RFA-TS-25-036_20241009.pdf

Centers for Disease Control and Prevention

AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY

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

RFA-TS-25-036

11/04/2024

Table of Contents 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

Overview

Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations 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 U01- Cooperative Agreement

Notice of Funding Opportunity Type Reissue of TS-24-010 Agency Notice of Funding Opportunity Number

RFA-TS-25-036

Assistance Listings Number(s) 93.061 Category of Funding Activity HL - Health NOFO Purpose Amendment 1: The purpose of this modification is to clarify the page limit of Research Strategy component of the Research Plan is 12 pages.

The Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (CDC/ATSDR) is seeking investigator-initiated research that will further the understanding of potential risk factors for Amyotrophic Lateral Sclerosis (ALS), while supporting the 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. CDC/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, environmental exposures, and infectious agents. Research proposals on preferred topics can be funded under one of three funding options, Funding Option A, Funding Option B, or Funding Option C.

Funding Option A is intended to support ALS risk factor research investigations that have an existing, well substantiated evidence base and would benefit from strengthened rigorous evaluation. Funding Option B is intended to support novel ALS risk factor research investigations that may or may not have an existing evidence base, may be supported by limited and insufficient preliminary research, and are exploratory and developmental in nature.

Funding Option C is intended to support research and better understanding of ALS risk including prevalence and incidence in communities such as racial and ethnic minority populations (e.g., Black or African American persons, Hispanic or Latino persons, Asian persons) and military veterans.

For Option A, B, or C applicants may elect to use data from the National ALS Registry. Note, this is not compulsory and will not preclude the applicant from consideration.

Key Dates Publication Date:

To receive notification of any changes to RFA-TS-25-036, 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:

10/01/2024 October 1, 2024

Application Due Date:

11/04/2024 November 4, 2024

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 11:59 PM U.S. Eastern Time.

Applicants will use a system or platform to submit their applications through Grants.gov and eRA Commons to CDC. ASSIST, an institutional system to system (S2S) solution, or Grants.gov Workspace are options. ASSIST is a commonly used platform because it provides a validation of all requirements prior to submission and prevents errors.

https://www.grants.gov/

For more information on accessing or using ASSIST, you can refer to the ASSIST Online Help Site at: https://era.nih.gov/erahelp/assist. Additional support is available from the NIH eRA Service desk via http://grants.nih.gov/support/index.html.

• E-mail: commons@od.nih.gov

• Phone: 301-402-7469 or (toll-free) 1-866-504-9552

• Hours: Monday - Friday, 7 a.m. to 8 p.m. Eastern Time, excluding Federal holidays

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:

02/25/2025 This is an estimated date.

Secondary Review:

07/29/2025 This is an estimated date.

Estimated Start Date:

09/30/2025 Expiration Date:

03/09/2025 Required Application Instructions It is critical that applicants follow the instructions in the How to Apply - Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both 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 12 pages.

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

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

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

Executive Summary The Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (CDC/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 CDC/ATSDR extramural research program is to fund research that promotes healthy community environments http://grants.nih.gov/support/index.html mailto:commons@od.nih.gov https://grants.nih.gov/grants/how-to-apply-application-guide.html 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. 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.

CDC/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.

Purpose: In this Notice of Funding Opportunity, CDC/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. Research proposals on preferred topics can be funded under one of three funding options, Funding Option A, Funding Option B, or Funding Option C.

Funding Option A is intended to support ALS risk factor research investigations that have an existing, well substantiated evidence base and would benefit from strengthened rigorous evaluation. Examples of proposals appropriate for Funding Option A may include, but are not limited, to investigations on well substantiated environmental, genetic, and other ALS risk factors that can be strengthened by prospective and retrospective longitudinal studies with appropriately addressed confounders; studies that improve upon past investigations with increased statistical power and expanded ALS and/or control population cohorts; and studies that seek to link risk factors to clinical diagnosis, treatment, and outcomes. Awards made under Funding Option A will be funded for up to $500,000 per year (including direct and indirect costs) for a period of performance of up to 3 years, pending the availability of funds.

Funding Option B is intended to support novel ALS risk factor research investigations that may or may not have an existing evidence base, may be supported by limited and insufficient preliminary research, and are exploratory and developmental in nature. Examples of proposals appropriate for Funding Option B may include, but are not limited to, investigations on risk factors without an existing evidence base (e.g., gut microbiome and other genomic, dietary or metabolic risk factors; aviation and other radiation-related risk factors; and sports related risk factors other than TBI [e.g., strenuous physical activity]). Funding Option B may also support

ALS risk factor investigations that utilize novel approaches. Awards made under Funding Option B will be funded for up to $300,000 per year (including direct and indirect costs) for a period of performance of up to 3 years, pending the availability of funds.

Funding Option C is intended to support research and better understanding of ALS risk including prevalence and incidence in communities such as racial and ethnic minority populations (e.g., Black or African American persons, Hispanic or Latino persons, Asian persons) and military veterans. Examples of proposals appropriate for Funding Option C may include research related to military veterans, health disparities and populations disproportionately impacted by ALS. Awards made under Funding Option C will be funded for up to $300,000 per year (including direct and indirect costs) for a period of performance of up to 3 years, pending the availability of funds.

Applicants must clearly indicate in the Abstract whether the research proposal intends to fall under Funding Option A, Funding Option B, or Funding Option C.

For Option A, B, and C applicants may elect to use data from the National ALS Registry. Note, this is not compulsory and will not preclude the applicant from consideration.

This Notice of Funding Opportunity aligns with the National Center for Environmental Health (NCEH)/ATSDR 2020-2024 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 U-01 for research cooperative agreements.

Funds Available and Anticipated Number of Awards: CDC/ATSDR intends to commit approximately up to $2,500,000 in FY 2025 to fund up to eight (8) applications, pending the availability of funds. 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 Period of Performance: An applicant is expected to request a period of performance of up to three (3) years for Funding Option A, Funding Option B, or Funding Option C. For applications funded under Funding Option A, the maximum total project funding amount is $1,500,000 over the expected three-year period of performance, with a maximum of $500,000 per award per year (including direct and indirect costs). The period of performance for this award is expected to run from 9/30/2025 to 9/29/2028. For applications funded under Funding Option B, the maximum total project funding amount is $900,000 over the expected three-year period of performance, with a maximum of $300,000 per award per year (including direct and indirect costs). The period of performance for this award is expected to run from https://www.atsdr.cdc.gov/about/mission_vision_goals.html https://www.atsdr.cdc.gov/about/docs/NCEHATSDR_priorities_2014_final.pdf

9/30/2025 to 9/29/2028. For applications funded under Funding Option C, the maximum total project funding amount is $900,000 over the expected three-year period of performance, with a maximum of $300,000 per award per year (including direct and indirect costs). The period of performance for this award is expected to run from 9/30/2025 to 9/29/2028.

Throughout the period of performance, 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/PIss must include their eRA Commons Identification in the Credential Field of the Senior/Key Person Profile Component of the SF-424 (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.

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

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

Special Date(s): A pre-application teleconference call will be conducted on 9/17/2024 to address questions from prospective applicants regarding NOFO RFA-TS-25-036 Identify and Evaluate Potential Risk Factors for Amyotrophic Lateral Sclerosis (ALS). The call will begin at 1:00PM Eastern Standard Time (EST) and end at 1:50PM Eastern Standard Time (EST), or sooner if all questions are addressed. Questions and answers from the discussion will be included in an amended NOFO approximately 3 weeks after the call.

Participant Access Information:

• Call Date: September 17, 2024

• Call Start Time: 1:00pm Eastern Standard Time (EST)

• Call End Time: 1:50pm Eastern Standard Time (EST)

• Call Leader: Candis Hunter, PhD, MSPH, REHS, Scientific Program Official

• Webinar Link:

https://cdc.zoomgov.com/j/1600849897?pwd=cmQxTXZaZ0pTb2ZzeFJ1WnVHc2gxdz0

• Webinar ID: 160 084 9897

• Passcode: J4$9pyzN

• Call-In Numbers:

o +1 646 828 7666 US (New York) o +1 646 964 1167 US (US Spanish Line) o +1 669 254 5252 US (San Jose) o +1 551 285 1373 US (New Jersey) o +1 415 449 4000 US (US Spanish Line) o +1 669 216 1590 US (San Jose) o Passcode: 00330476

Application Materials. See Section IV.1 for application materials

Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: 1-888- 232-6348.

Section I. Funding Opportunity Description http://www.grants.gov https://cdc.zoomgov.com/j/1600849897?pwd=cmQxTXZaZ0pTb2ZzeFJ1WnVHc2gxdz09 https://cdc.zoomgov.com/j/1600849897?pwd=cmQxTXZaZ0pTb2ZzeFJ1WnVHc2gxdz09

Statutory Authority This program is authorized under Sections 317(k)(2) and 399S of the Public Health Service Act [42 U.S.C. 247b(k)(2) and 42 U.S.C. 280g-7.

1. Background and Purpose Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig'’s disease, is a progressive and often fatal neuromuscular disease that presents in familial (fALS) and sporadic (sALS) forms. As of 2017, over 30,000 people in the U.S. lived with ALS and most people die within two to five years of being diagnosed with the disease (Mehta et al., 2022). 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 (Vasta, 2021; 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, environmental exposures, 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 (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 (e.g., American football and soccer) 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 (Daneshvar, 2021; 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.

ALS Racial Disparities Previous studies have indicated that racial and ethnic minority populations have experienced disparities in ALS symptom onset, diagnosis, access to care, and interventions compared to non- Hispanic white populations (Roberts, 2016; Gwathmey, 2023; Brand, 2021). Diagnostic delay may be associated with multiple factors including socioeconomic, misdiagnosis, lack of awareness, and accessibility to affordable care. All of these and other factors can contribute to underrepresented populations getting inadequate ALS treatment and care which can reduce their survival. ATSDR seeks additional research to determine and identify the barriers and how they may be overcome to reduce the accessibility burden for groups disproportionately impacted.

CDC/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.

CDC/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 National ALS Registry. CDC/ATSDR is especially interested in innovative research applications that propose to conduct an epidemiological investigation using the 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 CDC/ATSDR can be found at https://www.cdc.gov/als/ALSExternalResearchfundedbyRegistry.html.

For NOFO RFA-TS-25-036, 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 such as American Football or soccer

• injury or microbial infection (e.g., bacterial, fungal, viral) resulting in neuroinflammation or innate immune system activation

• nutritional intake, or lack thereof

• 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.

In addition to having two research objectives related to scientific intent, this NOFO offers three funding options to address the research objectives. Applicants may submit a research proposal under either Funding Option A, Funding Option B, or Funding Option C:

• Funding Option A is intended to support ALS risk factor research investigations that have an existing, well substantiated evidence base and would benefit from strengthened rigorous evaluation. Examples of proposals appropriate for Funding Option A may include, but are not limited, to investigations on well substantiated environmental, genetic, and other ALS risk factors that can be strengthened by prospective and https://www.cdc.gov/als/ALSExternalResearchfundedbyRegistry.html retrospective longitudinal studies with appropriately addressed confounders; studies that improve upon past investigations with increased statistical power and expanded ALS and/or control population cohorts; and studies that seek to link risk factors to clinical diagnosis, treatment, and outcomes. Awards made under Funding Option A will be funded for up to $500,000 per year (including direct and indirect costs) for a period of performance of up to 3 years, pending the availability of funds.

• Funding Option B is intended to support novel ALS risk factor research investigations that may or may not have an existing evidence base, may be supported by limited and insufficient preliminary research, and are exploratory and developmental in nature.

Examples of proposals appropriate for Funding Option B may include, but are not limited to, investigations on risk factors without an existing evidence base (e.g., gut microbiome and other genomic, dietary or metabolic risk factors; aviation and other radiation-related risk factors; and sports related risk factors other than TBI [e.g., strenuous physical activity]). Funding Option B may also support ALS risk factor investigations that utilize novel approaches. Awards made under Funding Option B will be funded for up to $300,000 per year (including direct and indirect costs) for a period of performance of up to 3 years, pending the availability of funds.

• Funding Option C is intended to support research and better understanding of ALS risk including prevalence and incidence in communities such as racial and ethnic minority populations (e.g., Black or African American persons, Hispanic or Latino persons, Asian persons) and military veterans. Examples of proposals appropriate for Funding Option C may include research related to military veterans, health disparities and populations disproportionately impacted by ALS. Awards made under Funding Option C will be funded for up to $300,000 per year (including direct and indirect costs) for a period of performance of up to 3 years, pending the availability of funds.

Applicants must clearly indicate in the Abstract whether the research proposal is intended to fall under Funding Option A, Funding Option B, or Funding Option C.

For Option A, B, or C, applicants may elect to use data from the National ALS Registry. Note, this is not compulsory and will not preclude the applicant from consideration.

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 CDC/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 https://health.gov/healthypeople.

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 https://health.gov/healthypeople 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-25-036 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 partnership 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). Additional reports from annual ALS meetings can be found at https://www.cdc.gov/als/AnnualMeetings.html

References:

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

2. Mehta P, Raymond J, Punjani R, Han M, Larson T, Kaye W, Nelson LM, Topol B, Muravov O, Genson C, Horton DK. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener.

2023 Feb;24(1-2):108-116. doi: 10.1080/21678421.2022.2059380. Epub 2022 Apr 15. PMID:

35422180; PMCID: PMC9568617.

3. 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.

4. 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 https://www.cdc.gov/als/AnnualMeetings.html and hypotheses, data collection measures, and period of performance. 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: Retrospective and 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 CDC/ATSDR National ALS Registry: National ALS Registry data are available for researchers to identify potential risk factors for ALS. For Option A, B, or C, applicants may elect to use data from the National ALS Registry. Use of the National ALS Registry is not required for consideration of funding under this announcement. However, applicants are encouraged to include 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/ALSRegistryResearchApplicationInfo.html (currently approved under OMB Control Number 0923-0041, expiration date 01/31/2023). 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-25-036 and who wish to use the 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 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 CDC/ATSDR National ALS Biorepository: Applicants should not submit proposals that intend to use biospecimens from the National ALS Biorepository for the RFA-TS-25-036 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 https://www.cdc.gov/als/ALSRegistryResearchApplicationInfo.html biospecimen repository must be sufficiently high to provide meaningful epidemiological analyses.

Applications must be responsive to NOFO RFA-TS-25-036 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

Objectives/Outcomes For NOFO RFA-TS-25-036, 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, or lack thereof

• 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.

Data collection, acquisition, and analysis: Applicants must identify and describe appropriate data sources and provide evidence of their ability to acquire and/or collect data of sufficient quantity and quality to conduct the proposed research within the period of performance.

Applications should clearly describe and justify the proposed sampling methods, sample size, power estimates, and data collection methods for the primary outcome(s), at a minimum, and other proposed secondary measures and subgroup analyses. The timeline for data acquisition (requests for extant data and or primary data collection) must be specified.

Protection of Human Subjects and Personally Identifiable Information: The Research Strategy section of the application is expected to clearly describe the type, source, access to, and protections of the data and human subjects participating in the study. Access to non-publicly available, previously collected data must be clearly described in the Research Strategy and documented with a signed Data Sharing Agreement or Letter of Support. Access to publicly available, previously collected data must be clearly described in the Research Strategy.

Protection of previously collected data includes, but is not limited to, protection of personally identifiable information from loss and/or misuse. The application is expected to identify each performance site that will be conducting human subjects research and include the Federal Wide Assurance (FWA) number for the applicant institution and each performance site engaged in human subjects research. Research conducted with more than one institution will be expected to use a single Institutional Review Board (sIRB) to conduct the ethical review required by HHS regulations. See Section IV. Application and Submission Information, 10 Funding Restrictions, Human Subjects for details.

Population of Focus NOFO RFA-TS-25-036 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 National ALS Registry enrollees, as appropriate, in their research plans. The National ALS Registry tool for researcher access can be found at https://www.cdc.gov/als/ALSRegistryResearchApplicationInfo.html (currently approved under OMB Control Number 0923-0041, expiration date 5/31/2026).

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 period of performance. The applicant organization cannot serve as a "pass through" to fund another entity to conduct the majority of the research.

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 or Registry staff along with ERPO staff will visit the grantee’s institution 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 SF-424 Research and Related Budget D.

Travel.

3. Funding Strategy N/A

Section II. Award Information

Funding Instrument Type:

CA (Cooperative Agreement) A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

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:

Under this NOFO there are three funding options:

• Awards under Funding Option A will have a Total Period of Performance Length with funds of 3 years. The award ceiling for applications submitted for Funding Option A is $500,000 per year (including direct and indirect costs), pending availability of funds.

• Awards under Funding Option B will have a Total Period of Performance Length with funds of 3 years. The funding ceiling for applications submitted for Funding Option B is $300,000 per year (including direct and indirect costs), pending availability of funds.

• Awards under Funding Option C will have a Total Period of Performance Length with funds of 3 years. The funding ceiling for applications submitted for Funding Option C is $300,000 per year (including direct and indirect costs), pending availability of funds

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

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 (https://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.

If you are successful and receive a Notice of Award, in accepting the award, you agree that the award and any activities thereunder are subject to…