PKG00264821-instructions.pdf

Centers for Disease Control and Prevention

Agency for Toxic Substances and Disease Registry Extramural Research Program Office

Identify and Evaluate Potential Risk Factors for Amyotrophic Lateral Sclerosis (ALS)

RFA-TS-21-001

Application Due Date: 03/29/2021

Identify and Evaluate Potential Risk Factors for Amyotrophic Lateral Sclerosis (ALS)

RFA-TS-21-001

TABLE OF CONTENTS

Part 1. Overview Information Key Dates Required Application Instructions Executive Summary

Part 2. Full Text 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

Part 1. Overview Information Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations Agency for Toxic Substances and Disease Registry Notice of Funding Opportunity (NOFO) Title Identify and Evaluate Potential Risk Factors for Amyotrophic Lateral Sclerosis (ALS) Activity Code Applications in response to this NOFO will be funded using the R01 activity code.

Notice of Funding Opportunity Type New Agency Notice of Funding Opportunity Number

RFA-TS-21-001

Assistance Listings (CFDA) Number(s) 93.161 Category of Funding Activity:

Health NOFO Purpose The Agency for Toxic Substances and Disease Registry (ATSDR) is seeking investigator initiated research that will further the understanding of potential risk factors for ALS, while supporting the ATSDR National ALS Registry's mission. The National ALS Registry's goals are to estimate the number of new ALS cases each year, estimate the number of people who have ALS at a specific point in time, better understand who gets ALS, and identify what contributing factors, including environmental, may affect ALS. ATSDR is seeking investigator-initiated research that will identify and evaluate risk factors contributing to ALS, with preferred focus in this Notice of Funding Opportunity on factors related to military service, contact sports, traumatic brain injury, neuroinflammation and infectious agents.

Key Dates Publication Date: To receive notification of any changes to RFA-TS-21-001, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link. An email address is needed for this service.

Letter of Intent Due Date: 02/05/2021 Letters of Intent are requested by February 5, 2021. Although a letter of intent is not required to apply to this NOFO, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows ATSDR staff to estimate the potential review https://www.grants.gov workload and plan the review.

Application Due Date: 03/29/2021 Applications are due March 29, 2021 at 5:00PM EST. Please carefully review and follow the instructions in Section IV. Application and Submission Information 9. Submission Dates and Times in order to ensure timely receipt of your application by March 29, 2021 at 5:00PM EST.

On-time submission requires that electronic applications be error-free and made available to CDC for processing from the NIH eRA system on or before the deadline date. Applications must be submitted to and validated successfully by Grants.gov no later than 5:00 PM U.S.

Eastern Time. Applications must be submitted using the Application Submission System & Interface for Submission Tracking (ASSIST) module which is a web-based service used for the preparation and submission of grant applications to CDC through Grants.gov. ASSIST provides the ability for applicants to prepare their applications online, and offers the applicant additional capabilities including the ability to preview the application image, validate the application against required business rules, and prepopulate data from an applicant organization's records, therefore identifying issues earlier in the application submission process.

Note: HHS/CDC grant submission procedures do not provide a grace period beyond the application due date time to correct any error or warning notices of noncompliance with application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review: 07/13/2021 This date is an estimate.

Secondary Review: 07/26/2021 This date is an estimate.

Estimated Start Date: 09/30/2021 Estimated start date is September 30, 2021.

Expiration Date: 05/12/2021 Due Dates for E.O. 12372: Due no later than 60 days after the application receipt date.

Required Application Instructions

**ELECTRONIC APPLICATION SUBMISSION VIA ASSIST IS PREFERRED**

It is recommended that applicants use ASSIST for the electronic preparation and submission of applications through Grants.gov to CDC. ASSIST is an alternative method to prepare and submit applications, and provides many features to facilitate the application submission process which improves data quality (e.g., pre-population of organization data, pre-submission validation of business rules, and preview of the application image used for review). Use of the Grants.gov downloadable Adobe application packages and submission process will still be supported.

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf in the Application Guide and the NOFO) 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.

Note: The Research Strategy component of the Research Plan is limited to 25 pages.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Pages that exceed page limits described in this NOFO will be removed and not forwarded for peer review, potentially affecting an application's score.

Telecommunications for the Hearing Impaired: TTY 1-888-232-6348

Executive Summary The Agency for Toxic Substances and Disease Registry (ATSDR) is committed to protecting people's health from environmental hazards by investigating the relationship between environmental factors and health, developing guidance, and building partnerships to support healthy decision making. The intent of the ATSDR extramural research program is to fund research that promotes healthy community environments by assessing the available scientific data to determine whether or not people are at risk because of their exposures to harmful chemicals in the environment.

Approximately 5-10% of ALS cases can be attributed to familial, or heritable, genetic mutations. However, the majority of ALS cases are sporadic, for which the underlying cause(s) are largely unknown, and for which a complex set of risk factors including genetic susceptibility, environment, time, and occupation may interact to produce clinical disease.

Many epidemiological investigations have shown a role for specific genetic mutations in multiple genes and exposures to persistent organic pollutants (POPs), organophosphate pesticides, and cyanobacteria.

Purpose: In this Notice of Funding Opportunity, ATSDR is seeking investigator-initiated research that will identify and evaluate risk factors contributing to ALS, with preferred focus on research proposals that will examine factors related to military service, contact sports, traumatic brain injury, neuroinflammation and infectious agents.

Past studies suggest that prior military service increases risk for ALS due to potential exposures to pollutants, radiation or explosion blast overpressure mediated traumatic brain injury (TBI).

Other studies have suggested a role for impact mediated TBI in the development of ALS, in the context of intense contact sports, possibly from the initiation of ALS related proteinopathies and/or dysregulated neuroinflammation leading to neuronal toxicity. Finally, studies have evaluated the role of infectious agents, include mycoplasma, neurotoxin producing cyanobacteria and fungi, and viruses in increased ALS risk. ATSDR seeks additional research to identify and determine how environmental and other factors may contribute to increased risk of ALS, with an emphasis on statistically well powered study approaches adequately controlling for potential biases and confounding factors.

This Notice of Funding Opportunity aligns with the National Center for Environmental Health (NCEH)/ATSDR 2014-2016 strategic plan, available at https://www.atsdr.cdc.gov/about/mission_vision_goals.html, and supports the specific ATSDR goal to identify, characterize, and monitor health outcomes and environmental exposures to guide actions that protect and promote health. Additional information about ATSDR priorities is available at https://www.atsdr.cdc.gov/about/docs/NCEHATSDR_priorities_2014_final.pdf.

Mechanism of Support: The funding mechanism for this Notice of Funding Opportunity (NOFO) will be a research grant.

Funds Available and Anticipated Number of Awards: ATSDR intends to commit approximately up to $2,500,000 in FY 2021 to fund up to five (5) applications. Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications. Because the nature and scope of the proposed research will vary from application to application, it is also anticipated that the size and duration of each award may also vary. The total amount awarded and the number of awards will depend upon the number, quality, duration and cost of the applications received and approved.

Budget and Project Period: The maximum award amount will be $500,000 per award for the first 12 month budget period. This includes both direct and indirect costs. An applicant may request a project period of up to three (3) years. The maximum total project funding amount is $1,500,000 (including both direct and indirect costs) over the expected three year project period length, with a maximum of $500,000 per award per year. The project period for this award is expected to run from 9/30/2021 to 9/29/2024. Throughout the project period, ATSDR's commitment to continuation of awards will be conditional on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and the determination that continued funding is in the best interest of the Federal government.

Application Research Strategy Length: Page limits for the Research Strategy are clearly specified in Section IV. Application and Submission Information of this announcement.

Eligible Institutions/Organizations: Institutions/organizations listed in Section III. Eligibility Information 1. Eligible Applicants are eligible to apply.

Eligible Project Directors/Principal Investigators (PDs/PIs): Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. NOTE: CDC/ATSDR does not make awards to individuals directly.

Early Stage Investigators Applications in which the contact Eligible PD/PI meets NIH Early Stage Investigator (ESI) status, as verified via the NIH Determination of Investigator Status process, and whose application has a meritorious peer review score, may be considered for prioritization during the second level of review (see Section V. Application Review Information Part 4. Review and Selection Process). For the contact PI/PD Determination of Investigator Status:

Prior to application submission, PD/PIs are encouraged to verify and/or enter the date of their terminal research degree or the end date of their post-graduate clinical training in their eRA Commons Profile to ensure the correct identification. NIH systems will automatically calculate the status of each investigator and display it within their eRA Commons personal profile. The ESI status of the PD/PIs on any R01 or R01 equivalent application will be flagged at time of submission. Investigators should make sure their status is correctly marked in their profile. If your status is incorrect, please contact the NIH eRA Service Desk.

Number of PDs/PIs: An application may name more than one PD/PI; their names must appear on the face page of the application. However:

One (1) principal investigator must be designated as the contact PD/PI for all correspondence related to the application.

All PD/PIs must include their eRA Commons Identification in the Credential Field of the Senior/Key Person Profile Component of the SF424 (R&R) Application Package.

Institutions/organizations proposing multiple PDs/PIs must visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF-424 (R&R) Application Guide.

Number of Applications: Eligible applicant organizations may submit more than one application to this NOFO, provided that each application is scientifically distinct. However, applicant institutions can submit only one application with the same contact PD/PI. Only one application per contact PD/PI will be funded under this announcement. If two or more applications from the same contact PD/PI are received for this NOFO, the only application that will be submitted for review will be the last application received based on the document’s time and date stamp in Grants.gov (http://www.grants.gov). The applicant must ensure that duplicate applications are withdrawn prior to the application review date. Additionally, applicant institutions submitting applications with essentially the same proposed research to two or more CDC/ATSDR NOFOs will not be funded under more than one NOFO.

Application Type: NEW https://grants.nih.gov/policy/early-investigators/index.htm https://grants.nih.gov/policy/early-investigators/index.htm#dis https://grants.nih.gov/support/index.html

Special Date(s): A pre-application teleconference call will not be conducted for this NOFO.

Applicant questions to clarify information in the text of this NOFO during the NOFO open period are strongly encouraged. Please contact the Scientific/Research Contact, Peer Review Contact via email at NCIPC_ERPO@cdc.gov, or the Financial/Grants Management Contact listed in Section VII. Agency Contacts with questions. All applicant questions (redacted of personal or application related identifying information) received by February 1, 2021 and ATSDR responses to these questions will be included in an amended NOFO that will be published approximately by February 15, 2021. Please see Section VII. Agency Contacts for specific contact information.

Application Materials: See Section IV.1 for application materials.

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority This program is authorized under Section 399S of the Public Health Service Act, [42 U.S.C.

Section 280g-7], as amended.

1. Background and Purpose Amyotropic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive and often fatal neuromuscular disease that presents in familial (fALS) or sporadic (sALS) forms.

Almost 16,000 people in the U.S. lived with ALS in 2013 and most people die within two to five years of being diagnosed with the disease (Mehta et al., 2018). Approximately 5-10% of all ALS cases can be attributed to familial, or heritable, genetic mutations. However, the majority of ALS cases are sporadic, for which the underlying cause(s) are largely unknown, and for which a complex set of risk factors including genetic susceptibility, environment, time, and occupation may interact to produce clinical disease (Bradley, 2018; Oskarsson, 2018; Wang, 2016; Al-Chalabi, 2013). Studies have evaluated possible ALS risk factors including familial and sporadic genetic susceptibility, employment in certain occupations, exposure to heavy metals, cyanotoxins and infectious agents, physical activity, and trauma (Andrew, 2017;

Sutedja, 2009; Factor-Litvak, 2013; Bettencourt, 2015; Bradley, 2013; Watanabe, 2017; Pupillo, 2017; Fang, 2011). ATSDR is seeking investigator-initiated research that will identify and evaluate risk factors contributing to ALS, with preferred focus in this Notice of Funding Opportunity on factors related to military service, contact sports, traumatic brain injury, neuroinflammation and infectious agents.

Military Service Past population-based cohort studies provide limited and suggestive evidence of associations between military service in World War II and the Korean, Vietnam, and Gulf Wars and the development of ALS (Cragg, 2017; Beard, 2016; Weisskopf, 2015; Weisskopf, 2005; Horner, 2005; Haley, 2003). While the reasons for increased ALS risk among military veterans are unknown, selective environmental exposures to persistent organic pollutants, herbicides http://grants.nih.gov/grants/guide/pa-files/PAR-11-022.html#SectionIV1

(including Agent Orange), ionizing radiation, burn agents, cyanotoxins etc. may play a part in increased risk during military service (Beard, 2016; Oskarsson, 2015; Cox, 2009; Weisskopf, 2005). Additionally, duration of time served and exposure to repetitive explosion-mediated blast overpressure leading to traumatic brain injury (TBI) in combat settings may also contribute to ALS susceptibility and severity of disease (Beard, 2016; Heyburn, 2019). ATSDR seeks additional research to determine if and how these or other military service-related factors contribute to increased risk of ALS, with an emphasis on statistically well powered study approaches adequately controlling for potential biases and confounding factors (Academies IoMotN, 2006).

Sports and Traumatic Brain Injury Participation by athletes in certain contact sports is associated with an increased risk of developing ALS. Past studies cite intense physical activity, head and neck musculoskeletal trauma, and repeated concussions leading to mild, moderate, or severe TBI as potential contributing factors (Blecher, 2019; Gotkine M, 2014; Lehman EJ, 2012; Chio A, 2009; Chio A, 2005). However, it is unclear to what degree contact sports related trauma, and the severity and repetition of TBI, influence ALS development. Additional research is needed that examines the role of impact mediated TBI from participation in contact sports in the development of ALS, including consideration of differential diagnosis of and co-morbidity with ALS and chronic traumatic encephalopathy post-TBI (Walt, 2018; Lehman EJ, 2012). Research on TBI that investigates whether and how additional risk factors can work in concert with TBI to increase ALS risk is also sought. Such risk factors may include, but are not limited to, athletic exposure to playing field pesticides or grass or soil-associated infectious agents, the intensity of physical activity, and athlete participant demographics including pre-existing genetic susceptibility, gender, and age at the time of exposure (Franz, 2019).

Neuroinflammation and Infectious Agents Neuroinflammation is a primary cause of secondary brain injury following TBI. Emerging research suggests that neuroinflammation, including dysregulated innate immune system activation, may contribute to the development of ALS through neuronal toxicity (McCauley, 2018; Kjaeldgaard, 2018). Research evaluating the role of TBI in neuroinflammatory and innate immune response pathways in the development of ALS, including identification of relevant inflammatory and immune biomarkers in persons with ALS, is sought. Past studies have suggested that exposure to microbial infectious agents, including mycoplasma, cyanobacterial neurotoxins, fungal neurotoxins, and viruses, may be a risk factor for ALS (French, 2019;

Douville, 2011; Caller, 2009; Cox, 2009; Nicolson, 2002). ATSDR solicits further research on the etiologic role that infectious agents may have in contributing to ALS, including their impact on neuroinflammation and innate immune response activation.

ATSDR National ALS Registry Uncertainty about the incidence and prevalence of ALS, the etiology of the disease, and risk factors associated with disease development and progression created a need for structured data collection. The ALS Registry Act (P.L. 110-373 (2008)), passed in October 2008, amends the Public Health Service Act to require the Secretary of DHHS, acting through the Director of CDC, to (1) develop a system to collect data on ALS; and (2) establish a national registry for the collection and storage of ALS data. In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR), in partnership with the Centers for Disease Control and Prevention, launched the National ALS Registry to collect data that would:

describe the incidence and prevalence of ALS in the US;

examine factors such as environmental, occupational, genetics, that might be associated with the disease;

better outline key demographic factors (such as age, race or ethnicity, gender, and family history of individuals who are diagnosed with the disease) associated with the disease;

and facilitate examination of the connection between ALS and other motor neuron disorders that can be confused with ALS, misdiagnosed as ALS, and in some cases progress to ALS.

ATSDR National ALS Registry data are available for researchers to identify potential risk factors for ALS. Applicants are encouraged to consider submitting proposals on research topic areas not currently funded by the ATSDR National ALS Registry. ATSDR is especially interested in innovative research applications that propose to conduct an epidemiological investigation using the ATSDR National ALS Registry and/or using a third party ALS registry on risk factors related to military service, contact sports, traumatic brain injury, neuroinflammation and infectious agents. Examples of ALS registry research previously funded by ATSDR can be found at https://www.cdc.gov/als/ALSExternalResearchfundedbyReg istry.html.

For NOFO RFA-TS-21-001, through the use of human ALS epidemiological data sources, including those that contain information on potential environmental, demographic, occupational, behavioral and familial associations, and through the use of epidemiological, environmental health, and laboratory research approaches, applications funded under this NOFO must address both of the following objectives:

Objective One: Identify potential risk factors for ALS in humans including, but not limited to, risk factors listed below:

environmental and occupational risks, including from past military service traumatic brain injuries, including blast or impact TBI associated with military service or contact sports injury or microbial infection (e.g., bacterial, fungal, viral) resulting in neuroinflammation or innate immune system activation nutritional intake, and https://www.cdc.gov/als/ALSExternalResearchfundedbyRegistry.html https://www.cdc.gov/als/ALSExternalResearchfundedbyRegistry.html pharmaceutical use (e.g., statins)

Objective Two: Characterize how or why the(se) risk factor(s) are potentially associated with or contribute to the etiology, progression, and pathophysiology of ALS in humans.

Research funded under this NOFO is expected to be innovative and produce outcomes that will help ATSDR better understand the etiology and epidemiology of ALS, prioritize topics for future research initiatives, and inform the development of new ATSDR ALS Registry risk factor surveys for persons with ALS.

Healthy People 2030 and other National Strategic Priorities ATSDR is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2030" and to measuring program performance as stipulated by the Government Performance and Review Act (GPRA). This research NOFO directly supports the DHHS Healthy People 2030 goals and objectives as described in: http://www.healthypeople.gov/.

The proposed program of research addresses the Healthy People 2030 priority area of environmental health infrastructure and surveillance and is in alignment with ATSDR's performance goal to conduct a targeted program of research to identify, characterize, and monitor health outcomes and environmental exposures to guide actions that protect and promote health. Specifically this research NOFO supports the Healthy People 2030 goal to promote healthier environments and Healthy People Objective EH-06 to reduce the amount of toxic pollutants released into the environment.

Public Health Impact The public health impact of applications funded under RFA-TS-21-001 will result in the addition of new information to existing literature on epidemiological associations between environmental and other risk factors and ALS and a stronger understanding of the etiology of ALS pathogenesis. Research outcomes will help ATSDR prioritize topics for future National ALS Registry research initiatives and the ALS Registry risk factor surveys.

Relevant Work The ALS Registry Act (P.L. 110-373), passed in October 2008, amends the Public Health Service Act to require the Secretary of DHHS, acting through the Director of CDC, to (1) develop a system to collect data on ALS; and (2) establish a national registry for the collection and storage of ALS data. ATSDR, in coordination with CDC, launched the National ALS Registry in October 2010. The Registry tracks ALS cases in the United States by using existing national administrative databases and a secure web portal that allows patients to self-enroll and take brief risk factor surveys. ATSDR released the first National ALS Registry Report in July 2014 (covering 2010-2011), the second National ALS registry Report in August 2016 (covering 2012-2013), and the third National ALS registry Report in February 2018 (covering 2014).

References:

http://www.healthypeople.gov/

1. US Public Health Service. ALS Registry Act. Washington, DC: 110th Congress. Public Law 2008;122 Stat 4047:110-373.

2. Mehta, P; Kaye, W; Raymond, J; et. al.; Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. MMWR February 23, 2018; 67(7):216?218

3. Mehta, P; Kaye, W; Bryan, L; et. al.; Prevalence of Amyotrophic Lateral Sclerosis: United States, 2012-2013. MMWR August 5, 2016; 65 (8); 1-12

4. Mehta, P; Antao, A; Kaye, W; et. al.; Prevalence of Amyotrophic Lateral Sclerosis: United States, 2010-2011; MMWR July 25, 2014; 63 (SS07); 1-14

5. Horton DK, Mehta P, Antao VC. Quantifying a nonnotifiable disease in the United States: the National Amyotrophic Lateral Sclerosis Registry model. JAMA 2014;312:1097-8.

6. Bryan L, Kaye W, Antao V, Mehta P, Muravov O, Horton DK. Preliminary results of National Amyotrophic Lateral Sclerosis (ALS) Registry risk factor survey data. PLoS One 2016;11:e0153683.

2. Approach ATSDR is soliciting innovative investigator-initiated research that will help expand and advance our current knowledge of the role that potential risk factors, including environmental risk factors, may have on ALS etiology, with special emphasis on identification and evaluation of ALS risk factors related to military service, contact sports, traumatic brain injury, neuroinflammation and infectious agents.

It is expected that the application's research plan will reflect rigorous quantitative and qualitative experimental designs and include data analytic plans that are appropriate to the research design and hypotheses, data collection measures, and project period. The experimental approach should anticipate and evaluate the effects of methodological challenges to the internal and external validity of the specified research design. The statistical power for investigations must be sufficiently high to provide meaningful toxicological and epidemiological analyses.

Research approaches may include, but are not limited to: population-based case-controlled epidemiological studies, including direct and indirect exposure assessments and dataset analyses, environmental toxicant composition and concentration analyses in human biospecimens; genome wide association and next generation sequencing studies; and molecular, histological and computational analyses of phenotypic biological effects (including biochemical, genetic, epigenetic, and physiological) that can help identify potential risk factors for ALS in humans and evaluate how or why the(se) risk factor(s) are potentially associated with or contribute to the etiology, progression, and pathophysiology of ALS in humans.

ALS case control studies and epidemiological datasets: Prospective cohort studies are preferred. Retrospective case-control studies and ecological studies may also be considered.

Analyses of existing ALS epidemiological datasets, such as from large observational studies, are acceptable. Datasets should be of sufficient size to support robust analyses. ALS epidemiological data may include environmental, demographic, occupational, behavioral and familial risk factors, etc. as appropriate for the research plan. ALS epidemiological data may be provided by the applicant and/or may be requested from the ATSDR National ALS Registry.

Use of the ATSDR National ALS Registry: ATSDR National ALS Registry data are available for researchers to identify potential risk factors for ALS. Use of the ATSDR National ALS Registry is not required for consideration of funding under this announcement. However, applicants are encouraged to include ATSDR National ALS Registry enrollees, as appropriate, in their research plans. Applicants are encouraged to consider submitting an application to use ATSDR’s ALS Research Notification tool to recruit ALS patients from the National ALS Registry, when applicable to the research plan, available at https://www.cdc.gov/als/ALSRegistr yResearchApplicationInfo.html (pending OMB re-authorization). The ATSDR ALS Research Notification tool will enable Registry grantees to receive email notifications about their approved studies sent to persons with ALS enrolled in the Registry. Applicants awarded a grant under NOFO RFA-TS-21-001 and who wish to use the ATSDR National ALS Registry will be required to enter into a Data Use Agreement (DUA) with ATSDR to protect the confidentiality of data in accordance with the terms of the DUA and applicable laws. Applicants may use, alone or in conjunction with the ATSDR National ALS Registry, applicant-provided or third-party sourced ALS and case-control registries in their research plans, as appropriate for their research proposals.

Use of the ATSDR National ALS Biorepository: Applicants should not submit proposals that intend to use biospecimens from the ATSDR National ALS Biorepository for the RFA-TS-21- 001 funding cycle. However, applicants may use applicant-provided or third-party sourced ALS biospecimens in their research plans, as appropriate for the research design. Applicants using applicant-provided or third-party sourced ALS biospecimens must include, as part of their research plan, use of a matched ALS epidemiological registry for identification and evaluation of ALS risk factors. The statistical power for the applicant-provided or third-party sourced ALS biospecimen repository must be sufficiently high to provide meaningful epidemiological analyses.

Applications must be responsive to NOFO RFA-TS-21-001 in order to be forwarded for peer review. Responsiveness criteria are listed in Section III. Eligibility Information 5.

Responsiveness of this NOFO. It is the applicant’s responsibility to ensure that the submitted research proposal meets all responsiveness criteria listed in Section III. Eligibility Information

5. Responsiveness.

Objectives/Outcomes For NOFO RFA-TS-21-001, through the use of human ALS epidemiological data sources, including those that contain information on potential environmental, demographic, occupational, behavioral and familial associations, and through the use of epidemiological, environmental health, and laboratory research approaches, applications funded under this NOFO must address both of the following objectives:

https://www.cdc.gov/als/ALSRegistryResearchApplicationInfo.html https://www.cdc.gov/als/ALSRegistryResearchApplicationInfo.html

Objective One: Identify potential risk factors for ALS in humans including, but not limited to, risk factors listed below:

environmental and occupational risks, including from past military service traumatic brain injuries, including blast or impact TBI associated with military service or contact sports injury or microbial infection (e.g., bacterial, fungal, viral) resulting in neuroinflammation or innate immune system activation nutritional intake, and pharmaceutical use (e.g., statins)

Objective Two: Characterize how or why the(se) risk factor(s) are potentially associated with or contribute to the etiology, progression, and pathophysiology of ALS in humans.

Research funded under this NOFO is expected to be innovative and produce outcomes that will help ATSDR better understand the etiology and epidemiology of ALS, prioritize topics for future research initiatives, and inform the development of new ATSDR ALS Registry risk factor surveys for persons with ALS.

Target Population NOFO RFA-TS-21-001 supports the conduct of research that will benefit all persons with ALS and those at risk for developing ALS such as males, non-Hispanics, persons with a history of military service, and persons with a history of participation in contact sports. Although it is not required for consideration of funding under this announcement, applicants are encouraged to include the ATSDR National ALS Registry enrollees, as appropriate, in their research plans.

The ATSDR National ALS Registry tool for researcher access can be found at https://www.cdc.gov/als/ALSRegistryResearchApplicationInfo.html (pending OMB re-authorization).

Collaboration/Partnerships The application must include letters of support, or memoranda of understanding, documenting the proposed partnership(s). Specifically, for all collaborations, documentation must clearly describe the nature of the proposed partnership, including the roles and responsibilities of the Principal Investigator(s) and of the outside entities or partner agencies, the existing working relationship, plans for the proposed research, the nature and extent of the involvement to be provided by the applicant institution and outside entity, the outside entity's scope of work, and how the partnership will ensure implementation and sustainability of the proposed research plan. Applicants must describe all data sources and processes used to ensure data access.

Evidence of access to the data from outside entities may be demonstrated by data sharing agreements, memoranda of understanding, or Letters of Support detailing the data availability.

The proposed budget should include travel funding for research staff to directly meet with and monitor study implementation within both the program and partner sites if the sites are not local to the research investigators.

For all applications the majority (60% or greater) of the proposed research work plan, as evidenced by the proposed budget, must be directly carried out by the applicant organization throughout the project period. The applicant organization cannot serve as a "pass through" to fund another entity to conduct the majority of the research. Applications that submit a research plan budget in SF-424 Research and Related Budget reflecting less than 60% of direct effort from the applicant organization will be considered nonresponsive and will not be forwarded for peer review.

Evaluation/Performance Measurement Applicants are expected to provide an evaluation and performance measurement plan with measures of effectiveness. The plan must be able to demonstrate the feasibility of accomplishing the proposed project objectives. Measures of effectiveness must relate to the goals stated in the “Purpose” section of this announcement and be able to measure the intended outputs and outcomes described. Outcomes to be evaluated should be clearly specified.

Performance measures should include the number of participants recruited into the study, the participation rate, and types of samples collected.

Translation Plan Applicants should provide evidence of the potential for widespread dissemination, implementation, and sustainability of the proposed strategy to ensure that the approach, if effective, is scalable without prohibitive costs or resources. Research findings should be disseminated through publications, including articles in peer reviewed journals and research briefs for diverse audiences, as well as presentations at professional conferences and other venues. An explanation for how the scientific findings could be translated into public health programs, policies or practice should be included in the application.

Grant awardees will be required to attend at least one reverse site visit in Atlanta with ATSDR program staff during the period of performance to review their progress and findings and to discuss opportunities for widespread dissemination of their research achievements and lessons learned. Travel costs for attending this meeting must be included the application's travel budget submitted in response to this NOFO.

Section II. Award Information Funding Instrument Type: Grant A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed:

New - An application that is submitted for funding for the first time. Includes multiple submission attempts within the same round.

Estimated Total Funding: $7,500,000

Anticipated Number of Awards: 5

Awards issued under this NOFO are contingent on the availability of funds and submission of a sufficient number of meritorious applications.

Award ceiling and floor are for the first 12-month budget period only.

Award Ceiling: $500,000 Per Budget Period Award Floor: $0 Per Budget Period Total Period of Performance Length: 3 year(s)

Throughout the Period of Performance, CDC's commitment to continuation of awards will depend on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and CDC’s determination that continued funding is in the best interest of the Federal government.

HHS/CDC grants policies as described in the HHS Grants Policy Statement (http://www.hhs.gov/ sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf) will apply to the applications submitted and awards made in response to this NOFO.

Section III. Eligibility Information

1. Eligible Applicants Eligibility Category: State governments

County governments City or township governments Special district governments Independent school districts Public and State controlled institutions of higher education Native American tribal governments (Federally recognized) Public housing authorities/Indian housing authorities Native American tribal organizations (other than Federally recognized tribal governments) Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education Nonprofits without 501(c)(3) status with the IRS, other than institutions of higher education Private institutions of higher education http://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf

Others (see text field entitled "Additional Information on Eligibility" for clarification)

Additional Eligibility Category:

The following types of Higher Education Institutions are always encouraged to apply for CDC 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

Nonprofits (Other than Institutions of Higher Education):

Nonprofits (Other than Institutions of Higher

Education)

Other:

Faith-based or Community-based

Organizations Regional Organizations Foreign Organizations: a Foreign

Organization is a public or private organization, whether non-profit or for-profit, located in a country other than the United States (U.S.) and its territories that is subject to the laws of the country in which it is located, irrespective of the citizenship of project staff or place of performance.

Bona Fide Agents: A Bona Fide Agent is an agency/organization identified by the state as eligible to submit an application under the state eligibility in lieu of a state application.

If applying as a bona fide agent of a state or local government, a legal, binding agreement from the state or local government as documentation of the status is required.

Attach with "Other Attachment Forms."

Federally Funded Research and Development Centers (FFRDCs): FFRDCs are operated, managed, and/or administered by a university or consortium of universities, other not-for-profit or nonprofit organization, or an industrial firm, as an autonomous organization or as an identifiable separate operating unit of a parent organization. A FFRDC meets some special long-term research or development need which cannot be met as effectively by an agency's existing in-house or contractor resources. FFRDC's enable agencies to use private sector resources to accomplish tasks that are integral to the mission and operation of the sponsoring agency. For more information on FFRDCs, go to https://gov.ecfr.io/cgi-bin/searchECFR

2. Foreign Organizations Foreign Organizations are eligible to apply.

Foreign (non-US) organizations must follow policies described in the HHS Grants Policy Statement (http://www.hhs.gov/asfr/ogapa/aboutog/hhsgps107.pdf), and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide. International registrants can confirm DUNS by sending an e-mail to ccrhelp@dnb.com, including Company Name, D-U-N-S Number, and Physical Address, and Country. Special Instructions for acquiring a Commercial and Governmental Entity (NCAGE) Code: https://eportal.nspa.nato.int/AC135 Public/Docs/US%20Instructions%20for%20NSPA%20NCAGE.pdf.

Foreign components of U.S. Organizations are eligible to apply.

For this announcement, applicants may include collaborators or consultants from foreign institutions. All applicable federal laws and policies apply.

3. Additional Information on Eligibility Additional Eligibility Category:

The following types of Higher Education Institutions are always encouraged to apply for CDC 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, Native American tribal organizations (other than Federally recognized tribal governments), Faith-based or Community-based Organizations, Regional Organizations

Bona Fide Agents: A Bona Fide Agent is an agency/organization identified by the state as eligible to submit an application under the state eligibility in lieu of a state application. If https://gov.ecfr.io/cgi-bin/searchECFR?ob=r&idno=&q1=FFRDC&r=&SID=1510a9feb7999d185d40b026ad998cc0&mc=true https://gov.ecfr.io/cgi-bin/searchECFR?ob=r&idno=&q1=FFRDC&r=&SID=1510a9feb7999d185d40b026ad998cc0&mc=true http://www.hhs.gov/asfr/ogapa/aboutog/hhsgps107.pdf mailto:ccrhelp@dnb.com https://eportal.nspa.nato.int/AC135Public/Docs/US%20Instructions%20for%20NSPA%20NCAGE.pdf https://eportal.nspa.nato.int/AC135Public/Docs/US%20Instructions%20for%20NSPA%20NCAGE.pdf applying as a bona fide agent of a state or local government, a legal, binding agreement from the state or local government as documentation of the status is required. Attach with "Other Attachment Forms."

Federally Funded Research and Development Centers (FFRDCs): FFRDCs are operated, managed, and/or administered by a university or consortium of universities, other not-for-profit or nonprofit organization, or an industrial firm, as an autonomous organization or as an identifiable separate operating unit of a parent organization. A FFRDC meets some special long-term research or development need which cannot be met as effectively by an agency's existing in-house or contractor resources. FFRDC's enable agencies to use private sector resources to accomplish tasks that are integral to the mission and operation of the sponsoring agency. For more information on FFRDCs, go to https://dap.dau.mil/acquipedia/Pages/ArticleDetails.aspx?aid=5e3079b8-44f2-43df-a0e7- 9f379e8c48ed

Foreign Organizations are eligible to apply.

4. Justification for Less than Maximum Competition

5. Responsiveness There must be an overall match between the proposed research objectives as described in the applicant's abstract and the research objectives of this announcement as described in Section I under the heading Objectives/Outcomes. Applications that do not provide an overall match between the proposed research objectives (as described in the applicant's abstract) and the research objectives of this announcement (as described in Section I under the heading Objectives/Outcomes) will be considered non-responsive and will not be forwarded for peer review.

Funds are available for the identification of potential risk factors, including environmental, for ALS development and progression that uses data from a human ALS registry. Applications proposing research outside of the stated focus area of this NOFO (e.g., research on non-ALS diseases, etc.) will be considered non-responsive and will not be forwarded for peer review.

While applicants may include specific aims comparing environmental toxicant-mediated etiology of ALS to the etiology of other non-ALS neuromuscular diseases (e.g. chronic traumatic encephalopathy, CTE), applications proposing research which focuses primarily on non-ALS neuromuscular diseases will be considered non-responsive and will not be forwarded for peer review.

ATSDR National ALS Biorepository biospecimens will not be provided to applicants for the RFA-TS-21-001 funding cycle. However, applicants may use applicant-provided or third-party sourced ALS biospecimens in their research plans, as appropriate for the research design. Applicants must include, as part of the research plan, use of a matched applicant-provided or third-party sourced ALS epidemiological registry alongside the use of their selected biospecimen repository for identification and evaluation of ALS risk factors. Applications proposing research using applicant-provided or third-party sourced ALS biospecimens in the research plan without also using a matched ALS epidemiological registry as the primary aim for identification and evaluation of ALS risk factors will be considered non-responsive and will not be forwarded for peer review.

Applicants may use human ALS or ALS-like animal models (e.g. SOD1 or TDP-43 mouse models or other mammalian) in their research plans as appropriate for their research proposals. However, applicants must include in the research plan, as the primary research aim, a human health epidemiological investigation to identify and evaluate ALS risk factors from human ALS epidemiological data sources as described in Section I under the heading Objectives/Outcomes. Applications using animal models must clearly describe and justify in their research plan how the animal model will be used to support the primary human epidemiological investigation to identify and evaluate potential risk factors for human ALS through the use of a human ALS epidemiological registry.

Applications proposing research on ALS risk factors in non-human species, including mammalian animal models, as the primary aim of the proposal will be considered non-responsive and will not be forwarded for peer review.

The SF-424 Biographical Sketch for the contact PD/PI and/or Co-Investigator must include documentation of prior expertise, experience, and knowledge directing human epidemiological, environmental health and ecological empirical research on ALS risk factors, including the use of prospective and retrospective case-controls, large epidemiological datasets, and toxicological/molecular laboratory approaches, as appropriate to the research plan. Expertise must be documented with at least one first-authored, peer-reviewed publication, as defined by the NIH National Library of Medicine, directly relevant to the research plan proposed or by serving as a principal investigator on a grant, cooperative agreement, or contract in these subject matter areas (include description and references in the biographical sketch). Experience requirements may be demonstrated through the combined experiences of a Principal and Co-Investigator(s) (if applicable). The citation of the relevant publication(s) or research experience must be clearly identified (by bold text or highlight) in the appropriate SF-424 Biographical Sketch.

Applications that do not meet this requirement will be considered non-responsive and will not be forwarded for peer review.

https://www.nlm.nih.gov/nichsr/stats_tutorial/section3/mod6_peer.html

Partnerships between the applicant institution and outside entities may be necessary to complete the proposed work. However, the majority (60% or greater) of the proposed research work plan, as evidenced by the proposed budget, must be directly carried out by the applicant organization throughout the project period. The applicant organization cannot serve as a "pass through" to fund another entity to conduct the majority of the research. Applications that submit a research plan budget in SF-424 Research and Related Budget reflecting less than 60% of direct effort from the applicant organization will be considered non-responsive and will not be forwarded for peer review.

6. Required Registrations Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award.