RFA-TS17-001 Amend 2.pdf

Image Description: Centers for Disease Control

Centers for Disease Control

Agency for Toxic Substances and Disease Registry Extramural Research Program Office

Identify and Characterize Potential Environmental Risk Factors for Amyotrophic Lateral Sclerosis (ALS) and Evaluate Their Impact on ALS Disease Incidence and Progression

RFA-TS-17-001

Application Due Date: 04/28/2017

Identify and Characterize Potential Environmental Risk Factors for Amyotrophic Lateral Sclerosis (ALS) and Evaluate Their Impact on ALS Disease Incidence and Progression

RFA-TS-17-001

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 Components of Participating Organizations Agency for Toxic Substances and Disease Registry Extramural Research Program Office (ATSDR ERPO) Agency for Toxic Substances and Disease Registry (ATSDR) Funding Opportunity Announcement (FOA) Title Identify and Characterize Potential Environmental Risk Factors for Amyotrophic Lateral Sclerosis (ALS) and Evaluate Their Impact on ALS Disease Incidence and Progression Activity Code Applications in response to this FOA will be funded using the R01 activity code.

Funding Opportunity Announcement Type New Funding Opportunity Announcement Number

RFA-TS-17-001

Catalog of Federal Domestic Assistance (CFDA) Number(s) 93.061 Category of Funding Activity:

Health FOA Purpose The Agency for Toxic Substances and Disease Registry (ATSDR) is soliciting investigator-initiated research that will identify and characterize environmental toxicants in human biological samples that may be potential environmental risk factors for Amyotrophic Lateral Sclerosis (ALS). Applications are also sought that will evaluate the impact of environmental toxicants on the development and progression of ALS, including gene-environment interactions. Information gleaned from this investigator-initiated research will provide a greater understanding of the possible link between exposures to environmental toxicants and the etiology of

ALS.

The purpose of Amendment 1 to this FOA is to provide additional clarifying information based on questions received from potential applicants prior to and during the Pre-Application Conference Call held on February 13, 2017. A summary of the questions and answers can be found in Section VIII. Other Information of the amended FOA.

The purpose of Amendment 2 to this FOA is to edit the Eligibility Section of the FOA and to modify the application due date.

Key Dates Publication Date: To receive notification of any changes to RFA-TS-17-001, 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: 03/06/2017 Letters of Intent are requested by March 6, 2017. Letters of Intent are optional.

https://www.grants.gov

Application Due Date: 04/28/2017 Applications are due April 28, 2017

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

HHS/CDC grant submission procedures do not provide a period of time beyond the application due date 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: 06/21/2017 Estimated date is June 21, 2017. The actual review may occur in June or July 2017.

Secondary Review: 07/12/2017 Estimated date is July 12, 2017. The actual review may occur in July or August 2017.

Estimated Start Date: 09/30/2017 Estimated start date is September 30, 2017

Expiration Date: 05/30/2017 Due Dates for E.O. 12372: Executive Order 12372 does not apply to this program.

Required Application Instructions It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this FOA. Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

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.

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.

Purpose: ATSDR is soliciting investigator-initiated research that will identify and characterize environmental toxicants in human biological samples that may be potential environmental risk factors for Amyotrophic Lateral Sclerosis (ALS). Applications are also sought that will evaluate the impact of environmental toxicants on the development and progression of ALS, including gene-environment interactions. Information gleaned from this investigator-initiated research will provide a greater understanding of the possible link between exposures to environmental toxicants and the etiology of ALS.

Research FOA RFA-TS-17-001 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 http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf https://www.atsdr.cdc.gov/about/mission_vision_goals.html 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 FOA will be a research grant.

Funds Available and Anticipated Number of Awards

ATSDR intends to commit up to $2,500,000 in FY17 to fund up to five applications for this FOA. The awards issued under this FOA 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 anticipated that the size and duration of each award may also vary. The total amount awarded will depend upon the number, quality, duration and cost of the applications received.

Budget and Project Period

The total award for the first year of funding will not exceed $2,500,000 (including direct and indirect costs).

Each budget period will be twelve months. The maximum award amount, per award and including direct and indirect costs, will be $500,000 for the first 12-month budget period.

The project period will be up to three years, anticipated for September 30, 2017 to September 29, 2020. An applicant is expected to request a project period of three years but may request a project period of no less than two years in order to complete the proposed research plan. The maximum total funding, including direct and indirect costs, for an award with a three year project period is expected to be up to $1,500,000 per award.

Applicants must specifically describe the level of annual funding and project period requested.

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. 1 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 does not make awards to individuals directly. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply.

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 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. Applicant organizations may submit more than one application, provided that each application is scientifically distinct. However, applicant institutions can submit only one grant application with the same principal investigator in response to this FOA. Only one application per principal investigator will be funded under this FOA. Additionally, applicant institutions submitting applications with essentially the same proposed research to two or more CDC FOAs will https://www.atsdr.cdc.gov/about/docs/NCEHATSDR_priorities_2014_final.pdf http://grants.nih.gov/grants/guide/pa-files/PAR-11-022.html#SectionIV not be funded under more than one FOA .

Application Type. NEW Special Date(s). A pre-application teleconference call will be conducted on February 13, 2017 to address questions from prospective applicants regarding FOA RFA-TS-17-001, Identify and Characterize Potential Environmental Risk Factors for Amyotrophic Lateral Sclerosis (ALS) and Evaluate Their Impact on ALS Disease Incidence and Progression. The call will begin at 2:00PM Eastern and end at 3:00PM Eastern, or sooner if all questions are addressed. Questions and answers from the discussion will be included in an amended FOA approximately 3 weeks after the call.

Participant Access Information

Call Date: February 13, 2017 Call Start Time: 2:00 PM Eastern Call End Time: 3:00 PM Eastern Call Leader: Marcienne Wright, PhD, Scientific Program Official Toll-Free Number: 1-877-201-5465 Conference ID: 14914695

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

Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY:

(770) 488-2783.

Part 2. Full Text Section I. Funding Opportunity Description

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

1. Background and Purpose Background:

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, 2016). 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 (Wang 2016; Al-Chalabi, 2013; Wingo, 2011).

Research suggests that associations may exist between exposure to organophosphates (e.g. pesticides), heavy metals, or other persistent environmental toxicants and the incidence and progression of ALS (reviewed in Sutedja, 2009; Su, 2016; Yu, 2014; Morahan, 2007). However the specific environmental toxicants and the etiologic role(s) they play in the development and progression of ALS, including the existence and influence of gene-environment interactions that may promote genetic susceptibility to ALS, are not well defined (Al-Chalabi, 2013; Clerc, 2016). Additional research using human-based epidemiological, molecular, and/or computational approaches is needed to better elucidate if and how exposure to organophosphates, heavy metals, or other persistent environmental toxicants can precipitate ALS, whether these environmental toxicants play a causal or contributory role in the development and progression of ALS, to what degree initial http://grants.nih.gov/grants/guide/pa-files/PAR-11-022.html#SectionIV1 exposure or exposure over time these environmental toxicants influence the development and progression of ALS, and the key biological pathways and genes that these environmental toxicants may act on in persons with ALS.

The uncertainty about the incidence and prevalence of ALS, as well as the lack of knowledge about the etiology of the disease, created a need for structured data collection. The ALS Registry Act (H.R. 2295), 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) launched the National ALS Registry to collect data that would:

describe the incidence and prevalence of ALS in the US;

examine factors, including environmental and occupational, 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.

The use of biological sample repositories (“biorepositories”) has advanced our understanding of environmental determinants and mediators of diseases, and the underlying gene-environment interactions involved in disease incidence and progression. In 2014, NCEH/ATSDR coordinated an ALS pilot feasibility study to identify the best way to collect and store biological samples from persons with ALS. In the fall of 2016, ATSDR launched the National ALS Biorepository. The National ALS Biorepository stores biological samples from in-home collection (e.g., blood, hair, or saliva) and postmortem collection (e.g., brain, bone, spinal cord, cerebrospinal fluid, muscle, and skin). Specimens from the National ALS Biorepository are collected from a geographically representative sample of persons with ALS who are self-enrolled in the Registry. Samples from the National ALS Biorepository are paired with completed risk factor data from the National ALS Registry, including demographic and other environmental and occupational data currently being provided by persons with ALS.

National ALS Biorepository samples and National ALS Registry data are available for researchers to examine potential exposures to environmental toxicants and their relationship to demographic, environmental, and occupational data in order to better understand the etiologic role(s) environmental, genetic, and epigenetic risk factors play in the development and progression of various forms of ALS.

Purpose:

The purpose of this funding opportunity announcement (FOA) is to solicit investigator-initiated research that will identify and characterize environmental toxicants (e.g., organophosphates, heavy metals, and other persistent environmental chemicals) in biological samples that may be potential environmental risk factors for amyotrophic lateral sclerosis (ALS). Funds are available to conduct evaluation on the influence of environmental toxicants on the development and progression of ALS, including potential gene-environment interactions. Information gleaned from this investigator-initiated research will provide a greater understanding of the possible link between exposures to environmental toxicants and the etiology of ALS.

The intended results expected as a consequence of research funded under this announcement are listed in more detail in the Objectives/Outcomes section of this document.

Objectives:

The applicant shall address all of the following objectives:

a) Identify and characterize the composition and concentrations of organophosphate metabolites (or associated biomarkers), heavy metals, or other persistent environmental toxicants in biological samples of persons with ALS.

b) Evaluate environmental toxicant associated linkage(s) between analyzed human biological samples and sample-matched ALS epidemiological data, including environmental, demographic, occupational, and sample-matched ALS epidemiological data, including environmental, demographic, occupational, behavioral and familial risk factors, etc.

c) Examine the functional relationship between environmental toxicants in human biological samples and key biological pathways or genes associated with the development and/or progression of ALS.

Research funded under this FOA is expected to produce outcomes that will advance our understanding of whether correlates exist between environmental toxicant (or relevant biomarker) concentrations in human biological samples and the incidence of ALS; whether linkages between environmental toxicant exposures and other demographic risk factors for ALS disease risk and/or progression can be identified; whether gene-environment interactions contribute to the development and progression of ALS, and, if so, the mechanism(s) by which these interactions may influence genetic susceptibility to ALS.

References:

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

1.

Rowland LP et al. Amyotrophic lateral sclerosis. NEJM 2001. 344(22):1688-1700 (2001).2.

Wang MD, Little J, Gomes J, et al. Identification of risk factors associated with the onset and progression of amyotropic lateral sclerosis using systematic review and meta-analysis. Neurotoxicity 2016. http://dx.doi.org/10.1016/j.neuro.2016.06.015

3.

Al-Chalabi A and Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment, and time. Nature Rev Neurology 2013. 9:617-628

4.

Wingo T, Cutler D, Yarab N et al. The heritability of amyotropic lateral sclerosis in a clinically ascertained United States research registry. PLoS One. 2011. 6(11):e27985

5.

Sutedja N, Veldink JH, Fischer K et al. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: A systematic review. Amyotrophic Lateral Sclerosis. 2009.10: 302–309

6.

Su FC, Goutman S, Chernyak S, et al. Association of environmental toxins with amyotropic lateral sclerosis. JAMA Neurol. 2016. 73(7):803-11

7.

Yu Y, Su FC, Callahan BC et al. Environmental risk factors and amyotropic lateral sclerosis (ALS): a case control study of ALS in Michigan. PLoS One. 2014. 9(6):e1011186

8.

Morahan JM, Yu B, Trent RJ et al. Genetic susceptibility to environmental toxicants in ALS. Am J Med Genet B Neuropsychiatr Genet. 2007. 144B(7):885-890

9.

Clerc P, Lipnick S, and Willet C. A look in to the future of ALS research. Drug Discov Today. 2016.

21(6):939-949

10.

Factor-Litvak P, Al-Chalabi A, Ascherio A, et al. Current pathways for epidemiological research in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2013.14(Suppl 1):33–43.

11.

Talbot EO, Malek AM, and Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Hand Clin Neurol 2016. 138:225-238.

12.

Chio A, Logrosino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 2013. 41:118–30.

13.

Roelofs-Iverson RA, Mulder DW, Elveback LR, et al. ALS and heavy metals: a pilot case-control study. Neurology 1984. 34:393–5.

14.

Carlesi C, Pasquali L, Piazza S, et al. Strategies for clinical approach to neurodegeneration in amyotrophic lateral sclerosis. Arch Ital Biol 2011;149:151–67.

15.

Wang MD, Gomes J, Cashman NR, Little J, Krewski D. A meta-analysis of observational studies of the association between chronic occupational exposure to lead and amyotrophic lateral sclerosis. J Occup Environ Med 2014;56:1235–42.

16.

Bradley WG, Borenstein AR, Nelson LM, et al. Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases? Amyotroph Lateral Scler Frontotemporal Degener 2013.14:325–33.

17.

Oskarsson B, Horton DK, Mitsumoto H. Potential environmental factors in amyotrophic lateral18.

sclerosis. Neurol Clin 2015. 33:877–88.

Beard JD, Kamel F. Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival. Epidemiol Rev 2015;37:55–70.

19.

Kaye WE, Sanchez M, Wu J. Feasibility of creating a national ALS registry using administrative data in the United States. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:433–9.

20.

Healthy People 2020 and other National Strategic Priorities ATSDR is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2020" and to measuring program performance as stipulated by the Government Performance and Review Act (GPRA). This research FOA directly supports the United States Department of Health and Human Services (DHHS) Healthy People 2020 goals and objectives as described in: http://www.healthypeo ple.gov/.

The proposed program of research addresses the Healthy People 2020 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 FOA supports the Healthy People 2020 goal for promoting high-quality, longer lives free of preventable disease and Healthy People Objective EH-21 to improve the quality, utility, awareness, and use of existing information systems for environmental health.

Public Health Impact ALS is a progressive and often fatal neuromuscular disease that affects almost 16,000 people, and their families, in the United States. Yet, little is known about the incidence, prevalence, or etiology of the disease, including the role that environmental toxicants play in the development or progression of various forms of ALS. This research will expand our current understanding of the potential environmental risk factors for ALS.

Relevant Work The ALS Registry Act (H.R. 2295), 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 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) and the second National ALS registry Report in August 2016 (covering 2012-2013).

References

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; Bryan, L; et. al.; Prevalence of Amyotrophic Lateral Sclerosis — United States, 2012–2013. MMWR August 5, 2016; 65 (8); 1-12

3. 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

4. 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.

5. 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 http://www.healthypeople.gov/ http://www.healthypeople.gov/

ATSDR is soliciting innovative investigator-initiated research that will help expand and advance our current knowledge of role that environmental risk factors may have on ALS etiology. There is interest in learning if and how exposure to environmental toxicants influence the development and progression of ALS. The identification and characterization of organophosphates (e.g. pesticides), heavy metals, and other persistent environmental toxicants in biological samples of persons with ALS will advance our understanding of whether environmental toxicants cause and/or contribute to ALS, and if environmental toxicants interact with susceptibility genes and biological pathways associated with ALS. Information produced from this research will help ATSDR better understand if there are specific environmental risk factors and environment-gene interactions that may or may not increase the likelihood and/or progression of ALS.

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. 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 blood and body fluid and tissue samples; 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 may result in the identification of human ALS susceptibility genes and key biological pathways impacted by environmental exposures.

Biological sample selection and analysis: For human biological sample analysis, investigators are encouraged to use standardized and recognized practices (e.g., College of American Pathology) to ensure sample integrity and quality assurance. While variability may exist in the selection of biological samples, investigators should attempt to conduct analyses with large uniform sample sizes. Where appropriate, a control group should be identified to sample for comparison purposes.

ALS case control studies and epidemiological datasets: Prospective or retrospective case-control studies may be considered and analyses of existing ALS epidemiological datasets 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.

Biological samples and ALS epidemiological data may be provided by the applicant and/or may be requested from the National ALS Biorepository and National ALS Registry. For evaluation of environmental toxicant-associated linkage(s) between analyzed human biological samples and ALS epidemiological data (FOA Objective B), the ALS epidemiological data must be sample-matched to the biological samples being evaluated. The applicant is required to address, in the application’s research plan:

a) the availability and quality of biological samples and ALS epidemiological data research resources proposed for evaluation, b) a justification for the use of the specific biological sample and ALS epidemiological data resources, c) an attestation that the biological samples and ALS epidemiological data are sample-matched, and d) limitations in the analysis of the specific biological samples and ALS epidemiological data proposed for evaluation.

Although it is not required for consideration of funding under this announcement, applicants are encouraged to include the National ALS Biorepository samples and National ALS Registry enrollees, as appropriate, in their research plans. The National ALS Biorepository and National ALS Registry tools for researcher access can be found at wwwn.cdc.gov/als/ALSRegistryResearchApplicationInfo.aspx.

Applicants should be aware that for institutions awarded a grant under FOA RFA-TS-17-001, the principal investigator and key personnel requesting access to the National ALS Biorepository and 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.

Funds are available for environmental toxicant risk factor research on ALS that uses human biological https://wwwn.cdc.gov/als/ALSRegistryResearchApplicationInfo.aspx samples from an ALS biorepository and data from a sample-matched human ALS registry.

Applications proposing studies outside of the stated focus area of this FOA (e.g., research on non-ALS diseases, etc.) will be considered nonresponsive.

While applicants may include specific aims comparing environmental toxicant-mediated etiology of ALS to the etiology of other non-ALS neuromuscular diseases, applications proposing research which focuses primarily on non-ALS neuromuscular diseases will be considered nonresponsive.

While applicants may evaluate similarities between human ALS and neuromuscular diseases in non-human species, applications proposing research which focuses primarily on ALS or ALS-like neuromuscular diseases in non-human species will be considered nonresponsive.

While applicants may identify non-environmental risk factor correlates to the development and progression of ALS in biological samples, applications proposing research which focuses primarily on non-environmental risk factors (e.g. electric shock, physical injuries, infectious agents, etc.) in the development or progression of ALS will be considered nonresponsive.

Objectives/Outcomes The applicant shall address all of the following objectives:

a) Identify and characterize the composition and concentrations of organophosphate metabolites (or associated biomarkers), heavy metals, or other persistent environmental toxicants in biological samples of persons with ALS.

b) Evaluate environmental toxicant associated linkage(s) between analyzed human biological samples and sample-matched ALS epidemiological data, including environmental, demographic, occupational, behavioral and familial risk factors, etc.

c) Examine the functional relationship between environmental toxicants in human biological samples and key biological pathways or genes associated with the development and/or progression of ALS.

Research funded under this FOA is expected to produce outcomes that will advance our understanding of whether correlates exist between environmental toxicant (or relevant biomarker) concentrations in human biological samples and the incidence of ALS; whether linkages between environmental toxicant exposures and other demographic risk factors for ALS disease risk and/or progression can be identified; whether gene-environment interactions contribute to the development and progression of ALS, and, if so, the mechanism(s) by which these interactions may influence genetic susceptibility to ALS.

Target Population This FOA supports the conduct of research that will benefit all ALS patients. Although it is not required for consideration of funding under this announcement, applicants are encouraged to include the National ALS Biorepository samples and National ALS Registry enrollees, as appropriate, in their research plans. The applicant is encouraged to consider submitting an application to use samples from the National ALS Biorepository and data from the National ALS Registry. The National ALS Biorepository and National ALS Registry tools for researcher access can be found at wwwn.cdc.gov/als/ALSRegistryResearchApplic ationInfo.aspx .

Collaboration/Partnerships Applicant researchers are expected to develop collaborations pertinent to the proposed research plan.

Documentation of effective and well-defined working relationships with any organization and/or outside entity expected to participate in the proposed research that will ensure implementation and sustainability of the proposed activities should be included in the application. These relationships should be evidenced by letters of support or memoranda of understanding or agreement detailing the nature and extent of the involvement from the performing organization and outside entities.

Evaluation/Performance Measurement Applicants should include analytic plans that describe the research design and hypotheses, data collection measures, and methods to evaluate the effectiveness of the proposed research strategy to address the hypotheses within the project period. Outcomes to be evaluated should be clearly specified.

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. This must be reflected in the grantee's budget in their application submitted in response to this FOA.

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 FOA 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: $350,000 Per Budget Period Total Project Period Length: 3 year(s)

Throughout the project period, 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 FOA.

Section III. Eligibility Information

1. Eligible Applicants Eligibility Category: State governments http://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf

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 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:

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 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" when submitting via www.grants.gov.

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 https://dap.dau.mil/acquipedia/Pages/ArticleDetails.aspx?aid=5e3079b8-44f2-43df-a0e7-9f379e8c48ed

2. Foreign Organizations Foreign Organizations are not eligible to apply.

Foreign components of U.S. Organizations are not eligible to apply.

For this announcement, applicants may not include collaborators or consultants from foreign institutions.

All applicable federal laws and policies apply.

3. Special Eligibility Requirements

NONE

N/A

4. Justification for Less than Maximum Competition N/A

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.”

Funds are available for environmental toxicant risk factor research on ALS that uses human biological samples from an ALS biorepository and data from a sample-matched human ALS registry.

Applications proposing studies outside of the stated focus area of this FOA (e.g., research on non-ALS diseases, etc.) will be considered nonresponsive.

While applicants may include specific aims comparing environmental toxicant-mediated etiology of ALS to the etiology of other non-ALS neuromuscular diseases, applications proposing research which focuses primarily on non-ALS neuromuscular diseases will be considered nonresponsive.

While applicants may evaluate similarities between human ALS and neuromuscular diseases in non-human species, applications proposing research which focuses primarily on ALS or ALS-like neuromuscular diseases in non-human species will be considered nonresponsive.

While applicants may identify non-environmental risk factor correlates to the development and progression of ALS in biological samples, applications proposing research which focuses primarily on non-environmental risk factors (e.g. electric shock, physical injuries, infectious agents, etc.) in the development or progression of ALS will be considered nonresponsive.

The biosketch for the PI, co-PI, or Co-Investigator must include documentation of expertise, experience, and knowledge related to research studies using large datasets; evaluating ALS epidemiologic demographic risk factors; characterizing toxicants, metals and/or their biomarkers in biological samples; and evaluating gene-enviroment interactions. Expertise is illustrated by evidence of at least one peer-reviewed publication or 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-Principal Investigator (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 review.

The Letters of Support Section must include documentation of effective and well-defined working relationships between the grantee institution and any organizations or outside entities expected to participate in the proposed research that will ensure implementation and sustainability of the proposed activities. This should be evidenced by letters of support or memoranda of understanding or agreement detailing the nature and extent of the involvement from the grantee organization and outside entities. Applications that do not meet this requirement will be considered non-responsive and will not be forwarded for 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. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

(Foreign entities only): Special Instructions for acquiring a Commercial and Governmental Entity (NCAGE) Code: https://eportal.nspa.nato. int/AC135Public/Docs/US%20Instructions%2 0for%20NSPA%20NCAGE.pdf System for Award Management (SAM) – must maintain current registration in SAM (the replacement system for the Central Contractor Registration) to be renewed annually, https://www.sam.gov/portal/SAM/#1.

Grants.gov eRA Commons

All applicant organizations must register with Grants.gov. Please visit www.Grants.gov at least 30 days prior to submitting your application to familiarize yourself with the registration and submission processes.

The “one-time” registration process will take three to five days to complete. However, it is best to start the registration process at least two weeks prior to application submission.

All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization. All registrations must be successfully completed and active before the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

7. Universal Identifier Requirements and System for Award Management (SAM) All applicant organizations must obtain a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements.

The DUNS number is a nine-digit number assigned by Dun and Bradstreet Information Services. An AOR should be consulted to determine the appropriate number. If the organization does not have a DUNS number, an AOR should complete the US D&B D-U-N-S Number Request Web Form or contact Dun and Bradstreet by telephone directly at 1-866-705-5711Image Description: Image Description: (toll-free) to obtain one. A DUNS number will be provided immediately by telephone at no charge. Note this is an organizational number. Individual Program Directors/Principal Investigators do not need to register for a DUNS number.

Additionally, all applicant organizations must register in the System for Award Management (SAM).

Organizations must maintain the registration with current information at all times during which it has an application under consideration for funding by CDC and, if an award is made, until a final financial report is submitted or the final payment is received, whichever is later. SAM is the primary registrant database for the Federal government and is the repository into which an entity must provide information required for the conduct of business as a recipient. Additional information about registration procedures may be found at the SAM internet site at https://www.sam.gov/index.html.

If an award is granted, the grantee organization must notify potential sub-recipients that no organization may receive a subaward under the grant unless the organization has provided its DUNS number to the grantee organization.

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 https://www.sam.gov/portal/SAM/%231 https://www.Grants.gov https://public.era.nih.gov/commons/public/login.do?TYPE=33554433&REALMOID=06-1edb031f-46c7-44b3-b803-60b537de74d2&GUID=&SMAUTHREASON=0&METHOD=GET&SMAGENTNAME=-SM-938PYmoLVb4VrDeXo04LZUDVDvc%2b3899ByInEAjuSUvWNIGfB2zRpWiCivYGCogG&TARGET=-SM-http%3a%2f%2fpublic%2eera%2enih%2egov%2fcommons https://www.Grants.gov http://fedgov.dnb.com/webform https://www.sam.gov/index.html

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

9. Cost Sharing This FOA does not require cost sharing as defined in the HHS Grants Policy Statement (http://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf).

10. Number of Applications As defined in the HHS Grants Policy Statement,(http://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf), applications received in response to the same funding opportunity announcement generally are scored individually and then ranked with other applications under peer review in their order of relative programmatic, technical, or scientific merit. HHS/CDC will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application.

Applicant institutions may not submit applications with the same, or similar, proposed research to two or more funding opportunities from CDC. Eligible applicant organizations may submit more than one application to this FOA, provided that each application is scientifically distinct. However, applicant institutions can submit only one application with the same principal investigator. Only one application per principal investigator will be funded under this announcement. If two or more applications from the same PI are received, the only application that will be submitted for review will be the first application received based on the time and date stamp for submission in Grants.gov (http://www.grants.gov).

Section IV. Application and Submission Information

1. Address to Request Application Package Applicants must download the SF424 (R&R) application package associated with this funding opportunity from www.Grants.gov.

If access to the Internet is not available or if the applicant encounters difficulty accessing the forms on-line, contact the HHS/CDC Office of Grants Services (OGS) Technical Information Management Section (TIMS) staff at (770) 488-2700Image Description: or ogstims@cdc.gov for further instructions. Hours: Monday - Friday, 7am – 4:30pm U.S. Eastern Time. CDC Telecommunications for the hearing impaired or disabled is available at: TTY 1-888-232-6348Image Description: .

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide http://grants.nih.gov/grants/how-to-apply-application-guide.htm and here:

http://grants.nih.gov/grants/how-to-apply-application-guide/forms-d/general-forms-d.pdf, except where instructed in this Funding Opportunity Announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.