RFA-DD-21-001.pdf

Centers for Disease Control and Prevention

National Center on Birth Defects and Developmental Disabilities Extramural Research Program

Office

Study to Explore Early Development (SEED) Follow up Studies

RFA-DD-21-001

Application Due Date: 11/10/2020

Study to Explore Early Development (SEED) Follow up Studies

RFA-DD-21-001

TABLE OF CONTENTS

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

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

Part 1. Overview Information Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations National Center on Birth Defects and Developmental Disabilities Notice of Funding Opportunity (NOFO) Title Study to Explore Early Development (SEED) Follow up Studies Activity Code U01 Amendment 2 (10/22/20):

Section I, #2. Approach, Requirements for Component A, item #4.

For Component A, two LOIs will be required in Y2. The NOFO has been updated to remove the conflicting statement of requirements for Y2. This is in reference to Q12 in Appendix C.

Section I, #2. Approach, Requirements for Component A, item #11.

For Component A, participant eligibility criteria for inclusion in the follow-up surveys has been updated. Former SEED participants are eligible if they received a final study classification of ASD, DD or POP and the mother or primary caregiver consented to future follow-up. This is in reference to Q3 in Appendix C.

Section I, #2. Approach, Introduction to Requirements for Component B

For Component B, participant eligibility requirements have been updated. Former SEED participants are eligible if they (1) received a final class of ASD or DD in SEED 1,2, or 3;

(2) completed the clinic visit, including the Mullen Scales of Early Learning, during SEED 1,2 or 3; and (3) completed the first follow-up survey in Component A. This is in reference to Q3 in Appendix C.

Section III, Eligibility Information, #3. Additional information on Eligibility

The entities previously funded by CDC to collect data for SEED 1,2, or 3 have been updated to include the Regents of the University of Colorado. This is in reference to Q31 in Appendix C.

Section VIII. Other Information

Applicant questions and CDC responses have been added to Appendix C. Additional Q&As have been added to Appendix C (Questions from Potential Applicants and CDC Responses).

Amendment 1 (9/18/20): Added informational webinar for applicants that will be held on October 2, 2020, from 11:00am-12:30pm. For details, see Part 1, Executive Summary under

Special Date(s).

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

RFA-DD-21-001

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

Health NOFO Purpose The purpose of this NOFO is to gain knowledge about autism spectrum disorder (ASD), including risk factors for ASD and the expression of ASD, from childhood through early adulthood to improve the health and functioning of individuals with ASD as they mature. This will be accomplished through five funding components (described in the Executive Summary of this NOFO). Together, these five funding components will support 1) analysis of existing data and biospecimens from preschool aged children and their families who participated in the CDC funded study known as the Study to Explore Early Development (SEED), a multi-phase, multi-site, case-control study of children identified at age 2-5 years with ASD, other developmental disabilities (DD), and from the general population (POP); and 2) longitudinal follow-up surveys and research on previous SEED participants to obtain information through early adulthood on their health and functioning, service use and needs, and the impact of ASD on their families.

Key Dates Publication Date: To receive notification of any changes to RFA-

DD-21-001, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link.

An email address is needed for this service.

Letter of Intent Due Date: 10/05/2020

Application Due Date: 11/10/2020

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.

https://www.grants.gov

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: 01/13/2021

Secondary Review: 02/22/2021

Estimated Start Date: 07/01/2021

Expiration Date: 11/11/2020 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 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 gain knowledge about autism spectrum disorder (ASD), including risk factors for ASD and the expression of ASD, from childhood through early adulthood, and to obtain information that can be used to improve the health and functioning of individuals with ASD as they mature. This will be completed through http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf

1) analysis of existing data and biospecimens from preschool-aged children and their families who participated in the CDC funded study known as the Study to Explore Early Development (SEED), a multi-phase, multi-site, case-control study of children identified at age 2-5 years with ASD, other developmental disabilities (DD), and from the general population (POP); and 2) longitudinal follow-up of and research on previous SEED participants to obtain information through early adulthood on their health and functioning, service use and needs, and the impact of ASD on their families.

These activities will be accomplished through five components (A-E):

Component A: Enhanced Epidemiologic Research Using Existing SEED Data and Follow-up Surveys of Existing SEED Participants To conduct analyses of existing SEED data and follow-up surveys of participants from SEED Phases 1, 2, and 3 (referred to as SEED 1-3) to

1. Address current research gaps, and publish findings related to risk factors for ASD and the characteristics and needs of children with ASD; and

2. Support the implementation of follow-up surveys in collaboration with CDC from an existing list of SEED participants in SEED 1-3.

Component B: In-Person Assessment of Intellectual Abilities of SEED Participants To conduct follow-up assessments of intellectual abilities on a subset of children and adolescents (aged >= 8 years), who were initially identified as having ASD or another DD in SEED 1-3 and who completed the follow-up surveys implemented through Component A of this NOFO. To be funded for Component B, applicants must apply and be funded for Component A.

Component C: Maternal Auto-Antibody Testing To conduct assays of maternal autoantibodies reactive to proteins in the fetal brain using stored SEED 1 and 2 samples and to conduct analyses of the association between these maternal autoantibodies and ASD. To be funded for Component C, applicants must apply and be funded for Component A.

Component D: Genetic Analyses To identify analytic priorities for generating and analyzing SEED genetic data; to develop and implement methods for combining existing SEED 1 genetic data and newly generated SEED 2 and 3 genetic data for use by SEED investigators and contribution to data repositories; and to support SEED investigators conducting analyses to increase understanding of the genetic risk factors for ASD and their interaction with environmental risk factors. To be funded for Component D, applicants must apply and be funded for Component A.

Component E: Biorepository To maintain a repository of biospecimens previously collected from SEED 1-3 participants. To be funded for Component E, applicants must apply and be funded for Component A.

Applicants should clearly indicate the components for which they are applying and should include, at the beginning of the title, the respective component under which the application should be considered (i.e., Component A, B, C, D, and/or E). A separate application is required for each component.

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

(direct and indirect) for the period of performance is $16,370,000 to support up to six anticipated awards for Component A, up to two awards for Component B, one award for Component C, one award for Component D, and one award for Component E, for a total of up to 11 awards for the five components.

Component A: Enhanced Epidemiologic Research Using Existing SEED Data and Follow-up Surveys of Existing SEED Participants Period of Performance: 5 years (7/1/2021 - 6/30/2026) Anticipated Number of Awards: Up to six Ceiling: $750,000 (direct and indirect costs) (Note: the ceiling assumes the awardee will collaborate with two or more former SEED sites to contact participants and have a minimum of 2,400 eligible participants in their sample pool.)

Floor: $230,000 (direct and indirect costs) Estimated Average Award (Note: this average award is based on an eligible sample of 800 participants with the funding adjusted up or down based on the number of participants):

Budget Year 1: $425,000 (direct and indirect costs) Budget Years 2-5: $405,000 (direct and indirect costs)

Estimated Total Funding: $12,270,000 (direct and indirect costs) Component B: In-Person Assessment of Intellectual Abilities of SEED Participants Period of Performance: 4 years (7/1/2021 - 6/30/2025) Anticipated Number of Awards: Up to two Ceiling: $20,000 (direct and indirect costs) (Year 1 only) Floor: $0 Estimated Average Award:

Budget Year 1: $20,000 (direct and indirect costs) Budget Years 2-4: $160,000 (direct and indirect costs)

Estimated Total Funding: $1,000,000 (direct and indirect costs) Component C: Maternal Auto-Antibody Testing Period of Performance: 3 years (7/1/2021 - 6/30/2024) Anticipated Number of Awards: One Ceiling: $200,000 (direct and indirect costs) Floor: $0 Estimated Average Award for First Year: $200,000 (direct and indirect costs) Estimated Total Funding: $600,000 (direct and indirect costs) Component D: Genetic Analyses

Period of Performance: 5 years (7/1/2021 - 6/30/2026) Anticipated Number of Awards: One Ceiling: $540,000 (direct and indirect costs) (Note: the ceiling assumes the awardee will provide secure access to high-capacity computing servers that meet Federal standards for security and confidentiality for approved SEED investigators. Applicants who are not able to provide access to high-capacity computing servers for approved investigators will receive an award closer to the average of $450,000.)

Floor: $0 Estimated Average Award for First Year: $450,000 (direct and indirect costs) Estimated Total Funding: $2,250,000 (direct and indirect costs) Component E: Biorepository Period of Performance: 5 years (7/1/2021 - 6/30/2026) Anticipated Number of Awards: One Ceiling: $50,000 (direct and indirect costs) Floor: $0 Estimated Average Award for First Year: $50,000 (direct and indirect costs) Estimated Total Funding: $250,000 (direct and indirect costs) Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications. Because the nature and scope of the proposed research will vary from application to application, it is also anticipated that the amount of each award may also vary. The total amount awarded, and the number of awards, will depend upon the number, quality, duration and cost of the applications received.

Budget and Project Period. The estimated total funding (direct and indirect) for the first budget period, 7/1/2021 - 6/30/2022, is $3,290,000. The estimated total funding (direct and indirect) for the entire 5-year performance period (7/1/2021 - 6/30/2026), including all components, is $16,370,000.

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.A.

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 through their organization.

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.

http://www.cdc.gov/od/pgo/funding/grants/additional_req.shtm#SectionIV http://era.nih.gov/commons/index.cfm#SectionIII1A

Number of Applications. Only one application per institution (normally identified by having a unique DUNS number) is allowed per component for this NOFO. All eligible applicants for Component A can also apply for Components B, C, D, and/or E. To be funded for components B, C, D, and/or E, eligible applicants must apply for and be funded for Component A. Separate applications are required for each component.

Application Type. New.

Special Date(s). Informational webinar for applicants will be held on October 2, 2020, from 11:00am-12:30pm EST. Attendees are encouraged to submit questions in advance to ResearchNOFO@cdc.gov.

o Join ZoomGov Meeting https://cdc.zoomgov.com/j/1612051963?pwd=MkR1UkQ5MFVkRng

5SDRZVTlHZkF6QT09. Meeting ID: 161 205 1963, Passcode:

yT$RKLf3 Dial by your location: +1 669 254 5252 US (San Jose), +1 646 828 7666

US (New York), Meeting ID: 161 205 1963, Passcode: 42481162 Application Materials. See Section IV.1 for application materials. Please note that Form E is to be used when downloading the application package. http://grants.nih.gov/grants/how-to-apply-application-guide/forms-d/general-forms-d.pdf%20

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority Sections 301(a) [42 U.S.C. Section 241(a)] and 317C of the Public Health Service Act [42 U.S.C. Section 247b-4)], as amended. Further authorization is provided under Pub. Law No.

106-310, Public Health Service Act; Pub. Law No. 109-416, Combating Autism Act of 2006;

Public Law No. 113-157, Autism CARES Act of 2014; and Public Law No. 116-60, Autism CARES Act of 2019.

1. Background and Purpose Background In 2016, an estimated 1 in 54 children 8 years of age living in 11 communities across the United States had autism spectrum disorder (ASD) [1], a developmental disability that can cause significant social, communication, and behavior challenges. Total annual cost associated with ASD have been estimated between $11.5-$60.9 billion (2011 US dollars) [2], yet major gaps in knowledge remain about risk factors for ASD, and associated challenges and needs for persons with ASD and their families [3]. Most research on ASD has focused on children, yet ASD is considered a lifelong condition, and although an estimated 70,000 to 111,000 youth with ASD turn 18 years of age annually [4], little is known about the transition to adolescence and adulthood for persons with ASD [5]. Despite the call to address transition and lifespan issues in the Autism CARES Acts of 2014 and 2019, only 2% of ASD funding from 2008-2018 was spent on lifespan issues [6]. To address these gaps, this NOFO will assess risk factors for and characteristics of preschool age children with ASD using previously collected data and biospecimens from the Study to Explore Early Development, Phases 1, 2, and 3 (SEED 1-3) and https://cdc.zoomgov.com/j/1612051963?pwd=MkR1UkQ5MFVkRng5SDRZVTlHZkF6QT09 https://cdc.zoomgov.com/j/1612051963?pwd=MkR1UkQ5MFVkRng5SDRZVTlHZkF6QT09 http://grants.nih.gov/grants/ElectronicReceipt/submit_app.htm#SectionIV1 http://grants.nih.gov/grants/how-to-apply-application-guide/forms-d/general-forms-d.pdf%20 http://grants.nih.gov/grants/how-to-apply-application-guide/forms-d/general-forms-d.pdf%20 will conduct longitudinal follow-up studies of SEED 1-3 participants at older ages.

SEED 1-3 (also known as SEED) is a multi-phase, multi-site, case-control study comparing children with ASD, identified at ages 2-5 years, to children with other non-ASD developmental disabilities (DD), and from the general population (POP). SEED was established to address the Children's Health Act of 2000 which mandated CDC to conduct ASD surveillance and implement research programs to address the number, incidence, and causes of ASD and related developmental disabilities. Under this legislation, CDC's National Center on Birth Defects and Developmental Disabilities funded a network of five Centers for Autism and Developmental Disabilities Research and Epidemiology, that developed and implemented SEED. Through the three phases (2006-2011, 2011-2016, and 2016-2021), SEED was implemented in limited geographic areas within portions of eight states (California, Colorado, Georgia, Maryland, Pennsylvania, and North Carolina, during SEED 1 and 2; and in Colorado, Georgia, Maryland, Missouri, North Carolina, and Wisconsin, during SEED 3).

Across all three phases of SEED, the common scientific aims were to

1. Characterize the behavioral phenotypes and associated developmental, medical and behavioral conditions of ASD among preschool-aged children; and

2. Understand the genetic and environmental risk factors for ASD, with environmental factors focusing on infectious, immunological, hormonal, obstetric, gastrointestinal and socio-demographic features.

Comprehensive data collected through SEED includes study participant data (including information on pregnancy and early childhood exposures, services and treatments, maternal medical history, family socio-demographics, and child health and development), standardized functional assessments, and biospecimens. ASD status of children in the study is based on the results of comprehensive standardized evaluations [7].

While SEED 3 data collection is ongoing through mid-2021, analyses of data and biological specimens from SEED 1 and SEED 2 have increased our understanding of

1. Environmental risk factors for ASD (e.g., infectious, immunological, hormonal, obstetric, perinatal, and early childhood exposures) [8-23];

2. Genetic and epigenetic risk factors for ASD [24-26];

3. ASD phenotypes, co-occurring conditions, and health of children with ASD [27-35];

4. Safety considerations for children with ASD [36-39];

5. ASD screening, diagnosis, treatment, and use of services [40-44].

Yet, research gaps remain. With the completion of data collection in SEED 3, the large final sample size of the combined SEED 1-3 data set (including >6,000 children, of whom approximately 1,700 children with ASD will be included), will provide increased statistical power to explore research gaps such as those highlighted in the 2016-2017 Interagency Autism Coordinating Committee (IACC) Strategic Plan [6], and prioritized by major ASD advocacy organizations. Some of these gaps include differences in ASD characteristics and associated risk factors by sex or racial-ethnic groups; the association of maternal immune factors with ASD;

and the interaction of genetics and the environment in their association with ASD. Research gaps related to associations of ASD with maternal immune and genetic risk factors are described in more detail below in sections titled Maternal Immune Factors and Genetic Factors.

Support through this NOFO is meant to help address these research gaps.

In addition to the research gaps summarized above and described in more detail below, the IACC Strategic Plan indicated more information is needed about the services and supports needed to maximize the quality of life for people on the autism spectrum, especially as individuals with ASD progress into adulthood.

Given the size of the original SEED birth cohorts and the wealth of baseline information collected, a follow-up study of participants can help us to better understand the developmental trajectory of children with ASD, their health outcomes and co-occurring conditions at older ages, and the associated early predictors of these outcomes, including intellectual abilities (described in more detail below in the section titled Intellectual Abilities). Additionally, because most SEED 1 participants will reach young adulthood (i.e., age 18 years) in years 2021-2026, data collected through Component A of this NOFO will provide an opportunity to assess changes in service access and utilization that may occur following high school exit. This period is particularly challenging for young adults with ASD who can experience poor outcomes across multiple domains (i.e., employment, education, social engagement, independent living, and access to health and mental health care services [45, 46]) in association with the loss of well-integrated school-based services [47, 48]. Hence, through surveying SEED 1 participants before and after their anticipated exit from high school, data collected through Component A of this NOFO could provide important information on the loss of services and emerging issues that can inform service delivery and programs on the supports needed to achieve greater independence.

Initial follow-up surveys of SEED participants at older ages must be conducted with the parents of children who previously participated in SEED because they provided consent for follow-up studies. However, many emerging issues surrounding the transition to adulthood among adolescents with ASD require self rather than parental report (e.g., self-reported symptoms of anxiety, depression, quality of life, social camouflaging, gender identity, sexuality, and relationships). Thus, data collected through Component A of this NOFO also provides the opportunity to obtain important self-reported measures of well-being among young adults with

ASD.

Intellectual Abilities Intellectual functioning is one of the strongest predictors of key outcomes among adolescents and young adults with ASD [49], yet previous studies suggest intellectual development is highly malleable and variable in early childhood [50-53]. As such, the intellectual abilities assessed in SEED 1-3, when participants were 2-5 years of age, may not be an accurate predictor of outcomes in adolescents and young adults with ASD. Moreover, parent report of overall intellectual ability is only moderately correlated with measured intelligence and may be underestimated by parents whose child exhibits greater ASD symptom severity [54, 55].

Assessing intellectual ability at later ages, when intellectual level is more stable, provides a more accurate measure of future intellectual performance [56-58]. This NOFO will allow for an assessment and potential correction for changes in intellectual ability as children with ASD age to account for potential error in alternative measures of intellectual function (e.g., parental self-report), in association with key outcomes. Because it is expected that some of the children classified as DD in SEED 1-3 will subsequently receive an ASD diagnosis by the time of follow-up [59], applicants to Component B of this NOFO will have the opportunity to assess intellectual abilities of children in this group as well.

Recent evidence suggests that individuals with ASD with average to above average levels of intellectual functioning may still struggle with activities of daily living [60-63]. Yet, adults with special needs are often required to have an intellectual disability in order to qualify for services.

Data collected in Component B of this NOFO will allow investigators to describe the gap between intellectual ability and daily living skills in adolescents with ASD to inform public policies on eligibility for services.

Maternal Immune Factors Dysregulation of the maternal immune system during gestation has been associated with deleterious changes in neurodevelopment of children, and the study of the association of maternal immune factors with ASD is one of the original identified priorities for SEED.

Although antibodies that recognize central nervous system antigens cannot cross the blood brain barrier in healthy adults, they can penetrate the fetal brain while it is still immature [64]. Recent research indicates maternal autoantibodies reactive to central nervous system proteins are associated with increased risk of ASD [64, 65]. Additionally, these antibodies are more common among women with autoimmune disorders, and also can be stimulated by immune activation from infection or chronic metabolic conditions in pregnancy (e.g., maternal obesity, gestational diabetes, and hypertensive disorders), all of which have been associated with ASD [64, 66, 67]. Moreover, among children with ASD, those whose mothers have reactive autoantibodies have higher rates of certain behavioral phenotypes (e.g., stereotypical behaviors, developmental regression, language deficits) than those whose mothers do not have reactive autoantibodies [64-66]. Thus, some speculate the presence of reactive maternal autoantibodies could account for a unique subtype of ASD [66]. Support through NOFO Component C will provide the ability to test for the presence of maternal autoantibodies reactive to fetal proteins involved in neurodevelopment in serum and plasma samples of SEED 1-2 participants. The detailed phenotypic data on children and pregnancy history data on mothers from SEED, along with data on maternal autoantibodies will allow investigators to better understand the associations between maternal immune factors and ASD.

Genetic Factors The contribution of genetics to ASD is supported by its high heritability [68], yet there is also substantial evidence for environmental risk factors and gene by environment interactions [3, 69]. Research over the past decade has successfully identified a number of rare inherited and de novo gene variants conferring substantial risk for ASD [70-73]. Nonetheless, growing evidence suggests much of the risk for ASD and related neurodevelopmental and psychiatric disorders is attributable to the cumulative effects of multiple common variants, which in combination with environmental factors, can push individuals over a threshold for disease [70, 71, 74, 75].

However, it has been difficult to replicate studies identifying common variants related to ASD due to the relatively small effects of each variant and the need for larger sample sizes than available from existing studies [3, 71-73]. Similarly, most studies on gene by environment interactions related to ASD lack sufficient sample size and statistical power to account for multiple comparisons and variation in environmental exposures and data [3, 69].

Currently, SEED is the largest US-based study of ASD that has collected biospecimens and comprehensive developmental evaluations, along with detailed and standardized prenatal and early childhood environmental (non-genetic) exposure data; SEED thus offers an important opportunity to examine genetic, environmental, and epigenetic risk factors for ASD in the same individuals. For SEED 1, single nucleotide polymorphism (SNP), copy number variation (CNV), and DNA methylation data were generated on ASD and general population control (POP) mothers and children, and were used to identify potential genetic and epigenetic correlates of ASD, including potential immune pathways and environmental exposures (i.e., smoking) associated with increased risk [24-26]. SEED 2-3 biospecimens are also available but, to date, no genetic or epigenetic data have been generated. Obtaining sufficient sample size and increased statistical power to estimate small effects from common genetic variants and environmental interactions will require the full set of SEED data and combining SEED data with other large studies [3, 69]. Support through Component D of this NOFO will provide investigators the opportunity for genetic analyses by providing SEED collaborators with the needed expertise in analytic techniques for merging multiple datasets generated on different genotyping platforms and adjusting for temporal differences [76]. Finally, support for a biorepository (Component E of this NOFO) is essential for providing the biospecimens necessary to address gaps in knowledge in the associations of ASD with both maternal immune factors and genetic factors.

Purpose The purpose of this NOFO is to gain knowledge about ASD, including risk factors for and the expression of ASD, from childhood through early adulthood, and to obtain information that can be used to improve the health and functioning of individuals with ASD as they mature. This will be completed through 1) analysis of existing data and biospecimens from preschool-aged children and their families who participated the CDC funded study known as the Study to Explore Early Development (SEED), a multi-phase, multi-site, case-control study of children identified at age 2-5 years with ASD, other developmental disabilities (DD), and from the general population (POP); and 2) through longitudinal follow-up and research of previous SEED participants to obtain information through early adulthood on their health and functioning, service use and needs, and the impact of ASD on their families.

Healthy People 2030 and other National Strategic Priorities This NOFO supports the Healthy People 2030 topic areas of Adolescent Health, Disability & Health, and Mental Health & Mental Disorders. This includes the following objectives

Adolescent Health (AH) o AH-9 Reduce the proportion of adolescents and young adults who are neither enrolled in school nor working

Disability & Health (DH) o DH-3 Reduce the proportion of persons with intellectual and developmental disabilities enrolled in publicly funded, long-term services and supports (LTSS) who live in congregate care residences with 7 or more people o DH-5 Increase the proportion of students with disabilities who spend at least 80 percent of their time in regular education programs

Mental Health & Mental Disorders (MHMD) o MHMD-2 Reduce suicide attempts by adolescents o MHMD-3 Increase the proportion of children with mental health problems who receive treatment o MHMD-6 Increase the proportion of adolescents with major depressive episodes (MDEs) who receive treatment o MHMD-8 Increase the proportion of primary care office visits where adolescents and adults are screened for depression

Public Health Impact Information about biologic and environmental risk factors for ASD and the characteristics and needs of persons with ASD and their families will inform strategies to prevent the often debilitating outcomes associated with ASD, as well as strategies to improve the health and functioning of individuals with ASD as they age. Data collected through this NOFO may inform strategies to avoid or eliminate modifiable risk factors for ASD; improve our understanding of which co-occurring conditions are most prevalent; increase our understanding of the needs of individuals with ASD, and how these needs may change with age and can be best met at different points in development; and inform research and public health policies. Specifically, research through this NOFO will provide data to inform public policies on eligibility for needed services and public health outreach efforts that could provide opportunities for education, employment and social connection to improve the health, functioning, and quality of life among persons with ASD and their families.

Relevant Work As indicated in the Background and Purpose section of this NOFO, SEED 3 is ongoing in six sites through mid-2021. Five study sites in Colorado, Maryland, North Carolina, Wisconsin, and Missouri are currently funded through CDC (RFA-DD16-001). The sixth SEED 3 study site in Georgia is operated by CDC. Each funded site in the SEED 3 Network conducts ASD research and is required to enroll a specific number of participants in three study groups (ASD, DD, and POP) and collect detailed data on prenatal and early childhood environmental and non-environmental exposures, family and child health and demographics, service utilization, developmental data through in-depth clinic assessments, and biological samples. Two previous SEED study sites in California and Pennsylvania participated in SEED 1 (CDC-RFA-DD06-03) and SEED 2 (DD11-002). Funding through this current NOFO allows for analysis of data from the completed SEED (SEED 1-2) study phases, and in combination with SEED 3 data currently being collected, provides ongoing analytic opportunities to address the objectives of SEED. In addition, the data collected on children and families who participated in SEED 1-3 provide a baseline for follow-up surveys and research studies (see Appendix A).

During SEED 1-3, biospecimens from participants were collected, processed and maintained for long-term storage. During SEED 1-2, both blood and buccal (SEED 1) or saliva (SEED 2) samples were collected from children and their biological mothers and fathers. During the first half of SEED 3, saliva and blood were collected from children and their biological mothers, and saliva from fathers when available in the ASD and population control (POP) groups. However, no samples were collected from participants in the group of children with other developmental disabilities (DD), and blood collection was discontinued midway through SEED 3 for all participants.

For samples collected, a number of specimen types were frozen, including PAXgene samples, buffy coat, plasma, serum, cell pellets, peripheral blood mononuclear cells (PBMC), red blood cells (RBC), white blood cells (WBC), DNA (from buccal, saliva, buffy coat, and/or WBC), RNA derived from PAXgene tubes, and dried blood spots (DBS). In total, an estimated 200,000 aliquots are in long-term storage from biospecimens previously collected from SEED 1-3 participants. These biospecimens are an essential resource for addressing gaps in knowledge of the contribution of maternal immune factors (i.e., autoantibodies) and genetics to ASD.

In addition to the SEED 1-3 studies of preschool children, during SEED 3, a pilot study, known as SEED Teen, was implemented to follow SEED 1 participants at age 11 to 14 years and is ongoing through mid-2021. Through this pilot study, data are being collected on a subset of the original SEED 1 sites (Georgia, Maryland, North Carolina, and Pennsylvania), thus providing the opportunity to assess ASD-associated outcomes in pre- and early adolescence.

Scientific aims of the SEED Teen pilot study are to

1. Understand the long-term health, functioning, educational achievement, and support needed among children identified at young ages as having ASD in comparison to children identified as having other developmental disabilities and children from the general population;

2. Understand the developmental trajectory of children identified at young ages as having

ASD;

3. Establish a mechanism to maintain contact for future follow-up studies of the cohort (i.e., SEED 1 birth cohort) as they began to transition to adulthood.

An important preliminary outcome of SEED Teen is the demonstration that follow-up studies of SEED participants are feasible. While the SEED Teen study is ongoing, as of the second quarter of FY2020, contact has been established with approximately 90% of eligible participants invited. Of those contacted, over 75% have enrolled, and of those enrolled who have had sufficient time to complete the study, 84% (57% of the original participants) have finished the complete data collection protocol.

Additional follow-up data on SEED 1 participants as they approach late adolescence and early adulthood and participants in SEED 2 and 3 birth cohorts get older (see Appendix A) provides a unique opportunity to better understand the specific medical, mental health, and behavioral conditions and service needs that may emerge at different developmental periods (i.e., childhood, adolescence, and young adulthood).

2. Approach The Study to Explore Early Development (SEED) Follow-up Study will collect information from follow-up surveys and in-person assessments on the health and functioning of individuals during childhood, adolescence, and young adulthood. Eligible participants will include those who were previously identified at ages 2-5 years with ASD, other developmental disabilities (DD), and in the general population (POP) through their participation in the original SEED 1-3 studies, as shown in Appendix A. Specific areas of health and functioning to be collected through the surveys and in-person assessments are shown in Appendix B. Awardees are expected to implement certain project components, including participation in SEED work groups and committees, data collection, project staffing, laboratory and data analyses, and reporting. The expected outcome is to produce high-quality data and analyses that can be used to establish an evidence base to inform research and public health strategies to improve the health, functioning, and quality of life for individuals with ASD and their families.

This NOFO includes five separate funding components to meet program goals:

Component A: Enhanced Epidemiologic Research Using Existing SEED Data and Follow-up Surveys of Existing SEED Participants;

Component B: In-Person Assessment of Intellectual Abilities of SEED Participants;

Component C: Maternal Auto-Antibody Testing;

Component D: Genetic Analyses;

Component E: Biorepository.

Applicants may apply for multiple components but must submit a separate application for each component. Periods of performance for each component are as follows:

Component A: 7/1/2021 - 6/30/2026 (Budget Years 1-5);

Component B: 7/1/2021 - 6/30/2025 (Budget Years 1-4);

Component C: 7/1/2021 - 6/30/2024 (Budget Years 1-3);

Component D: 7/1/2021 - 6/30/2026 (Budget Years 1-5);

Component E: 7/1/2021 - 6/30/2026 (Budget Years 1-5).

To be funded for Components B, C, D, or E, applicants must apply for and be funded for Component A. A separate application is required for each component.

To conduct analyses of existing data for Component A, after award, CDC will provide awardees restricted access to a de-identified pooled data set through a centralized web-based system that meets Federal standards for security and confidentiality.

Component A: Enhanced Epidemiologic Research Using Existing SEED Data and Follow-up Surveys of Existing SEED Participants.

5-year Period of Performance (7/1/2021 - 6/30/2026) Component A awardees are expected to participate in SEED meetings, conference calls and workgroups to provide individual input and advice on research gaps in risk factors for ASD and the characteristics and needs of children with ASD that can be addressed using existing SEED data; conduct and report results of priority analyses of existing SEED data, including publication and data verification; and support the conduct of standardized follow-up surveys, (Appendix B) including: i) an initial follow-up survey of parents from SEED 1-3; ii) a second follow-up survey of parents of adult children from SEED 1 (to assess changes in services at anticipated time of exit from school); and iii) a direct survey of adult children from SEED 1 (to obtain self-reported data).

Requirements for Component A:

Note: unless otherwise specified, the requirements are for the entire 5-year period of performance.

1. Provide Individual Site Input into Guidelines for Data Sharing and Publication (Funding Year 1). Awardees are expected to collaborate with other Component A awardees and CDC to provide individual site input for updating the Data Sharing and Publication Guidelines for Analysis, Presentation, Publication, and Release of SEED Data (available upon request -- see Section VII. Agency Contacts, Scientific/ Research Contact(s) Marcella Law to obtain a copy), taking into account CDC publication requirements and Federal data sharing guidelines.

2. Participate in Annual Meetings (online or in person as planned each year) to work collaboratively with funded awardees and CDC to

a. Re-assess and prioritize analysis proposals to address gaps in literature that can be addressed by SEED data;

b. Discuss and resolve issues related to study implementation;

c. Present ongoing analyses.

3. Participate in Monthly Conference Calls of the SEED Data Sharing Committee. At least one representative for each awardee is expected to serve on the SEED Data Sharing Committee and provide individual site review of all analysis proposals (known as Letters of Intent, or LOIs) for the use of SEED data.

4. Submit Proposals for Analysis of SEED Data. Awardees are expected to submit proposals and obtain approval from the SEED Data Sharing Committee for at least one LOI in Year 1 and two LOIs each year in Year 2-5.

a. SEED data refers to data from SEED 1-3, SEED Teen, or SEED data collected under the current NOFO (Funding Year 5).

b. LOIs are expected to provide an overview of what is known about the topic (brief literature review), what is added by the proposed analysis, variables to be included, statistical methods, and evidence of sufficient sample size for analysis objectives.

c. At least one LOI each year is expected to address a high priority topic as established under Requirement 2, above.

5. Complete High-Priority Analyses of SEED Data. Each awardee is expected to complete at least one analysis each year in Year 1-2 and two analyses each year in Year 3-5 using SEED data (SEED 1-3, SEED Teen or SEED data collected under the current NOFO [Funding Year 5]). At least one analysis per year is expected to address a high priority research topic established under Requirement 2, above.

6. Prepare Manuscripts Based on SEED Data. This includes approval through CDC clearance and/or submission to a journal for peer-review, and provision of an informational copy to other Component A and previous SEED awardees (to comply with original data sharing agreements). At least one manuscript is expected each year in Year 1-2 and at least 2 manuscripts in Year 3-5.

7. Provide Code for All Manuscripts Based on SEED Data. For all manuscripts accepted for publication, the lead author or analyst is expected to submit documentation of the analysis and final code to CDC, according to the specifications, for data reproducibility and establishment of a shared library of re-coded variables.

8. Provide Individual Site Input into the Development of Standardized Assessment Tools and Study Protocols (Funding Year 1). Work collaboratively with other Component A awardees and CDC to fully develop content for the SEED Follow-up Surveys (as outlined in Appendix B), and study implementation procedures including:

a. Participate in an in-person or virtual kickoff meeting;

b. Participate in regularly scheduled conference calls to review outcomes aligning with research priorities, refine measures to be collected in surveys, and develop protocols for obtaining consent from adult children for surveys.

9. Obtain IRB Approval (Funding Year 1). Each awardee is expected to collaborate with CDC to obtain IRB approval for study implementation under the new Common Rule requiring a single IRB approval for cooperative (i.e., multi-institutional) agreements in the United States.

Applicants must document ability to include

a. Consent to share identifiable, individual-level contact information (i.e., personally identifiable information (PII) -- including addresses and telephone numbers) with a central interviewing contractor;

b. Approval on protocols for obtaining informed consent from adult children from SEED.

10. Collaborate with a Central Interviewing Contractor and CDC to Develop Electronic Data Systems for Participant Tracking and Survey Data Collection (Funding Year 1).

a. Work with a central interviewing contractor to develop, test, and use a secure method for sharing participant contact information and study progress data (e.g., a File Transfer Protocol (FTP) site or encrypted email -- the contractor will be responsible for implementing the secure mechanism);

b. Participate in pilot testing for computer-assisted telephone interviews (CATI) and any other data capture systems developed by the central interviewing contractor;

c. Provide feedback to the central interviewing contractor on all data systems, manuals and guidance as requested.

11. Trace Contact Information for SEED 1-3 Participants and Mail Survey Invitations (Funding Years 2-4). Component A funding awardees are expected to identify updated contact information for all eligible SEED 1-3 participants from at least one cohort of the original SEED 1-3 study sites, mail initial invitation packets, and collaborate with a central interviewing contractor to reach no less than 90% of eligible participants at the site(s). To do this, awardees are expected to

a. Generate a list of all eligible SEED 1-3 participants based on the following criteria

i. Child participated in SEED 1, 2, or 3 and received a final classification of ASD, DD or POP was enrolled in SEED 1-3 and completed the clinic visit

ii. Primary caregiver or mother consented to be contacted in the future for possible follow-up studies;

b. Mail introductory packets to all eligible participants as an initial invitation to participate in the follow-up surveys;

c. Inform the central interviewing contractor of returned invitation packets and provide any available information to support tracing additional contact information for potential participants with the goal of establishing contact with no less than 90% of all eligible participants.

12. Collaborate with a Central Interviewing Contractor to Enroll and Maintain Contact with SEED Follow-up Study Participants (Funding Year 2-5). Awardees are expected to collaborate with a central interviewing contractor to enroll no less than 75% of eligible SEED participants of at least one cohort from the original SEED 1-3 study who are successfully contacted for the first follow-up survey. Additionally, they are expected to assist the contractor in maintaining contact with eligible SEED 1 participants to achieve no less than a 40% completion rate for the second follow-up surveys (parent and adult child).

a. Depending on awardee IRB regulations and approvals, within 7-14 days of mailing the invitation packet, awardees are expected to complete either activity i or ii listed below:

i. Conduct telephone calls to contact the participant and obtain permission to share PII with the central interviewing contractor (i.e., pre-consent); on a weekly basis, awardees are expected to send to the central interviewing contractor

a. a list of interested and eligible participants, including their name, the date of pre-consent, and their telephone numbers;

b. a list of participants who were contacted and refused participation;

c. a list of eligible participants who could not be contacted and need additional tracing to identify a working phone number and address.

ii. Provide information for the central interviewing contractor to attempt to contact eligible participants by telephone and enroll participants without pre-consent; on a weekly basis, awardees are expected to send to the central interviewing contractor

a. a list of eligible participants to whom invitation packets were mailed, including their names, the…