PKG00264013-instructions.pdf

Centers for Disease Control and Prevention

National Center on Birth Defects and Developmental Disabilities Extramural Research Program

Office

Characterizing the Natural History of Fragile X Syndrome to Inform the Development of

Intervention Outcome Measures

RFA-DD-21-002

Application Due Date: 01/11/2021

Characterizing the Natural History of Fragile X Syndrome to Inform the Development of

Intervention Outcome Measures

RFA-DD-21-002

TABLE OF CONTENTS

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

Part 2. Full Text Section I. Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 1. Overview Information Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations National Center on Birth Defects and Developmental Disabilities Notice of Funding Opportunity (NOFO) Title Characterizing the Natural History of Fragile X Syndrome to Inform the Development of Intervention Outcome Measures Activity Code U01, Research Project - Cooperative Agreement

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

RFA-DD-21-002

Assistance Listings (CFDA) Number(s) 93.073 Category of Funding Activity:

Health NOFO Purpose The purpose of this NOFO is to build on the foundation of the Fragile X Online Registry With Accessible Research Database (FORWARD) to conduct research to better characterize the natural history of fragile X syndrome (FXS) and meaningful outcome measures to improve the lives of children and adolescents with FXS with and without autism spectrum disorder (ASD), and from different racial/ethnic groups and geographic locations across the United States. The research will characterize the cognitive, behavioral, and adaptive skills, and other indicators of functioning of individuals with FXS. Also of interest are cognitive, behavioral, and adaptive skills outcomes for individuals with FXS as a function of diagnostic history, early intervention, and access to services. Finally, this study will explore the practical, financial, and psychological impact that caring for a family member with FXS has on caregivers and siblings of those with FXS. Planned post-award coordination of standardized in-person behavioral and functional assessments and follow-up telephone survey questionnaires with CDC's Study to Explore Early Development (SEED) Follow-up Study (RFA-DD-21-001) will facilitate comparison of health and functional outcomes for the FXS population with those for other related and frequently co-occurring conditions, such as ASD and developmental delay.

Key Dates Publication Date: To receive notification of any changes to RFA-DD-21-002, 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 https://www.grants.gov needed for this service.

Letter of Intent Due Date: 12/07/2020

Application Due Date: 01/11/2021

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

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

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

Scientific Merit Review: 03/29/2021

Secondary Review: 05/18/2021

Estimated Start Date: 09/01/2021

Expiration Date: 01/12/2021 Due Dates for E.O. 12372: Executive Order 12372 does not apply to this program.

Required Application Instructions

**ELECTRONIC APPLICATION SUBMISSION VIA ASSIST IS PREFERRED**

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

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both 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 http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

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

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

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

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

Executive Summary

Purpose. The purpose of this NOFO is to build on the foundation of the Fragile X Online Registry With Accessible Research Database (FORWARD) to conduct research to better characterize the natural history of fragile X syndrome (FXS) and meaningful outcome measures to improve the lives of children and adolescents with FXS with and without autism spectrum disorder (ASD), and from different racial/ethnic groups and geographic locations across the United States. The research will characterize the cognitive, behavioral, and adaptive skills, and other indicators of functioning of individuals with FXS. Also of interest are cognitive, behavioral, and adaptive skills outcomes for individuals with FXS as a function of diagnostic history, early intervention, and access to services. Finally, this study will explore the practical, financial, and psychological impact that caring for a family member with FXS has on caregivers and siblings of those with FXS. Planned post-award coordination of standardized in-person behavioral and functional assessments and follow-up telephone survey questionnaires with CDC's Study to Explore Early Development (SEED) Follow-up Study (RFA-DD-21-001) will facilitate comparison of health and functional outcomes for the FXS population with those for other related and frequently co-occurring conditions, such as ASD and developmental delay.

Mechanism of Support. Cooperative Agreement Funds Available and Anticipated Number of Awards. The estimated total funding

(direct and indirect) for the entire period of performance for this NOFO is $4,000,000.

The estimated total funding (direct and indirect) for Year 1 of this NOFO is $800,000.

Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications. A single award of an estimated $800,000 for year 1 is anticipated if applicants propose recruiting study participants from a group of clinics to achieve the overall study minimum sample size of 600 participants over the entire period of performance. Applicants may alternatively propose to recruit from a single clinic, in which case the award would reflect the proportionate proposed sample size. For example, if an applicant proposes to recruit 360 participants over the period of performance (i.e., 60% of the total sample needed for this study), the award ceiling would be approximately 60% of the total available funding. Five to seven smaller awards of an estimated $150,000 for year 1 are anticipated if applicants propose recruiting a smaller sample from an individual clinic. Because the scope of the proposed research may vary from application to application, it is also anticipated that the size of 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.

Budget and Period of Performance. The estimated total funding (direct and indirect) for the first budget period, 09/01/2021 to 08/31/2022, is $800,000. The estimated total funding (direct and indirect) for the entire period of performance, 09/01/2021 to 08/31/2026, is $4,000,000.

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. Applications may include more than one PI; however, the first PI listed on the application will be the contact PI for all correspondence. Any additional PIs are permitted but would be referred to as Co-PIs.

Number of Applications. Only one application per institution (normally identified by having a unique DUNS number) will be accepted.

Application Type. New Special Date(s). N/A Application Materials. See Section IV.1 for application materials

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority This program is authorized under Sections 301 and 317 C of the Public Health Service Act (42 USC Sections 241 and 247b-4), as amended.

1. Background and Purpose Background What is fragile X syndrome?

Over the past two decades, scientists have made advancements in understanding fragile X syndrome (FXS), a genetic disorder caused by changes in a gene that scientists called the fragile X mental retardation 1 (FMR1) gene when it was first discovered. FXS is the most common known inherited cause of intellectual disability (ID). FXS affects both males and females.

However, females often have milder symptoms than males. The exact number of people who have FXS is unknown, but a review of research studies estimated that about 1 in 7,000 males and about 1 in 11,000 females have been diagnosed with FXS. [1] People who have FXS can present with a range of ID [2] and may also experience a wide range of emotional, behavioral, [3] sensory, and/or social difficulties. [4] A notable proportion of people with FXS have been diagnosed with autism spectrum disorder (ASD), although the variability of estimates is wide ranging, from 30%-67% in males and 16%-23% in females with FXS. [5, 6, 7] FXS is characterized by mild-to-moderate ID, autistic behaviors, sensory integration problems, and physical features, such as long face and large prominent ears. FXS causes a range of developmental problems including learning disabilities and cognitive impairment. Over the past two decades, scientists have made advancements in understanding the genetics of FXS: it is a genetic disorder caused by a CGG trinucleotide repeat mutation in the FMR1 gene. In people with FXS, the CGG segment is repeated more than 200 times, while in people without FXS, it repeats from 5 to about 40 times.

What is FORWARD?

CDC has funded three studies to expand our understanding of FXS. The Fragile X Online Registry With Accessible Research Database (FORWARD) was developed and implemented to support collection and management of longitudinal data on individuals with FXS, incorporating the earlier-developed FXS Registry. There are two main components to FORWARD: (1) the registry, which collects primarily demographic information from families with FXS-associated disorders (full mutation, premutation, and noncarriers) and (2) the longitudinal database, which collects data from individuals with full mutation FXS by clinicians, primarily during a patient?s scheduled clinic visit, and by parents/caregivers.

The first study (CDC-RFA-DD-07-003; 2008 to 2011) piloted an infrastructure to conduct a study on FXS across multiple sites located in geographic regions across the United States. The Fragile X Clinical and Research Consortium (FXCRC), consisting of over 25 FXS specialty clinics, was successful in collecting data across multiple sites. This first study showed that using a consortium of clinics was an effective way to engage multiple clinics. Evaluation of data collection forms led to revisions agreed upon by members of the FXCRC, the FORWARD project staff, and CDC collaborators during that study period.

The second study (CDC-RFA-DD-11-007; 2011 to 2015) developed and piloted the infrastructure for a registry and for longitudinal data collection. [8] The goal of the registry was to develop a source of potential participants for FXS-related research conducted by CDC or by others. The longitudinal dataset was designed to support collection and analysis of data over time on a large cohort of individuals with FXS, a notable challenge given the prevalence of FXS. The most significant accomplishment of the second study was the successful creation of the infrastructure for investigators to coordinate with specialty clinics in the FXCRC to contribute longitudinal data to FORWARD. Building on this infrastructure will enhance understanding of FXS and its co-occurring conditions, to describe current services and their impact on outcomes and quality of life, and to identify service needs and barriers.

The third study (CDC-RFA-DD-15-003; 2015 to 2020) is ongoing and aims to build on the foundation created via the first two studies by providing information to guide parents and health professionals towards the best services and supports possible, as well as inspire future research questions. During the third study, FORWARD was expanded to include data from adults with FXS on co-occurring conditions as well as data on health care transition, health monitoring, vocational and educational status, and other areas that affect quality of life. Three clinics also received additional support to engage racial/ethnic minority and underserved populations and test ways to measure developmental changes in cognition, behavior, emotion, and neurobiology in the population affected by FXS.

Following the third study, a supplemental year awarded in 2020 allows for continued data collection from individuals already enrolled in the longitudinal database and from new participants to increase sample size for future analyses.

What has FORWARD accomplished?

Results from FORWARD published in recent years include publications related to symptoms, functioning, and co-occurring conditions of FXS. Kaufmann and colleagues [7] used data collected from 2012 to 2014 to find that over half of males met the diagnostic criteria for ASD and that the group with co-occurring ASD and FXS had higher prevalence of seizures, sleep problems, and behavior problems than those without co-occurring ASD. Additionally, an investigation using FORWARD data on the psychometric properties of the Social Communication Questionnaire and Social Responsiveness Scale in predicting an ASD diagnosis indicated that these instruments have limited use in this population. [9] The authors' proposal of adapted versions of these scales for characterizing ASD in the population affected by FXS added knowledge about outcomes measurement among individuals with FXS. Another analysis of FORWARD data about preventive healthcare services suggested that most children with FXS meet dental care and immunization but not physical activity guidelines, particularly individuals with co-occurring ASD. [10] More recent publications from the third study described bowel and bladder training [11] and irritability/aggression/agitation/self-injurious (IAAS) behaviors among individuals with FXS. [12] Which gaps in FXS knowledge will this NOFO address?

Although data collected in FORWARD advanced knowledge about FXS, its co-occurring conditions, and outcomes, gaps remain in the characterization of health and functional outcomes in association with medical care, education services, and support for transition across the lifespan. We are just beginning to understand how this complex condition affects individual developmental trajectory, how this condition affects individuals with FXS across the lifespan, the impact of FXS and co-occurring ASD, and how we can design early interventions to improve the lives of all of those affected. Data are also limited concerning the prevalence of other conditions co-occurring with FXS, such as attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and seizures. In addition, data are limited on the frequency of interventions used to treat symptoms, [13, 14] effectiveness of interventions, and receipt of health services among people with FXS. Research leading to a greater understanding of the unmet needs and challenges faced by individuals who have FXS could potentially benefit all individuals affected by intellectual disabilities.

To address these gaps, this NOFO will conduct longitudinal follow-up studies of individuals with FXS previously enrolled in FORWARD as well as enroll and collect data from new participants who receive care in FXS specialty clinics. In addition, this NOFO, in combination with the CDC's Study to Explore Early Development (SEED) follow-up study (RFA-DD21- 001), will address gaps in understanding how outcomes and needs differ between individuals with FXS and individuals with ASD who do not have FXS during early childhood to young adulthood and beyond. [15]

Purpose The purpose of this NOFO is to build on the foundation of FORWARD to conduct research to better understand the natural history of FXS and identify meaningful outcome measures to improve the lives of children and adolescents with FXS with and without ASD and among different racial/ethnic groups and geographic locations across the United States. This research will characterize the cognitive, behavioral, and adaptive skills, and other indicators of functioning of individuals with FXS. Also of interest are cognitive, behavioral, and adaptive skills outcomes for individuals with FXS as a function of diagnostic history, early intervention, and access to services. Finally, this study will explore the practical, financial, and psychological impact that caring for a family member with FXS has on caregivers and siblings of those with FXS. Planned post-award coordination of standardized in-person behavioral and functional assessments and follow-up telephone survey questionnaires with CDC's SEED Follow-up Study will facilitate comparison of health and functional outcomes for the FXS population with those for other related and frequently co-occurring conditions, such as ASD and developmental delay.

Healthy People 2030 and other National Strategic Priorities The National Center on Birth Defects and Developmental Disabilities (NCBDDD) of CDC within HHS 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). Specifically, this NOFO addresses the following Healthy People 2030 Goals:

DH-2030-5 Reduce the proportion of adults with disabilities who experience serious psychological distress

AH-2030-R2 Increase the proportion of students who are served under the Individuals with Disabilities Education Act (IDEA) who graduate high school with a diploma

MHMD-2030-D1 Increase the number of youths with serious emotional disturbance (SED) who are identified and receive treatment

MICH-2030-19 Increase the proportion of children and adolescents with special health care needs who receive care in a family-centered, comprehensive, and coordinated system

Public Health Impact FXS, one of the most common causes of inherited ID, is a lifelong condition that affects individuals, families, and health and education systems. By addressing gaps in knowledge about the health status of people living with FXS and effects of services, this research supports the long-term goal of improving health outcomes and quality of life among people with FXS.

Specifically, information about cognitive, behavioral, and developmental outcomes for individuals with FXS can provide a more complete epidemiologic profile of the FXS population to inform development and enhancement of interventions and services. Data collected through this NOFO is intended to improve the health, functioning, and quality of life among persons with FXS and their families by

1. improving our understanding of the relationship between earlier diagnosis, services received, and later cognitive, behavioral, and adaptive function;

2. informing the development of outcome measures for future drug treatment trials; and

3. informing public policies on eligibility for services.

Relevant Work As indicated above, this NOFO will build on three multi-year studies. The first pilot study (2008 to 2011) tested the infrastructure required to implement multi-site research in FXS, the Fragile X Clinical and Research Consortium (FXCRC). The second pilot study (2011 to 2015) tested the feasibility of longitudinal data collection across these multiple FXS specialty clinics.

During that study, FXS specialty clinics across the country, in collaboration with the FXCRC, contributed data on individuals diagnosed with FXS, from birth to 24 years of age. Data are currently being collected through FORWARD by 24 participating clinics, each with local IRB approval, using structured clinician and parent-report forms and standardized parent-report instruments on behavior and communication (i.e. SRS, SCQ, ABC-C). The third study (2015 to 2020) continued the work established in the pilot studies, expanding data collection for FORWARD and enabling longitudinal data collection for existing and new participants. That study also emphasized the enrollment of minority and underserved populations and adults with FXS over 24 years of age. Items in the registry were revised and questions relating to the health and quality of life of adults with FXS were added.

In addition to building on prior investments in FORWARD, this NOFO will leverage the infrastructure and the methods used in the SEED follow-up study (RFA-DD-21-001). SEED is an ongoing multi-phase, multi-site, case control study of children identified at age 2 to 5 years with ASD, other developmental disabilities and from the general population. SEED was originally conducted in three phases among children in three birth cohorts, i.e., children born 2003 to 2006, 2008 to 2012, and 2014 to 2017, and is ongoing through July 2021. As part of the SEED follow-up study, in 2021 to 2026, longitudinal follow-up and research on previous SEED participants will obtain information through early adulthood on their health and functioning, service use and needs, and the impact of ASD on their families. Similarity of methods of this FXS study with that in the SEED follow-up study will improve efficiency and consistency of data collection on cognitive, behavioral, adaptive skills, and other indicators of functioning for individuals with FXS with or without ASD. This cross-program coordination will increase understanding of differences in functioning, outcomes, diagnostic history, early intervention and service needs for children with FXS with and without ASD, and children with ASD without FXS in similar age groups from childhood through young adulthood.

2. Approach The work specified in this NOFO will build on FORWARD and include an even stronger focus on addressing gaps in knowledge identified from stakeholders and FXS experts, i.e., enhancing the understanding of cognitive, behavioral, adaptive skills and other indicators of functioning of individuals with FXS with and without autism spectrum disorder (ASD) and among different racial/ethnic groups and geographic locations.

Specifically, this NOFO includes collection of longitudinal cognitive, developmental, behavioral, clinical, and environmental data to accomplish the following:

describe the health and functioning of individuals with FXS during childhood, adolescence, and young adulthood;

inform our understanding of the relationship between earlier diagnosis and intervention and later cognitive/behavioral functioning;

analyze the impact of treatments and interventions on health outcomes and quality of life; and improve approaches to measuring cognitive and behavioral status in patients with FXS.

Required Elements

Computer Assisted Telephone Interviews (CATI). Each site is expected to share contact information of consented caregivers with a CDC contractor (one contractor for all of the FXS and SEED research sites). The contractor will conduct follow-up CATI with parents or caregivers.

Standardized assessments. This NOFO will capitalize on the data already collected via FORWARD, to include new data from standardized assessments to characterize the cognitive, behavioral, and adaptive skills, and other indicators of functioning of individuals with FXS born between 2003 and 2017 (inclusive). Each site is expected to conduct in-person, standardized assessments and enter data for those assessments into a secure, contractor-developed data transmission site. Each site is expected to also make the data available directly to CDC upon request.

Coordination with SEED. Planned coordination of the selection of standardized in-person assessments and telephone survey questionnaires with SEED Follow-up Study (RFA-DD-21-001) will facilitate comparison of health and functional outcomes for the FXS population as compared to individuals in the general population and individuals with other related and frequently co-occurring conditions, such as ASD without FXS, and developmental delay (DD). Sites are expected to collaborate with other recipients, CDC, and SEED Follow-up Study recipients to determine the list of in-person and CATI assessments that will be administered.

Structure of Study This NOFO will support an observational, longitudinal study on individuals with full mutation FXS aged 5 to 23 years who have previously participated in FORWARD data collection and new participants who did not previously participate in FORWARD. This study is expected to engage and complete data collection for at least 150 eligible participants each of the four years of data collection in this NOFO for a minimum of 600 participants over the 5-year project period. Although FORWARD provides a potential source of eligible participants aged 5 to 23 years for the current NOFO, investigators may also recruit new participants.

Applicants may propose recruiting study participants from an individual clinic or recruiting from a group of clinics with which the principal investigator has documented data sharing and collaborative agreements. Recipients are expected to coordinate and collaborate with the CDC and CDC contractor to ensure timely and accurate data collection. Recipients can collaborate with the FXCRC to facilitate access to study participants from the FXS specialty clinics.

Additionally, recipients are expected to participate in FXS meetings, conference calls, and workgroups to provide individual input and advice on research gaps in risk factors for FXS and the characteristics and needs of children with FXS that can be addressed using existing FORWARD data.

Recruitment of equal numbers of individuals across three birth cohorts with years similar to those for the SEED participants (i.e., individuals born 2003 to 2007, 2008 to 2012, and 2013 to 2017) will maximize statistical power for comparative analyses across studies. Applications for the full budget ceiling amount are expected to enroll, assess, and complete data collection (including telephone interviews) for a minimum of 150 individuals each of the 4 years of data collection in this NOFO, equally divided among the three birth cohorts. Applications for lower budget amounts are expected to enroll, assess, and complete data collection on a proportionate sample size (e.g., if requesting 60% of the funding ceiling, applicants are expected to enroll, assess, and complete data collection on a minimum of 90 individuals each year) to ensure the overall NOFO aims of complete data on at least 150 participants each year, a minimum of 600 participants over the project period.

Study Requirements:

1. Obtain institutional review board (IRB) approvals or reliances, and site-specific consent forms, as required based on the new common rule for a single IRB, and assist CDC in submitting an information collection request to the Office of Management and Budget for approval in Year 1 to share standardized assessment data from participants and personally identifiable, individual-level contact information of consented caregivers of all participants from each clinic with a central CDC contractor.

2. In Year 1, collaborate with CDC and a CDC contractor to develop, test, and use secure electronic data systems for sharing participant information, assessments, and conducting interviews.

3. Hire, train, and maintain clinic personnel. Recipients are expected to hire an investigator qualified to train and standardize psychometrists in each clinic enrolling participants, determine their field readiness, evaluate administration fidelity and scoring reliability, and answer questions from participants and families.

4. Enroll and maintain contact with participants. Enrolled participants are expected to be evenly split across the three birth cohorts. Recipients are expected to share the caregiver contact information with a CDC-funded contractor responsible for conducting telephone interviews and collaborate with CDC and the CDC contractor to achieve the minimum sample size for the overall study (i.e., at least 600 participants with CATI and standardized assessment data across the period of data collection, distributed equally across three birth cohorts).

5. Recipients will be expected to implement and provide data on the success of strategies to maximize enrollment of FORWARD and new participants within each clinic as well as maintain contact with study participants. Strategies should emphasize enrollment and retention of participants of diverse race/ethnicity and demographic backgrounds.

6. Conduct in-person standardized assessments. Recipients are expected to administer standardized psychometric assessments with participants with full-mutation FXS born between 2003 and 2017 (inclusive), who are already enrolled in FORWARD, or are new enrollees. They must employ staff for scheduling, obtaining informed consent and administering a standardized psychometric assessment of approximately 90 minutes in length.

7. Generate and provide feedback letters. Recipients are expected to provide caregivers who desire feedback with feedback on results of the psychometric assessment by sending a standardized letter to participants within one month of the assessment.

8. Maintain confidentiality of study documents and contribute site-specific data to a pooled dataset. Recipients are expected to store, enter, and transmit relevant data in a standardized and secure manner with common elements mutually agreed upon by CDC and recipients. This will become part of a pooled dataset that will be maintained and overseen by CDC and a CDC contractor and accessed by recipients and clinic sites through a CDC-approved mechanism that meets Federal standards for security and confidentiality.

9. During the participant enrollment and data collection period, share participant contact information with the CDC-funded contractor that will be conducting the follow-up telephone survey questionnaire. Recipients are expected to securely share personally identifiable, individual-level contact information of consented caregivers with the CDC contractor for CATI on a biweekly basis.

10. Serve as the point of contact for interested and enrolled participants throughout implementation of the follow-up surveys; work collaboratively with CDC's survey contractor to maximize participation. Recipients are expected to meet by phone or video call with CDC's central interviewing contractor on a biweekly basis to discuss study progress and troubleshoot any problems with study implementation.

11. Collaborate with other recipients, CDC, and CDC-funded recipients of the SEED Follow-up Study (RFA-DD-21-001). Recipients are expected to collaborate with other recipients and CDC to discuss and determine the list of in-person and CATI assessments that will be finalized during the first year of the cooperative agreement.

12. Collaborate with clinicians and researchers from the sites participating in the longitudinal database and CDC representatives to identify important clinical care and public health research questions and utilize data from the longitudinal database to address them.

13. Collaborate with the other recipients and CDC representatives to establish and implement guidelines and processes for data analysis and publications.

14. Complete at least two manuscripts submitted for publication each year in years 2 through 5 of this NOFO as first or co-author using previously collected FORWARD data and/or data collected under the current agreement. Manuscripts are expected to be prepared and submitted in accordance with guidelines and processes established in collaboration with CDC and other recipients.

15. Participate in a Steering Committee to encourage collaboration across recipients of this NOFO and provide the necessary expertise and oversight to ensure successful completion of the objectives.

Objectives/Outcomes Overall Study Objectives:

1. To ensure data collected are of high scientific quality and comparable to other sites by following a common methodology established with CDC and other recipients.

2. To implement methods to ensure high participation rates of previous FORWARD participants as well as new participants and maximize the number of completed surveys and in-person assessments.

3. To collect and analyze standardized, high-quality information via parental or caregiver (or participant) telephone interviews and in-person assessments to inform further research and improve key outcomes for individuals with FXS and their families across geographically diverse participating FXS clinics.

4. To interpret and disseminate analytic results to expand the evidence base that can inform research and public health action.

Expected Outcomes:

1. Produce timely, high-quality, longitudinal, standardized data on cognitive, behavioral, and adaptive skills outcomes for individuals with FXS, with and without ASD and among different racial/ethnic and geographic groups, and contribute to a common research database that will facilitate the following research goals:

a. Characterize the cognitive, behavioral, and adaptive functioning of individuals with FXS

b. Investigate differences in current cognitive, behavioral, and adaptive functioning as a function of earlier indicators (e.g., age at diagnosis and intervention, and access to services)

c. Investigate the relationship between earlier diagnosis and intervention, and later cognitive, behavioral, and adaptive functioning

d. Characterize the sequencing and circumstances of FXS diagnosis and other mental, developmental, and behavioral diagnoses

e. Characterize the practical, financial, and psychological impact of FXS on caregivers and siblings

f. Characterize FXS from childhood to young adulthood

2. Analyze and disseminate data on individuals with FXS and their families to better characterize the natural history of FXS and meaningful outcome measures to improve the lives of children, adolescents, and young adults with FXS with and without ASD and their families.

Target Population The target population is comprised of individuals with a diagnosis of full mutation FXS who visit FXS specialty clinics, who were born between 2003 and 2017 (inclusive), and represent the racial/ethnic diversity of the population in the FXS clinic catchment area. This study is expected to engage and complete data collection for at least 150 eligible participants each of the four years of data collection in this NOFO for a minimum of 600 participants over the 5-year project period. Applications for the full budget ceiling amount are expected to enroll, assess, and complete data collection on a minimum of 150 individuals each of the four years of data collection in this NOFO, approximately equally divided among the three birth cohorts.

Applications for lower budget amounts are expected to enroll, assess, and complete data collection on a proportionate sample size (e.g., if requesting 60% of the funding ceiling, applicants are expected to enroll, assess, and complete data collection on a minimum of 90 individuals each year), to ensure the overall NOFO aims of at least 150 participants each year and a minimum sample size of 600 participants. Participants can be those who have previously contributed to FORWARD or are new to the study, with clinics encouraged to first recruit previous FORWARD participants. Applicants are encouraged to recruit from populations that are diverse with respect to racial/ethnic groups, socioeconomic status, and other indicators of health disparities to represent their clinic population. Applicants will be expected to identify, establish, or extend partnerships with clinics or organizations that serve individuals with FXS, in order to support data collection, translation and dissemination of study findings.

Collaboration/Partnerships Recipients will be expected to collaborate with CDC, a CDC survey and data center contractor, and other FXS and SEED recipients to accomplish the data collection and other goals and objectives stated in this NOFO. All recipients will be expected to participate in workgroups with CDC and other recipients to discuss and finalize data collection instruments.

Recipients will be expected to contribute their site-specific individual participant data to a shared data pool for potential analysis by FXS investigators, SEED investigators, and CDC. For this purpose, they will be expected to adhere to the following:

1. Clinic-specific roles and responsibilities for maintaining the confidentiality and security of the personally identifiable information collected as part of this research; and

2. CDC-approved mechanisms for accessing pooled, de-identified data through a CDC-approved remote access system meeting Federal standards for maintaining security and confidentiality of participant data.

Evaluation/Performance Measurement Recipients are expected to participate in the planning and implementation of program and process evaluation of the longitudinal database in collaboration with CDC and create an evaluation plan by eight months post-award that monitors progress for completion of major requirements of the award. Proposed evaluation plans will be refined in collaboration with CDC after award.

Proposed evaluation plans are expected to

1. assess adherence to obtaining and maintaining appropriate staffing;

2. monitor achievement of proposed number and diversity of participants for access of initial contact information for telephone-administered and in-person assessments;

3. assess adherence to data quality, data confidentiality and security, and data management protocols;

Translation Plan Recipients are expected to disseminate findings through peer-reviewed journals, presentations at professional conferences, oral and written communication with the FXS population and the organizations that represent them, and through other appropriate mechanisms (e.g., social media, health education channels). Recipients are expected to develop a plan within 12 months post award for completion of priority analyses (including at least 2 peer-reviewed manuscript submissions each year in years 2 through 5) and their dissemination in collaboration with CDC.

The plan should describe

The priority topics for FXS data analyses, How findings will be disseminated through various channels with health policymakers and health systems, and

How data will inform public health actions to improve the health, functioning, and quality of life of individuals with FXS and their families.

OMB/PRA is expected to apply.

References:

1. Hunter, J. Rivero-Arias, O., Angelov, A., Kim, E., Fotheringham, I., & Leal, J. (2013).

Epidemiology of fragile X syndrome: A systematic review and meta-analysis. American Journal of Medical Genetics Part A, 164A,1648-1658.

2. Hall, S., Burns, D., Lightbody, A., & Reiss, A. (2008). Longitudinal changes in intellectual development in children with fragile X syndrome. Journal of Abnormal Child Psychology, 36, 927-939.

3. Hardiman, R., & McGill, P. (2018). How common are challenging behaviors amongst individuals with fragile X syndrome? A systematic review. Research in Developmental Disabilities, 76, 99-109.

4. Smith, L., Barker, E., Seltzer, M., Abbeduto, L. & Greenberg, J. (2012). Behavioral phenotype of fragile X syndrome in adolescence and adulthood. American Journal on Intellectual and Developmental Disabilities, 117(1), 1-17.

5. Harris, S., Hessl, D., Goodlin-Jones, B., Ferranti, J., Bacalman, S., Barbato I., et al.

(2008). Autism profiles of males with fragile X syndrome. American Journal of Mental Retardation, 113, 427-438.

6. Clifford, S., Dissanayake, C., Bui, Q., Huggins, R., Taylor, A., & Loesch, D. (2007).

Autism spectrum phenotype in males and females with fragile X full mutation and premutation. Journal of Autism and Developmental Disorders, 37, 738-747.

7. Kaufmann, W., Kidd, S., Andrews, H., Budimirovic, D., Esler, A., Haas-Givler, B., et al.

(2017). Autism spectrum disorder in fragile X syndrome: Co-occurring conditions and current treatment. Pediatrics, 139(Suppl 3), s194-s206.

8. Sherman, S., Kidd, S., Riley, C., Berry-Kravis, E., Andrews, H., Miller, R., et al. (2017).

FORWARD: A registry and longitudinal clinical database to study fragile X syndrome.

Pediatrics, 139(Suppl 3):s183-s193.

9. Kidd, S., Berry-Kravis, E., Choo, T., Chen, C., Esler, A., Hoffmann, A., et al. (2019).

Improving the diagnosis of autism spectrum disorder in fragile X syndrome by adapting the Social Communication Questionnaire and the Social Responsiveness Scale ? 2.

Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-019- 04148-0

10. Kidd, S., Lachiewicz, A., Barbouth, D., Blitz, R., Delahunty, C., McBrien, D. et al.

(2014). Fragile X syndrome: A review of associated medical problems. Pediatrics, 134(5), 995-1005.

11. Berry-Kravis, E., Kidd, S., Lachiewicz, A., Choo, T., Tartaglia, N., Talapatra, D., et al.

(2019). Toilet training in fragile X syndrome. Journal of Developmental and Behavioral Pediatrics, 40(9), 751-761.

12. Gilbertson, K., Jackson, H., Dziuban, E., Sherman, S., Berry-Kravis, E., Erickson, C., et

al. (2019). Preventive care services and health behaviors in children with fragile X syndrome. Disability and Health Journal, 12(4), 564-573.

13. Eckert, E., Dominick, K., Pedapati, E., Wink, L., Shaffer, R., Andrews, H., et al. (2019).

Pharmacologic interventions for irritability, aggression, agitation and self-injurious behavior in fragile X syndrome: an initial cross-sectional analysis. Journal of Autism and Developmental Disorders, 49(11), 4595-4602.

14. Lozano, R., Azarang, A., Wilaisakditipakorn, T., & Hagerman, R.,(2016). Fragile X syndrome: A review of clinical management. Intractable & Rare Diseases Research, 5(3), 145-157.

15. Trans-NIH Fragile X Coordinating Committee. (October, 2019). NIH Strategic Plan for Research on FMR1-Associated Conditions. Available at: https://www.nichd.nih.gov /sites/default/files/2019-11/NIH_ResearchPlan_FMR1_2019.pdf

Section II. Award Information Funding Instrument Type: 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: $4,000,000 The estimated total funding (direct and indirect) for the entire period of performance for this NOFO is $4,000,000. The estimated total funding (direct and indirect) for Year 1 of this NOFO is $800,000. Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications.

Anticipated Number of Awards: 1 A single award of an estimated $800,000 for year 1 is anticipated if applicants propose recruiting study participants from a group of clinics to achieve the overall study minimum sample size of 600 participants over the entire period of performance. Applicants may alternatively propose to recruit from a single clinic, in which case the award would reflect the proportionate proposed sample size. For example, if an applicant proposes to recruit 360 participants over the period of performance (i.e., 60% of the total sample needed for this study), the award ceiling would be approximately 60% of the total available funding. Five to seven smaller awards of an estimated $150,000 for year 1 are anticipated if applicants propose recruiting a smaller sample from an individual clinic. Because the scope of the proposed research may vary from application to application, it is also anticipated that the size of 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.

https://www.nichd.nih.gov/sites/default/files/2019-11/NIH_ResearchPlan_FMR1_2019.pdf https://www.nichd.nih.gov/sites/default/files/2019-11/NIH_ResearchPlan_FMR1_2019.pdf

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

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

Award Ceiling: $800,000 Per Budget Period Award Floor: $0 Per Budget Period Total Period of Performance Length: 5 year(s)

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

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

Section III. Eligibility Information

1. Eligible Applicants Eligibility Category: Unrestricted (i.e., open to any type of entity above), subject to any clarification in text field entitled "Additional Information on Eligibility"

Additional Eligibility Category:

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. Additional Information on Eligibility

For an application to be considered, the application must be responsive to these Special Eligibility Requirements. If your application is incomplete or non-responsive to the special eligibility requirements listed in this section, it will not enter into the review process.

All applicants must document that they will have access to individual contact information and data from previous FORWARD participants for all clinics they propose to include in their recruitment pool.

http://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf

Therefore, applicants must either:

1. be the entities that collected the original FORWARD data, and therefore have the information needed to reach these individuals for additional data collection;

OR

2. have established collaborative agreements to work with the entities that originally collected contact information and data from FORWARD participants (i.e., former FORWARD recipients) so that they can reach the FORWARD participants for the data collection as outlined in this NOFO.

4. Justification for Less than Maximum Competition N/A

5. Responsiveness If the Responsiveness information requested below is incomplete or non-responsive to these requirements, the application will not enter into the review process.

All applicants must document that they will have access to individual contact information and data from previous FORWARD participants for all clinics they propose to include in their recruitment pool as evidenced by one of the following methods:

1. Applicants must provide evidence (e.g., notice of award for the original FORWARD studies) that their…