indolent, requiring only careful monitoring, or progressive, thus requiring appropriate intervention. The goal of this initiative is to achieve comprehensive cellular and molecular characterizations of early lesions, including the tumor cell and its microenvironment, and to identify features that distinguish indolent from aggressive and/or progressive lesions.

This Funding Opportunity Announcement (FOA) solicits applications from multi-disciplinary teams to undertake a comprehensive characterization of tumor cell and microenvironment components of screen-detected early cancers, interval cancers, and symptom-detected cancers. The development of such studies will include: 1) establishing a biorepository (from existing or new collections), in which specimen annotation includes whether the lesion was detected by screening or due to symptomatic clinical presentation; and 2) determining distinguishing molecular and cellular characteristics of screen-detected lesions and/or surrounding tissue environment compared with interval and symptom-detected cancers.

Projects are expected to pursue one or more aspects of cellular or molecular analysis of one or more of the specified tumor sites (breast, prostate, lung, pancreas, melanoma). Use of enabling approaches and technologies (e.g., genomics, epigenomics, proteomics, imaging, single cell analyses, laser capture micro-dissection, and patient-derived xenografts) will be encouraged to determine both the cellular and molecular phenotypes of cancer and stromal cells, to assess the degrees to which the behaviors of these early lesions are predictable or stochastic, and to allow better predictions of the fate of early lesions.

To achieve the goal of a comprehensive characterization of screen-detected lesions, each research team should include: cancer biologists with expertise in molecular and cellular characterizations; clinicians; pathologists; imagers; statisticians and epidemiologists as appropriate.

The individual research teams funded through this FOA are expected to participate in a collaborative Consortium. In addition to individual research projects, a major collaborative effort will be the establishment of an annotated biospecimen repository of screen-detected lesions and interval cancers. Research teams will also be expected to share results freely within the Consortium, and develop trans-Consortium collaborative projects that make use of the combined expertise and technological capabilities present in all of the programs. In the final selection of the programs to be funded under this initiative, the NCI will, if possible, attempt to ensure that most of the specified tumor sites are represented.

The teams funded under the auspices of this Consortium will be expected to participate in collaborative efforts in the planning and development of resources and reagents necessary for the characterization of screen-detected lesions that will be made available to the broader research community. Collaborative arrangements with other Federal and State programs, supporting autopsy-based sample collections, are also anticipated through interagency agreements. Examples of collaborative efforts to be undertaken by the Consortium may include establishing repositories and generating and distributing novel reagents such as stromal markers and cell lines, or the development of novel technologies that distinguish indolent from progressive lesions. Collaborations with other NCI Programs [e.g., Early Detection Research Network (EDRN; www.cancer.gov/edrn), Tumor Microenvironment Network (TMEN; http://tmen.nci.nih.gov), Breast Cancer Surveillance Consortium (BCSC; http://breastscreening.cancer.gov), Prostate, Lung, Colorectal and Ovary Screening Trial (PLCO; www.plcostars.com), Population-based Research Optimizing Screening through Personalized Regimens (PROSPR; http://appliedresearch.cancer.gov/networks/prospr) are highly encouraged.

This initiative is intended to support a network of approximately eight to ten multi-disciplinary, multi-institutional research teams (Molecular Characterization Laboratories or MCLs). Each team will receive funding for research projects, as described above. Additional funds in the form of administrative supplements may be provided to support collaborative projects developed within the Consortium. Such an infrastructure is intended to provide a novel and essential venue to facilitate interdisciplinary collaborations and progress, and to make information on molecular and cellular characteristics of early lesions accessible to the broader research community.

The core members of the Consortium will be the investigators funded via this initiative, but may be expanded to include investigators already supported by other mechanisms (e.g., R01s and P01s, NIH intramural investigators). Through the Consortium, the individual research teams and thereby the investigators, will have access to resources, information, technologies, ideas, and expertise that are beyond the scope of any single research team. Individual teams funded through this initiative will operate independently, but will be linked through a central focus on characterizing screen-detected early lesions, a common bioinformatics infrastructure, a shared repository of screen-detected and interval lesions, and a Steering Committee. For this purpose, a Coordination and Data Management Group (CDMG) will also be established. Members of the CDMG will work with the MCL teams to ensure that future data are collected according to established protocols and Standard Operating Procedures (SOPs), Common Data Elements (CDEs), etc. NCI staff will provide oversight and help manage Consortium activities.

In addition to the establishment of standards for data collection on specimens, subject accruals, and clinical attributes, a coherent and comprehensive strategy is expected for study design for the discovery of intra- and inter-cellular molecular interactions and metabolic pathways relevant to screening. The Steering Committee of the Consortium will have the responsibility for the scientific management and oversight of all Consortium activities. The details on the SC are provided in Section VI. 2. Cooperative Agreement Terms and Conditions.

The FOA plans to establish Molecular Characterization Laboratories (MCLs) for cellular, molecular, and systems studies toward developing signatures to distinguish early lesions from interval and symptom-detected tumors. MCLs will form the main scientific units of the Consortium. The responsibilities of MCLs are to conduct molecular characterization of screen-detected lesions from one of the specified tumor sites, including human breast, lung, or prostate cancer, or melanoma compared to symptomatic, interval cancers. In the context of this FOA: screen-detected cancer refers to cases detected as part of the existing routine screening; interval cancers refers to cases diagnosed after a negative screen typically by symptom; and symptom-detected refers to non-screening to cases not undergoing screening and presenting with symptoms or diagnosed through incidental procedure and without symptoms.

This FOA will also entertain applications on other cancer types for which there is no widespread screening in place, but which may serve as biological models for studying progression of early preneoplastic lesions. For example, preneoplastic lesions are often found in the pancreas, including pancreatic intraepithelial neoplasia (PanIN) and pancreatic cystic neoplasms. The progression rates of these lesions are ill-defined, and the resulting uncertainty may lead to overtreatment, including resection of the pancreas. To achieve the broad goal of distinguishing indolent from progressive lesions, the proposed research may include (but is not limited to) the areas listed below. However, it should be noted that the characterization of lesions alone in the absence of tissue or surrounding biological factors, such as microenvironment, genetic, nutritional, and other relevant factors will not be considered responsive to the FOA.

Examples of specific research areas and types of characterizations appropriate for this FOA are listed below.

• Molecular comparison (genomic, transcriptomic, proteomics, or metabolomic) of recurrent and non-recurrent screen-detected lesions and interval cancers, to determine whether a subset of aggressive, screen-detected lesions shares features with interval cancers that likely indicate their rapidly progressing phenotypes.
  
  
• Analysis of tumor heterogeneity, including topographic variation within lesions, by single cell analyses, to determine whether lesions can be distinguished based on the extent of their heterogeneity in relation to immune infiltrates, matrix components, fibroblast/stromal cell features, adipose, vessels, etc.
  
  
• Phenotyping of cellular components of lesions, including tumor cells and the microenvironment. This activity may require the development of novel panels of reagents that specifically identify distinct subsets (e.g., antibodies) and methods to analyze small amounts of human tissue samples. The goal is to generate molecular signatures to detect early malignant lesions associated with increased case fatalities.
  
  
• Detection of secreted factors in tumor microenvironment and/or in serum specific to a subset of early lesions along with careful topographic tissue mapping to relate molecular characteristics of tumor to surrounding microenvironment or other features such as central necrosis, patterns of tissue invasion.
  
  
• Generation of a repository of screen-detected lesions/cancers and interval cancers from existing repositories and from new, prospectively collected samples, as necessary; and a data management center for the annotation and distribution of biospecimens to other components of the Consortium. Prospective collection of specimens must be based on well-described and statistically justified study designs appropriate for the organ-site and type of cancer focused by the proposed research and correspondingly well-defined and accepted terms of "indolent" and "interval" lesions. The collection and assembly of such repositories must also follow previously established PRoBE study design principles and guidelines (J Natl Cancer Inst. 2008 October 15; 100(20): 1432 1438).
  
  
• Leveraging knowledge based on genome-wide chromosomal instability and genome-wide association studies (GWAS) to predict progression from benign to malignant cancers. Develop molecular tests based on already characterized regions of the genome that can potentially identify genes associated with risk of progression of very early lesions.
  
  
• Application of systems biology approaches and modeling using experimental data (genomics, epigenomics, proteomics, imaging, etc.) to define disease dynamics, e.g., trajectories of each of these lesions -- growth rate, genetic and phenotypic evolution, and corresponding risk of development of clinically significant malignancy. In cases where sequential imaging is possible, appropriate imaging approaches can assist in elucidating dynamic changes occurring during progressive disease and providing insights into molecular and cellular events intimately associated with lethal cancer versus non-lethal disease.
  
  
• In cases where preneoplastic specimens are not readily available, applicants can propose establishing novel mouse models, organoid cultures or patient-derived xenografts from screen-detected lesions which maintain the original architecture of the tumor in order to allow sufficient expansion for a detailed molecular analysis which could include:
  
  
• RNA expression profiles, non-coding RNA (ncRNA), proteomics, metabolomics, cell surface markers, secreted exosomes, and DNA methylation; and
  
• Analyses of both the cancer cell and cells of the microenvironment.
  
  
• With the advances made in genomic technologies using Whole Genome Sequencing (WGS) and Somatic Gene Alterations (SGA) one can develop phylogenies that infer the genomic ancestry of lesions which do or do not progress to cancer. These changes can be then modeled to investigate disease dynamics in space and time of a premalignant condition, which, under selective pressures of host and environmental risk and protective factors, progresses to cancer. How the selective forces and corresponding selected genotypes shape the evolution of a cancer during its progression to become invasive is of particular interest.

Potentially Useful Resources. Applicants responding to this FOA are strongly encouraged to take advantage of other available NCI-supported resources and relevant program. For example, applicants may use existing biospecimen collections such as those from the Prostate, Lung, Colon and Ovary (PLCO) Screening Trial (www.plcostars.com), National Lung Screening Trial (NLST; http://www.cancer.gov/clinicaltrials/noteworthy-trials/nlst), Women's Health Initiative (WHI; https://www.whi.org/SitePages/WHI%20Home.aspx), Carotene and Retinol Efficacy Trial (CARET; http://www.compass.fhcrc.org/caretweb/), etc. Potentially useful collaborations may involve such programs as NCI National Clinical Trials Network (NCTN, https://research.usc.edu/nci-national-clinical-trials-network-nctn-program/), The Tumor Genome Atlas (TCGA, http://cancergenome.nih.gov/). Other appropriate NCI-supported programs may include those engaged in mechanistic studies with potential to identify novel signaling and biochemical pathways to have broader applicability across different tumor types and determine the potential of these networks and pathways to detect and diagnose cancer, such as Tumor Microenvironment Network (TMEN; http://tmen.nci.nih.gov/Pages/Home.aspx), Integrative Cancer Biology Program (ICBP; http://icbp.nci.nih.gov/) etc.

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:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• 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
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

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.

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.

NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. 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:

Sudhir Srivastava, Ph.D., M.P.H.
Chief, Cancer Biomarkers Research Group
Division of Cancer Prevention
National Cancer Institute
9609 Medical Center Drive, Room 5E136, MSC 9790
Bethesda, MD 20892-9790 (for USPS Regular or Express delivery)
Rockville, MD 20850 (for non-USPS delivery)
Telephone: 240-276-7028
Fax: 240-276-7845
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• For this FOA, the Research Strategy must not exceed 30 pages.

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

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

a) The contact PD/PI must include a minimum of 1.8 person months of his/her time per year and all other PDs/PIs (if multiple) must include a minimum of 1.2 person months of their time per year to the award. This commitment cannot be reduced in later years of the award.

b) Applicants must budget for travel and per diem expenses for Steering Committee meetings. In the first year, applicants should plan for the PD/PI and an additional senior investigator to attend a Planning Meeting and two Steering Committee meetings. In the second and subsequent years, applicants should plan for the PD/PI and another investigator to attend two Steering Committee meetings per year.

c) Applicants must set aside 20 percent of their annual budgets from the second year onward for Consortium collaborative studies and/or for collecting specimens to fulfill specific Consortium needs.

The use of these set-aside funds will be restricted and must be reviewed and approved by the Consortium Steering Committee and then recommended to, and approved by the NCI for release from the individual awards. The set-aside amounts should be listed in the Other Expenses category under the heading Consortium Collaborative Funds. Applicants must budget for data collection on relevant common data elements (CDEs) for specimens during the course of study. For CDEs, please visit the caDSR website (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-semantics/metadata-and-models) and/or the EDRN website (http://edrn.nci.nih.gov/).

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

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

Specific Aims: Applicants must outline the scope of the proposed research and its relevance to a specific unmet clinical need in the management of human malignancies. The specific aims to be pursued and approach(es) to be employed must be also described in brief.

Research Strategy: Research Strategy must consist of the Sub-sections A-C outlined below.

Sub-section A. Overview

Outline the overall research theme of the proposed MCL. Highlight the potential to increase the understanding of the molecular and cellular factors distinguishing indolent from aggressive lesions, or screen-detected from symptom-detected, interval cancers. Address the overall translational potential and the relevance of the proposed studies to the clinical management of screen-detected versus interval cancers. Summarize the main strengths of the team in the context of these goals. In particular, address how the team ensures the complementary multidisciplinary scientific expertise required for integrated and comprehensive approaches to 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. This section should also clearly describe the formal organizational structure of the MCL, including lines of authority and responsibility, with particular attention to the relationship of the organizational structure to the MCL's major objectives. If applicable, describe any relevant partnerships or collaborations with the for-profit private sector. In structuring such partnerships or collaborations, applicants should take into account pre-existing intellectual property rights associated with the use of existing models/reagents and make appropriate licensing arrangements. Applicants and their technology licensing offices are encouraged to seek assistance as needed from the NCI Technology Transfer Branch (https://ttc.nci.nih.gov/) in determining whether such arrangements are appropriate and/or adequate.

Sub-section B. Research Project

Applicants must provide a brief description of the proposed project, as well as its Significance and Innovation in the context of a specific unmet clinical need in the management of human malignancies. Under "Background" applicants must address the current state-of-the-science of the fields of cancer detection, diagnosis, and prognosis, as well as the interaction of tumor cells with their microenvironment, including their preliminary findings as they relate to their proposed projects.

Approach. The proposed study may initially involve the analysis of biospecimens from patients with neoplastic lesions versus respective control biospecimens (case-control or cohort samples) and with adequate follow-up information. Applicants are strongly encouraged (and expected) to include in their team as a collaborator an investigator directly involved in relevant cohort studies. Such collaboration and the access to appropriate samples must be properly documented (see Letters of Support below). A study may involve the use of retrospectively and/or prospectively collected specimens. However, detailed eligibility criteria in reference to screen-detected, symptom-detected, and interval cancers must be defined and described. If the mode of detection was noted from other than the existing database, such as using questionnaire in face-to-face interview to collect demographics and mode of detection, the process should be described. Details should also be provided as to how the ascertainments were made for screen-detected and symptom-detected cases. If using retrospective cohorts (screening or treatment), criteria for eligibility and cohorts details must be provided along with detailed clinical information, such as data on follow-up: median (max) length of follow-up, which endpoints were ascertained (cancer progression, death, cause of death) and how the endpoints were ascertained; patient age; disease stage; tumor size; lymph node status; and any other relevant treatment details. In cases for which screen-detected versus symptom-detected cancer specimens are being assembled from different sources and populations in terms of geography, demographics, ethnicity, etc., applicants should address the possibility of potential biases in the study design to minimize such biases.

In addition, there should be clear statements of how tests for different potential microenvironments and other components related to tumors in screen-detected, symptom-detected, and symptom cancers are adjusted for multiplicity. It should be clear whether the proposed design is to control for family-wise Type I error rate or control false discovery rate. Also, there needs to be a clear statement of how statistical power is defined in multiple tests 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. Also, in case-control designs, there need to be clear definitions of whether matching is involved and what cofounders are adjusted for and why.

For cancer types for which there is no screening program in place, cross-sectional samples derived from routine examinations, e.g., community health providers, health maintenance organizations, etc., can be used, provided there were reasons for examinations, as well as presence of signs and symptoms before the testing event. In such situations, screen-detected and symptom-detected cases should be backed up by relevant follow-up data. In case of incidental findings, the case could be considered screen-detected if there were no associated symptoms. All of these approaches must have exclusion and inclusion criteria for selecting samples as cases or controls.

In cases where serial samples are not available, model systems (e.g., organoid cultures or xenografts) may be used to supplement experimental designs in humans. Autopsy specimens, especially for indolent cases, can also be used in experimental designs. In cases where autopsy series samples are proposed, procedures for acquiring samples and obtaining clearances from State and regulatory authorities, including those from an institutional review board (IRB), must be submitted.

Samples collected during the tenure of this funding must be deposited in the NCI-Frederick Central Repository Services facility for use as a shared-resource.

Sub-section C. Prospective Collection of Specimens

Applicants must document their ability to recruit patients, procure specimens prospectively, collect epidemiological and clinical data using previously developed (caDSR and/or EDRN) Common Data Elements (CDEs; http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-semantics/metadata-and-models; http://www.compass.fhcrc.org/edrnnci/bin/cde/DESearch.asp), and to process, track, and store specimens. Applicants should describe in detail any proposed retrospective and/or prospective specimen collections, either new or ongoing, that will be used for Consortium activities. 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. Active prospective collections can be proposed only 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 for major epithelial cancers to ensure the success of the collaborative Consortium research projects. If the applicants already have specimen repositories that they are willing to make available to Consortium collaborative studies, they should describe the purpose of the study(s) 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 Consortium 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 procedures for quality control and quality assurance. 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 the National Cancer Best Practice for Biospecimen Resources, which is available at http://biospecimens.cancer.gov/practices/default.asp.

Letters of Support: In addition to letters from collaborators and consultants, applicants must include letters provided by biospecimen repositories or cohorts on specimens and associated information available for the purpose of the proposed studies. Letters of collaborations from investigators directly involved in relevant cohort studies should clearly indicate their planned commitment level (in person-month) to the MCL.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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.

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 conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). 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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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.

Important reminders:
All PD(s)/PI(s) 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. See Section III of this FOA for information on registration requirements.

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. 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 by the Center for Scientific Review and responsiveness by the NCI, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project 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 project 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 project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project 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?

In addition, specific for this FOA: How significant is the theme of the proposed MCL to the understanding of the molecular and cellular factors distinguishing indolent from aggressive lesions, or screen-detected from symptom-detected, interval cancers? If the aims of the application are achieved, what is the likelihood that the findings will have a significant translational effect? How relevant are the proposed studies to the clinical management of screen-detected versus interval cancers?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

In addition, specific for this FOA: How appropriate are the expertise and experience of the PD/PI(s) and other researchers in the context of research on indolent versus aggressive tumor lesions and the understanding of the molecular and cellular factors distinguishing these lesions?

Does the investigative team bring sufficient complementary multidisciplinary scientific expertise required for integrated and comprehensive approaches to key research problems proposed?

Do the team members have a relevant record of collaborations within and outside the applicant institution? Does the team have the expertise to collect specimens, an important requirement of this FOA? Is the commitment of the PD(s)/PI(s) and other senior investigators adequate?

Innovation

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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?

In addition, specific for this FOA: How adequate are plans for flexible exploitation of emerging research opportunities? Are the planned activities sufficiently trans-disciplinary and scientifically well integrated? To what degree, does the applicant team take advantage of a collaborative and interactive model of research? Are the structure and activities planned for the MCL adequate for the needs of the proposed studies and the anticipated trans-Consortium activities?

How adequate are plans for prospective collection and use of specimens within the context of screen-detected and interval cancers?

If the project 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?

Environment

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?

In addition, specific for this FOA: How adequate are plans for flexible exploitation of emerging research opportunities? How likely is the proposed MCL to contribute unique expertise, capabilities, and/or resources to the entire Consortium?

Does the team have the resources to collect specimens, an important requirement of this FOA?

As applicable for the project 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.

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children

When the proposed project 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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project 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.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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 NCI, 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.

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 appropriate national Advisory Council or 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. During the final selection of the teams to be funded through this FOA, NCI will, if possible, attempt to ensure that most of the specified tumor sites are represented.

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.

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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:

The PD/PI (or multiple PDs/PIs, if applicable) under the Consortium auspices will have primary responsibilities in the following areas:

• Defining objectives and approaches, overseeing planning and conducting experiments, analyzing and interpreting results, and publishing reports of studies conducted under this award.
  
  
• Assuming responsibility and accountability to the applicant organization and to the NCI for the performance and proper conduct of the research in accordance with the terms and conditions of the award.
  
  
• Serving as voting members of the Consortium Steering Committee (the PD/PI and another senior investigator from each Consortium award (U01 or U24) will be required to attend Steering Committee meetings twice a year).
  
  
• Accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee to the extent consistent with applicable grant regulations;
  
  
• Coordinating efforts and cooperating with the other components of the Consortium and with NCI staff Members;
  
  
• Overseeing the implementation of the approved data sharing plan;
  
  
• Ensuring that experimental data and their format, analytical algorithms, computational modeling and visualizations, and other bioinformatics tools resulting from this FOA are compatible with the NIH-approved bioinformatics platforms, such as those designed and implemented by the NCI Center for Bioinformatics (http://cbiit.nci.nih.gov).
  
  
• The PDs/PIs and their awardee institutions will be accountable for implementing the approved research resource sharing plan.
  
  
• All institutions/organizations participating in the Consortium will be expected to share with each other knowledge, data, research materials, and any other resources necessary and relevant to the Consortium.
  
  
• Each Consortium awardee and the entire Consortium programmatic initiative will be subject to external evaluation (coordinated by the NIH). Consortium Awardees will be expected to participate in such evaluations.

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 HHS, PHS, and NIH policies.

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

Designated NCI Program Directors serving as Project Scientists/Coordinators will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

Main NCI responsibilities include the following:

• Coordinating and facilitating various activities of the CONSORTIUM programs;
  
  
• Participating in the activities of the Consortium Steering Committee;
  
  
• Serving as a liaison between the Steering Committee, the Consortium awardees, and the NIH;
  
  
• The NCI Project Coordinator(s), in cooperation with the NCI Center for Bioinformatics, will ensure that there are effective mechanisms to enable electronic communication among the Consortium components, and between the Consortium and the NCI;
  
  
• Assisting the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action;
  
  
• Assisting the investigators in avoiding unwarranted duplications of effort across the Consortium;
  
  
• Co-organizing and participating in the Consortium investigators meetings;
  
  
• Monitoring the scientific progress of individual Consortium awards and the entire program;
  
  
• Reviewing the compliance of Consortium awardees with the recommendations developed by the Steering Committee; and coordinating external evaluation of the Consortium.

The NCI reserves the right to adjust funding, withhold, suspend, or terminate the support to those Consortium awardee institutions that are unable to meet the performance requirements set forth in these Terms and Conditions of Award, or significantly change the level of performance.

The substantially involved NCI Project Scientist/Coordinators will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

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. A Program Official may also have substantial programmatic involvement (as Project Scientist/Coordinator). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NCI waiver as stated above.

Areas of Joint Responsibility include:
Steering Committee: The Steering Committee will be the main governing body for the Consortium, as defined below.

The Consortium Steering Committee will consist of the following voting members:

Two representatives from each Consortium award (the PD(s)/PI(s) or a PD/PI and a designated senior investigator) who will have one vote each; and

The two NCI Project Scientist/Coordinators (who will have one vote each for the NCI).

Additional NIH staff members may participate in Steering Committee meetings as non-voting members as needed (for example to provide additional expertise). The non-voting members may include representatives from NCI extramural divisions and a representative from the National Cancer Institute Center for Bioinformatics and Information Technology (NCI CBIIT).

The chair of the Steering Committee will be selected from the representatives of all awardees.

In addition, the chairs of each of the EDRN and TMEN programs or their designees will serve on the Consortium Steering Committee as ex officio members.

The Steering Committee will meet twice every year, at locations selected by the Steering Committee in consultation with the NCI.

Additional non-voting members to serve in an advisory capacity may be added to the Steering Committee as needed by a decision of the existing voting committee members.

The Steering Committee may decide to establish sub-committees for specific purposes. The NCI Project Scientists/Coordinators will serve on such sub-committees, as they deem appropriate.

The Steering Committee will have primary responsibility for:

Setting the overall research priorities for the Consortium; and identifying emerging research opportunities which can be best explored through a joint collaborative effort via the Consortium;

Serving as a nucleus for a broader outreach to the entire extramural research community investigating indolent versus aggressive cancers or cancers detected via existing screening programs or based on the appearance of clinical symptoms;

Optimizing the information flow among the funded programs and between the programs and NCI CBIIT, i.e., it will provide a central conduit for information dissemination to other NCI-funded programs and to the cancer research community; and

Promoting efforts to establish new reagents, methodologies, and/or experimental models to be shared among the Consortium members and with the research community at-large.

Joint Consortium Activities

A significant part of the Consortium will be Joint Consortium activities. While each funded MCL will be largely self-sufficient, investigators will be expected to devote a portion of their effort to participating in collaborative activities with other Consortium members. The individual MCLs will have access to resources, information, technologies, ideas, and expertise that are beyond the scope of any single research team. Awardees will be charged with developing collaborative projects, resources for the community, and where possible, Consortium-sponsored outreach activities. These efforts will require interaction and collaboration among Consortium-funded investigators and/or with other investigators. Support for these collaborative activities will be provided by the restricted funds of each UM1 award. The plans to use these restricted funds will be subject of review and approval by the Consortium Steering Committee and final approval by the NCI to release specific funds from the individual UM1 awards.

The Consortium will: provide an appropriate venue for close interactions among investigators; facilitate exchange of data and comparison of results obtained across a variety of tumors; and disseminate expertise that may be initially concentrated within a single MCL. The NCI will ensure common access to Consortium-generated resources and reagents for the broader cancer research community. The NCI will also encourage the Consortium members to interact with existing NCI-supported multidisciplinary teams, such as the Early Detection Research Network (EDRN), and the Integrated Cancer Biology Program (ICBP).

To facilitate communications among the participants in the Consortium and between the Consortium and the NCI, the NCI will establish and maintain an Internet-based information technology solution for rapid data and document transmission and electronic communications for the Consortium.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting; one NIH designee; and a third designee with expertise in the relevant area who is chosen by the other two. In the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: [email protected]

For questions related primarily to cancer prevention research, contact:

Sudhir Srivastava, Ph.D., M.P.H.
National Cancer Institute (NCI)
Telephone: 240-276-7028
Email: [email protected]

For questions related primarily to cancer biology research, contact:

Suresh Mohla, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6220
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Barbara Liesenfeld
National Cancer Institute (NCI)
Telephone: 240-276-6294
Email: [email protected]

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 Parts 74 and 92.