RFA-DD-16-001 amendment 2 Q&As.pdf

Centers for Disease Control and Prevention

National Center on Birth Defects and Developmental Disabilities Extramural Research Program Office

Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE): Study to Explore Early Development

(SEED) 3

RFA-DD-16-001

Application Due Date: 02/11/2016

Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE): Study to Explore Early Development

(SEED) 3

RFA-DD-16-001

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 Extramural Research Program Office (NCBDDD ERPO) National Center on Birth Defects and Developmental Disabilities (NCBDDD)

Funding Opportunity Announcement (FOA) Title

Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE): Study to Explore Early Development

(SEED) 3

Activity Code

U01

Amendment 2 – Responses to questions from potential applicants.

February 1, 2016

Question 1: I wondered if there was any flexibility with the requirements that the catchment area included 40,000 live births in 2014. On page 62 of the SEED3 protocol, it states that sites are assume to have 50% of the potential ASD sources to provide a sample of cases. However, X Hospital provides ASD diagnoses to a majority of children in our catchment area (far more than 50%), but the proposed catchment area has less than 40,000 births. According to the SEED3 protocol children with an ASD diagnosis are not randomly selected (page 40, section ‘a’ of protocol), so it would seem to be appropriate to sample from, for example, our ASD patients.

In summary, we would be able to identify and enroll 125 children with ASD from a catchment area that doesn’t include 40,000 births. If we can demonstrate this, would that be allowed or is the 40,000 live births a firm number? If it is, do you mind describing to me how the number was reached so I can fully understand how the numbers were chosen?

Answer: In the full study protocol (available to all applicants upon request) further explanation is provided that the 40,000 birth population size condition was stipulated because it will be difficult for a site to meet the enrollment target of 125 participants in each study group without this minimum.

Reviewers are thus asked to consider applications in light of the likelihood that the site will be able to enroll sufficient participants to meet the study targets of 125 mother-child pairs in each group who complete the data collection protocol. This includes considering the size of the site’s proposed study area birth population.

While, 40,000 births is not a specific eligibility requirement for this award, applicants proposing to recruit subjects from study areas with smaller birth populations, should take care to explain how they could reasonably meet the study enrollment and completion targets in smaller areas.

Question 2: I am wondering if you could share some cost estimates for some of the SEED protocol steps for our budget planning purposes. Specifically, we are interested in the costs for purchasing and shipping saliva kits and the costs for shipping blood to the central repository. I see in the protocol that blood is shipped in dual temperature kits, but it would be helpful to know if we are to ship with dry ice, overnight/2-day mail, etc. I don't think the Biologic Procedures manual was included in the SEED protocol materials you sent us. Finally, is there a rough estimate of the shipping costs for enrollment packets, maternal interview prep packets, and forms packets?

Answer:

Supplies

Applicants to Component A – SEED Recruitment sites do not need to budget for shippers, blood tubes, or saliva kits. The SEED Central Laboratory and Biosample Repository (CLBR) will purchase these and supply them to the sites.

SEED recruitment sites do need to purchase general phlebotomy supplies such as needles, blood collection sets, tourniquets, gauze, bandages, alcohol pads, sharps containers, biohazard bags, and gloves. Recruitment sites are expected to purchase these items directly from vendors. Access to a centrifuge is required to spin the SST tubes (1000-1300 x g). Also, the shipping packs will need to be refrigerated or frozen before use in the blood sample shipper.

Applicants to Component B – The CLBR must plan in their budget to purchase and ship the following items to sites: purple top EDTA tubes (3 ml), pink top EDTA tubes (6 ml), gold SST tubes (3.5 ml), Paxgene Blood RNA tubes, DNA Genotek Saliva Self-collection kits (OG-500), DNA Genotek Saliva Assisted kits with the swab (OG-575), additional swabs for assisted kits, and shipping materials. Shipping materials will include Category B Combo – Frozen / Refrigerated Shipping Systems, regulation required labels, refrigerant packs, absorbent materials, biohazard bags, bubble wrap pouch for blood tubes, Tyvek envelopes, insulated foil bag envelopes, and medium 95kPa canisters. Please refer to the FOA “Section 2. Approach” and SEED 3 protocol

(p. 93-99) “Section H. Study Instrument and Data Collection Method, 7. Clinic Visit Overview (ASD and POP workflows), c.

Anthropometry and collect saliva samples” for estimating the number of kits and tubes the CLBR will need to provide to sites.

Shipping

Applicants to Component A – Blood samples are required to be sent via overnight delivery from the recruitment site to the CLBR. Sites are to use the shippers and refrigerant packs provided by the CLBR, no dry ice is required. Shipping costs vary by commercial carrier and distance.

It is up to the recruitment site to decide upon mail carrier for sending forms and other materials to participants. At the GA SEED site, operated by CDC, we often use FedEx to ensure the gift cards are delivered to the correct recipient as well as to ensure delivery of time-sensitive information.

Question 3: This question relates to the developmental testing that takes place during the SEED study visit. When children come to XX Hospital for developmental testing, they undergo a multidisciplinary assessment that includes many of the assessments that are part of SEED3. The question we have is whether we can use the results from this assessment to use for SEED. We see many advantages to leveraging this process—it would mean lower costs, reduced burden on the family and therefore we believe could serve to increase response rates because the requirements for the study visit will be shortened.

Answer: As described in the SEED 3 protocol, developmental assessments must be conducted by individuals meeting certain education qualifications and must be supervised by SEED clinicians also meeting certain education criteria. Moreover, the supervising site clinicians and field clinicians must participate in standardized training procedures and be deemed research reliable according to a priori criteria established for SEED. Additionally, there are established ongoing QC requirements for developmental assessments conducted as part of SEED. Because of the need to ensure standardization across SEED sites and across various phases of SEED, data from developmental assessments conducted previously (before a child enrolls in SEED) are not accepted for this study.

Question 4: We are currently trying to prepare a budget for our SEED 3 application that includes supplies and shipping costs of buccal swabs and venous blood. The FOA seems to indicate we need to budget for these items and the Protocol refers to a Biologic Specimen Manual but it doesn’t seem to be included in the protocol appendices that were sent.

Can you provide any more information that would help us anticipate costs related to collecting and processing bio-samples?

Answer:

Supplies

Applicants to Component A – SEED Recruitment sites do not need to budget for shippers, blood tubes, or saliva kits. The SEED Central Laboratory and Biosample Repository (CLBR) will purchase these and supply them to the sites.

SEED recruitment sites do need to purchase general phlebotomy supplies such as needles, blood collection sets, tourniquets, gauze, bandages, alcohol pads, sharps containers, biohazard bags, and gloves. Recruitment sites are expected to purchase these items directly from vendors. Access to a centrifuge is required to spin the SST tubes (1000-1300 x g). Also, the shipping packs will need to be refrigerated or frozen before use in the blood sample shipper.

Applicants to Component B – The CLBR must plan in their budget to purchase and ship the following items to sites: purple top EDTA tubes (3 ml), pink top EDTA tubes (6 ml), gold SST tubes (3.5 ml), Paxgene Blood RNA tubes, DNA Genotek Saliva Self-collection kits (OG-500), DNA Genotek Saliva Assisted kits with the swab (OG-575), additional swabs for assisted kits, and shipping materials. Shipping materials will include Category B Combo – Frozen / Refrigerated Shipping Systems, regulation required labels, refrigerant packs, absorbent materials, biohazard bags, bubble wrap pouch for blood tubes, Tyvek envelopes, insulated foil bag envelopes, and medium 95kPa canisters. Please refer to the FOA “Section 2. Approach” and SEED 3 protocol

(p. 93-99) “Section H. Study Instrument and Data Collection Method, 7. Clinic Visit Overview (ASD and POP workflows), c.

Anthropometry and collect saliva samples” for estimating the number of kits and tubes the CLBR will need to provide to sites.

Shipping

Applicants to Component A – Blood samples are required to be sent via overnight delivery from the recruitment site to the CLBR. Sites are to use the shippers and refrigerant packs provided by the CLBR, no dry ice is required. Shipping costs vary by commercial carrier and distance.

It is up to the recruitment site to decide upon mail carrier for sending forms and other materials to participants. At the GA SEED site, operated by CDC, we often use FedEx to ensure the gift cards are delivered to the correct recipient as well as to ensure delivery of time-sensitive information.

In addition, applicants to Component B must include in their budget the costs for: extracting DNA; extracting RNA; purchasing, creating, and storing Guthrie blood spot cards; and creating and storing frozen biospecimens.

Amendment 1 -- Sections with changes are noted in bold red in the text below.

January 11, 2016

Part 1. Overview Information

Executive Summary:

Budget and Project Period: The estimated total funding (direct and indirect) for the entire project period, (07/01/2016 – 06/30/2021), is $21,600,000.

Component A (SEED 3): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $3,200,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $17,600,000. Estimated Number of Awards: up to 4. Average amount of each award is YR 1: $800,000 YRS 2-5: $900,000.

Component B (Biorepository for SEED-3): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $300,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $1,500,000. Estimated Number of Awards: 1. Average amount of each award for YRS 1-5:

$300,000.

Component C (Follow-up Study): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $500,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $2,500,000 Estimated Number of Awards: up to 2. Average amount of each award for YRS 1-5: $250,000.

Part 2. Full Text

Section II. Award Information

Estimated Total Funding:

Component A (SEED-3): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $3,200,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $17,600,000. Estimated Number of Awards: up to 4. Average amount of each award: YR 1: $800,000 YRS 2-5: $900,000.

Component B (Biorepository for SEED-3): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $300,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $1,500,000. Estimated Number of Awards: 1. Average amount of each award: YRS 1-5: $300,000.

Component C (Follow-up Study): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $500,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $2,500,000. Estimated Number of Awards: up to 2. Average amount of each award: YRS 1-5: $250,000

Part 2. Full Text

Section II. Award Information

Anticipated Number of Awards:

The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $4,000,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $21,600,000.

Part 2. Full Text

Section VIII. Other Information

Appendix A: SEED 1,2,3,4, Comparison Tables

Field work enrollment time period 2017 -2021

Field work data collection time period 2017 -2021

Funding Opportunity Announcement Type

New

Funding Opportunity Announcement Number

RFA-DD-16-001

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.073

Category of Funding Activity:

Health

FOA Purpose

This Funding Opportunity Announcement (FOA) is for applicants to support:

Component A) continuation of the epidemiological research capability of the Centers for Autism and Developmental Disabilities Epidemiology (CADDRE) Network with implementation of the Study to Explore Early Development (SEED) Phase 3.

SEED is a case-control study of genetic and environmental risk and protective factors for autism with multiple-source ascertainment of case and comparison groups; SEED Phase 3 is a continuation of SEED 1 and SEED 2 with the same basic study design but with some enhancements in study recruitment and some reductions in data collection.

Component B) implementation of the SEED Central Laboratory and Biosample Repository (CLBR) to support the maintenance and storage of the SEED Phase 1 and Phase 2 biosample repository and support the collection and storage of the SEED Phase 3 biosamples.

Applicants who apply for Component A may also apply for Component B.

Component C) development and implementation of a study protocol and feasibility assessment for a follow-up study of SEED 1 participants.

Component C is a project to develop and implement a short protocol and feasibility assessment for conducting a follow-up of the children who enrolled in SEED 1 and completed the SEED 1 study data collection protocol.

Key Dates

Publication Date: To receive notification of any changes to RFA-DD-16-001, 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: 01/04/2016 Is a LOI: Recommended but not Required

Application Due Date: 02/11/2016

On-time submission requires that electronic applications be error-free and made available to CDC for processing from eRA http://www.grants.gov

On-time submission requires that electronic applications be error-free and made available to CDC for processing from eRA Commons on or before the deadline date. Applications must be submitted to and validated successfully by Grants.gov/eRA Commons no later than 5:00 PM U.S. Eastern Time. Note: HHS/CDC grant submission procedures do not provide a period of time beyond the application due date to correct any error or warning notices of noncompliance with application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review: 04/07/2016

Secondary Review: 05/12/2016

Estimated Start Date: 07/01/2016

Expiration Date: 02/15/2016 Due Dates for E.O. 12372: Executive Order 12372 does not apply to this program.

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this FOA. Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

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

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

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

Executive Summary

Purpose. CDC has previously implemented a population-based epidemiological research study known as the Study to Explore Development (SEED). Data collection for SEED 1 is complete, data collection for SEED 2 is ongoing. The primary objectives of SEED are 1) to characterize the autism behavioral phenotype and associated developmental, medical and behavioral conditions of autism, with a special focus on identifying homogeneous autism subgroups for etiologic analysis, and 2) to understand the genetic and environmental risk factors for autism with a special focus on immunological, hormonal, obstetric, gastrointestinal and socio-demographic features. The focus of SEED is on preconception, prenatal, perinatal and early postnatal risk factors.

The activities under this FOA will be supported by three separate funding components:

Component A: CADDRE SEED Phase 3 to support the continuation of the epidemiological research capability of the Centers for Autism and Developmental Disabilities Epidemiology (CADDRE) network with implementation of a new Phase of the Study to Explore Early Development (SEED) Phase 3. The intent of this component is to carry out SEED Phase 3 with the same basic study design as SEED 1 and SEED 2 but with enhanced recruitment strategies to improve response rates, and a further reduction in the data collection protocol. Maintaining the same basic study design and overall protocol integrity will ensure that data pooling can be achieved across SEED phases.Both new sites and former SEED sites are encouraged to apply for this component.

1.

Component B: Biorepository an award for implementation of the SEED Central Laboratory and Biosample Repository.The objectives of Component B of this FOA are to support the maintenance and storage of the SEED Phase 1 and Phase 2 biosample repository and support the collection and storage of the SEED Phase 3 biosamples. It is CDC’s goal that all SEED biosamples (from Phases 1, 2, and 3) will be stored in one repository.To be funded for Component B, applicants must have a responsive application for Component A and receive Component A funding.

2.

Component C: SEED 1 Follow-up Study is a project to develop and implement a short protocol and feasibility assessment for conducting a follow-up of the children who enrolled in SEED 1 and completed the SEED 1 study data collection protocol.Both new sites, and former SEED 1 sites are encouraged to apply for this component. New sites must develop and submit agreements with one or more former SEED 1 sites to fully access all data needed to successfully conduct the follow-up study. Former SEED 1 sites may also propose follow-up of SEED 1 participants from other sites (in addition to their own) to maximize the sample size for this study. If former sites propose working with other SEED 1 sites, they must also develop and submit agreements documenting full data access.

3.

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, Component B, or http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf

Component C).

Mechanism of Support. Cooperative agreement Funds Available and Anticipated Number of Awards. The estimated total level of funding (direct and indirect for entire project period in dollars) that is available for the FOA is $21,600,000 to support up to 7 anticipated awards (over the 3 components). Awards issued under this FOA are contingent upon availability of funds and a sufficient number of meritorious applications. The total amount awarded and the number of awards will depend upon the number, quality, and cost of the applications received.

Budget and Project Period. The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $4,000,000. The estimated total funding (direct and indirect) for the entire project period, (07/01/2016 – 06/30/2021), is $21,600,000.

Component A (SEED 3): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $3,200,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016

– 06/30/2021), is $17,600,000. Estimated Number of Awards: up to 4. Average amount of each award is YR 1: $800,000

YRS 2-5: $900,000.

Component B (Biorepository for SEED-3): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016 – 06/30/2017), is $300,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016 – 06/30/2021), is $1,500,000. Estimated Number of Awards: 1. Average amount of each award for YRS 1-5:

$300,000.

Component C (Follow-up Study): The estimated total funding (direct and indirect) for the first budget period, (07/01/2016

– 06/30/2017), is $500,000. The estimated total funding (direct and indirect) for the entire 5-year project period, (07/01/2016

– 06/30/2021), is $2,500,000 Estimated Number of Awards: up to 2. Average amount of each award for YRS 1-5: $250,000.

Application Research Strategy Length: Page limits for the Research Strategy are clearly specified in Section IV. Appli cation 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.

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) is allowed for each component.”

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

Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: (770) 488-2783.

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority

Sections 301(a) [42 U.S.C. Section 241(a)] and 317(C) of the Public Health Service Act [42 U.S.C. Section 247b-4], as amended.

1. Background and Purpose

This FOA addresses new activities for the Study to Explore Early Development (SEED). SEED is a case-control study of risk and protective factors for autism spectrum disorder (ASD). Under this FOA, CDC will fund the third wave of data collection for the core SEED protocol, support a biorepository and sample processing for the saliva and blood specimens collected as part of the core SEED protocol, and initiate a brief follow-up of the first wave of SEED participants (SEED 1).

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by qualitative impairments in social interaction and communication and stereotyped behaviors and interests. Recent systematic population surveys and routine http://www.cdc.gov/od/pgo/funding/grants/additional_req.shtm#SectionIV http://www.cdc.gov/od/pgo/funding/grants/additional_req.shtm#SectionIV http://era.nih.gov/commons/index.cfm#SectionIII1A http://grants.nih.gov/grants/ElectronicReceipt/submit_app.htm#SectionIV1 monitoring systems in the US and other countries indicate the prevalence to be 1% to 2%. Accompanying advances in population-based monitoring of autism prevalence have been changes in diagnostic criteria and development of improved clinical methods, including growth in the number of standardized behavioral assessment tools, for autism screening and diagnosis. Yet, apart from the identification of some rare genetic conditions that are commonly associated with autism, causal mechanisms for the disorder largely remain unknown.

Overview of Funding History for SEED

The Children’s Health Act of 2000 mandated CDC to establish autism surveillance and research programs to address the number, incidence, and causes of autism and related developmental disabilities. Under the provisions of this act, NCBDDD funded five Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) through program announcements in FY2001 and FY2002 (California, Colorado, Maryland, North Carolina and Pennsylvania); CDC’s NCBDDD served as the sixth CADDRE site.

For the first funding cycle (2001-2006), each CADDRE grantee had three core objectives: to develop a protocol for a multi-site collaborative epidemiologic study focused on autism (which was eventually named the Study to Explore Early Development [SEED]); to conduct surveillance of autism and other developmental disabilities; and to conduct site-specific investigator-initiated studies on autism. In FY 2006, through a second CADDRE funding cycle, five grantees were awarded. The CADDRE activities for the second funding cycle (2006-2011) were limited to implementation of the first phase of SEED (subsequently known as SEED 1). CDC served as the sixth CADDRE SEED 1 site during this period. A second phase of SEED (SEED 2) was funded under a third funding cycle (2011 – currently ongoing with completion in 2016). Five CADDRE grantees received the awards.

Again, CDC served as the sixth SEED 2 site.

Both SEED 1 and 2 had the same primary scientific aims:

To characterize the autism behavioral phenotype and associated developmental, medical and behavioral conditions of autism, with a special focus on identifying homogeneous autism subgroups for etiologic analysis, and

1.

To understand the genetic and environmental risk factors for autism with a special focus on infectious, immunological, hormonal, obstetric, gastrointestinal and socio-demographic features.

2.

SEED Study Design

SEED uses a case-control design with multiple-source, population-based ascertainment of case and comparison groups. Cases (ASD group) comprise children meeting study definitions for ASD (see below). Two different control groups are enrolled: a group of children sampled from the general population (POP) and a comparison group of children with developmental disabilities other than ASD (DD group). Comparisons between ASD and POP are designed to identify risk factors for ASD relative to children in the general population. Comparisons between ASD and DD may provide the opportunity to distinguish risk factors for ASD independent of factors common to other developmental problems. The DD group also provides a means of controlling for recall bias that may arise more commonly among parents of children with developmental problems than among parents of typically developing children.

All three waves of SEED use the same basic study design. However, the SEED 2 protocol incorporated several revisions to the SEED 1 protocol including minor changes in eligibility criteria, recruitment strategies, and participant incentives, and a moderately streamlined data collection protocol. The SEED 3 protocol has been further streamlined in comparison to SEED 1 and 2.

A brief description of the differences between SEED 1 and SEED 2 protocols is provided below. A description of the additional revisions made to the SEED 3 protocol is provided in the following section, APPROACH. Also, Appendix A: SEED SUMMARY TABLES - contains summary tables that compare the three study waves.

Summary of SEED 1 and SEED 2 Protocols

Children were potentially eligible for SEED 1 if:

1. They were born in a study catchment area during the SEED 1 specified birth year range, 2 Still resided in the study catchment area during study implementation, 2 Still resided in the study catchment area during study implementation, 3 Lived with a knowledgeable caregiver (family member/caregiver of legal age who resided with and consistently cared for the child since s/he was aged 6 months or younger)

4 The knowledgeable caregiver was competent to communicate orally in English (or at two sites, in English or Spanish) and give consent; and

5 The child was physically able to complete developmental assessments. To remain eligible, enrolled children must also have been aged 30 to 68 months at the completion of the clinical developmental assessment to maintain the appropriate age range for validated study instruments.

Eligibility criteria for SEED 2 were the same as those for SEED 1 with one exception. In SEED 2 the requirement to live with a knowledgeable caregiver was narrowed to the biological mother. The reason for this revision was to ensure data on key pregnancy exposures were obtained on all SEED 2 participants.

In both SEED 1 and SEED 2, both potential ASD and DD children were ascertained through multiple sources serving or evaluating children with developmental problems, including early intervention, special education and related service programs for toddlers and young children, state autism registries, hospitals, clinics, and individual providers. Potential participants met specific criteria for ASD or an ASD-related exceptionality from early intervention/special education services (e.g., intellectually disabled, severe emotional disorder), or had received an ASD or ASD-related diagnosis or a diagnosis of one or more select conditions associated with ASD (e.g., conduct disorder, intellectual disability, significant developmental delay) from a clinical provider. This broad diagnostic net (“broad net”) for ascertainment of potential ASD cases ensured that both previously diagnosed and undiagnosed cases were identified. Parents who had a child with a documented ASD or ASD-related diagnosis/exceptionality could also contact the study directly and be considered for inclusion. Population control children were identified by randomly sampling state birth certificates of children born in the specified birth date range to mothers resident in a defined catchment area at delivery.

An invitation packet, written in English (and Spanish at two sites), was mailed to the primary caregiver (SEED 1) or biological mother (SEED 2) of all potentially eligible participants. Non-responders received a second invitation letter or were contacted via telephone call or email (9 attempts), depending on the site. During the study introductory telephone call, SEED staff members screened potential participants for eligibility. The Social Communication Questionnaire (SCQ), a 5-10 minute interview, was subsequently administered to the primary caregiver/biological mother of eligible participants to identify children who required a clinical diagnostic evaluation to determine final case status. Children with positive screens or a previous ASD diagnosis/exceptionality were assigned to the ASD workflow. DD or POP children with negative screens were assigned to the DD or POP workflow, respectively. Children in all 3 groups were seen in person for developmental evaluations; however the children in the ASD workflow received a much more extensive evaluation than the children in the DD and POP workflows.

Final participant classifications were dependent on the child’s ascertainment source (i.e., broad net or birth certificate), workflow classification and, for children in the ASD workflow, the results from both the Autism Diagnostic Observation Schedules (ADOS) (Lord et al. 2000, 2003) and the Autism Diagnostic Interview–Revised (ADI-R) (Le Couteur et al. 2003; Lord et al. 1994, 1997) administered during the SEED clinical diagnostic evaluation. SEED final participant classifications included: 1) Final ASD case,

2) Possible ASD case, 3) Final DD, and 4) Final POP.

Extensive data were collected via multiple modalities to address the SEED primary and secondary scientific aims: telephone interviews, self/parent-administered instruments, clinic visits for developmental evaluations and measurement of standard growth parameters, biosampling, and medical record abstraction. Support in completing self/parent-administered forms was provided as needed to overcome literacy barriers.

Data collection was uniform across all participants except that those in the ASD workflow completed additional instruments to assess specific ASD features.

The protocol for SEED 2 data collection was similar to the SEED 1 data collection protocol; however the data collection protocol was notably streamlined in SEED 2. Differences and similarities in data collected in SEED 1 and SEED 2 include the following:

Both SEED 1 and SEED 2 protocols included the SCQ screener, Child Behavior Checklist, Child Social Responsiveness Scale, Mullen Scales of Early Learning, Vineland Adaptive Behavior Scale, ADOS, ADI-R, and medical record abstractions (prenatal care and labor and delivery records from mother and neonatal care and pediatric care from child). The aforementioned forms were not modified between SEED 1 and SEED 2.

Both SEED 1 and SEED 2 protocols included an extensive maternal telephone interview that included questions on the mother’s reproductive history and her pregnancy with the index child, maternal and paternal medical history forms, and a child services and treatment form. These forms were similar between the two study phases; however some revisions were made.

Biosamples were collected in both SEED 1 and SEED 2 from the child, mother, and father if available. However, in SEED 1 buccal and blood specimens were collected and in SEED 2 saliva and blood specimens were collected to increase the DNA yield. Additionally hair specimens was collected in SEED 1 only.

Two forms were added to the SEED 2 protocol – a brief residential history form to allow for better assessment of potential environmental exposures and a child health history form. Of NOTE: much of the child health history form is comprised of various questions from some of the SEED 1 forms that were dropped from the SEED 2 protocol (below).

Several forms and examinations included in SEED 1 were dropped from the SEED 2 protocol. These include: the parental Social Responsiveness Scale forms; the Carey Temperament Scale; the Early Development Questionnaire; the family autoimmune disease history form; the paternal occupational exposure form; the child gastrointestinal questionnaire; the child sleep history questionnaire; the child diet diary; and the child stool diary. Of NOTE: select questions from the SEED 1 family autoimmune form, parental occupational form, child gastrointestinal form, and child sleep history forms were incorporated into the SEED 2 maternal, paternal, and child health history forms. Thus some key components of some of the “dropped” forms were retained in SEED 2 in a streamlined fashion.

SEED 1 included a child dysmorphology examination. In SEED 2 this assessment was dropped; however, basic growth parameter measurements were still collected in SEED 2.

For most SEED components (both SEED 1 and SEED 2), Quality Control (QC) procedures and standards were established a priori, including a variety of training exercises, initial “in-the-field” standards, and ongoing standards.

SEED established a Central Laboratory and Biologic Repository for initial processing and archiving of SEED biosamples and a Data Coordinating Center to develop, host and support the CADDRE Information System (CIS), a web-based application developed exclusively for CADDRE. The CIS provides the mechanisms for managing workflow and data processing through the course of the study. All participant data were entered into CIS by SEED staff and securely stored in a HIPAA-class facility. The CIS data from SEED 1 have subsequently been exported into analytic data files which are available to the SEED investigators.

Personally identifiable information (PII) is not included in the SEED analytic data files. SEED 2 CIS data will be similarly exported into analytic files and harmonized with SEED 1 data at the completion of the SEED 2 study phase.

In all, 3769 children and their caregivers were enrolled in SEED 1 and 2600 completed nearly all study steps. As of May 2014, 3250 families were enrolled in SEED 2 and 1971 had completed most study steps.

The SEED study sample sizes obtained through SEED 1 and SEED 2 are deemed sufficient for many principal analyses but are not sufficient for more detailed assessment of some key exposure subsets with low population prevalence, assessment of associations within important case subgroups, and many genetic analyses.

Rationale for SEED 3

This FOA to support SEED 3 will enhance our understanding of the genetic and environmental risk and protective factors for autism by building on the established SEED data resource. Implementing a third round of SEED data collection will increase the total SEED pooled sample size for investigation of high priority hypotheses thereby enhancing SEED’s analytic potential.

Maintaining the same basic study design and general protocol integrity will ensure that data pooling can be achieved across SEED phases for this purpose.

Modifications that will be implemented in the third round of data collection will include recruitment from a more recent cohort of children, strategies to improve response rates, and a further reduction in the data collection protocol.

Rationale for SEED 1 Follow-up Study

The children already enrolled in SEED 1 and SEED 2 represent a unique opportunity to better understand the long term trajectory of children identified as having autism at early ages. SEED includes one of the largest cohorts of children assembled with ASD.

Moreover, given the wealth of health, developmental, and risk factor data collected on both the children and parents included in the core SEED protocol, a follow-up study of the children presents unparalleled opportunities to better understand ASD etiologic subgroups, the long term health and functioning of children with ASD and other DDs, family impacts associated with ASD and other DDs, and service needs and use associated with ASD and other DDs.

In 2016, the oldest SEED children (SEED 1 children) will be adolescents – aged 11 to 14 years. This is an ideal time to begin a follow-up study as there are many gaps in the current scientific literature on the developmental trajectory and health consequences of ASD among adolescents. Additionally, beginning a follow-up study when the children are adolescents, allows investigators to incorporate methods into the protocol to remain in contact with the children and their families into adulthood and thus possibly continue the initial follow-up into a longer term longitudinal follow-up of children with ASD.

An ancillary benefit of the SEED follow-up study is that will also allow investigators to obtain important consents from SEED 1 families. SEED (as well as nearly all individual studies) are under-powered to address many important questions about genetics. In the years subsequent to the launch of SEED 1, genetic research consortiums have been established to allow genetic data from various studies of ASDs to be pooled. Because such consortia were not in existence when SEED 1 was planned and implemented, SEED participants were not appropriately consented to allow their genetic data (obtained from biosamples collected during SEED

1) to be shared in this manner.

The CDC IRB recently reviewed the SEED 1 consent forms, the current NIH guidance on submitting genetic data into biorepositories, and recent advances in technology that allow for potential identification of individuals based on their genetic data.

They determined that the existing SEED 1 consents do not sufficiently address the issue of genetic data sharing. A SEED follow-up study will provide an opportunity to obtain from SEED 1 participants specific consents for genetic data sharing and thus maximize the use of the SEED biorepository data.

Healthy People 2020 and other National Strategic Priorities This RFA addresses “Healthy People 2020” priority area(s) of Maternal, Infant, and Child Health and is in alignment with NCBDDD performance goal(s) to prevent birth defects and developmental disabilities.

(http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId=26)

Public Health Impact The prevalence of ASD is estimated to be 1% to 2%. Apart from the identification of some rare genetic conditions that are commonly associated with autism, causal mechanisms for the disorder largely remain unknown. SEED was developed to address important scientific aims:

1) To characterize the autism behavioral phenotype and associated developmental, medical and behavioral conditions of autism, with a special focus on identifying homogeneous autism subgroups for etiologic analysis, and

2) To understand the genetic and environmental risk factors for autism with a special focus on infectious, immunological, hormonal, obstetric, gastrointestinal and socio-demographic features.

This FOA to support the implementation of a third round of SEED data collection will increase the total SEED pooled sample size for investigation of high priority hypotheses thereby enhancing SEED’s potential to investigate ASD risk factors.

This FOA also supports the development and implementation of a SEED 1 follow-up study, which represents a unique opportunity to better understand the long term trajectory of children identified as having autism at early ages. Given the wealth of health, developmental, and risk factor data collected on both the children and parents included in the core SEED protocol, a follow-up study of the children will advance our understanding of ASD etiologic subgroups, the long term health and functioning of children with ASD and other DDs, family impacts associated with ASD and other DDs, and service needs and use associated with ASD and other DDs. The data generated from this follow-up study will directly impact public health program planning.

Relevant Work CDC currently funds five CADDRE/SEED sites through cooperative agreements (current funding scheduled to end June 2016).

Each funded site in the CADDRE/SEED network conducts autism research and is required to enroll a specific number of participants in each population group (CASE, DD, and POP). The data collected by the sites is entered into the CADDRE Information System (CIS) that is managed by a data coordinating center funded by the CDC. CDC provides scientific oversight for both the SEED project and the data coordinating center.

CADDRE principal investigators worked collaboratively with CDC to develop the original SEED protocol as well as the current SEED protocol. Multiple working groups were established by CADDRE in SEED 1 to organize and develop this large and multi-faceted case-control study. These working groups were retained in SEED 2 and will also be retained in SEED 3.

2. Approach

To meet the goals of the FOA, this announcement includes 3 separate funding components:

http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId=26

To meet the goals of the FOA, this announcement includes 3 separate funding components:

Component A: CADDRE SEED Phase 3 a continuation of the core SEED project with implementation of a new SEED Phase 3 using a new streamlined protocol.

1.

Component B: SEED Central Laboratory and Biosample Repository; implement and serve as laboratory and biosample repository for SEED Phase 3 study sites and serve as biosample storage source for SEED 1 and SEED 2. To be funded for Component B: Applicants must have a responsive application for Component A and receive Component A funding.

2.

Component C: SEED 1 Follow-up Study development and implementation of a study protocol and feasibility assessment for a follow-up study of SEED 1 participants.

3.

Applications should clearly indicate the Component for which the applicant is applying and should include at the beginning of the title, the respective component under which the application should be considered (i.e., Component A, Component B, or Component C).

Objectives/Outcomes Component A: CADDRE SEED Phase 3

The intent of this component is to carry out SEED Phase 3 with the same basic study design as SEED 1 and SEED 2 but with enhanced recruitment strategies to improve response rates, and a further reduction in the data collection protocol.

High priority scientific areas of interest for SEED Phase 3 remain the same as for SEED 1 and SEED 2 and include:

1) Characterize the autism behavioral phenotype and associated developmental, medical and psychiatric conditions of autism, with a special focus on identifying homogeneous autism subgroups for etiologic analysis, and

2) Understand the genetic and environmental risk factors for autism with a special focus on immunological, hormonal, obstetric, and socio-demographic features. Secondary areas of scientific interest will include investigation of the association of autism and maternal lifestyle factors in pregnancy (tobacco, alcohol and recreational drug use), maternal and paternal occupational history proximal to and during pregnancy, maternal residential history proximal to and during pregnancy, and assessment of child postnatal health characteristics.

Applicants under this FOA should describe how they will carry out the SEED Phase 3 protocol including:

1) Specific study population and catchment area;

2) Recruitment strategies;

3) Data collection and quality control procedures;

4) Collaboration with CDC and other sites through active participation in work groups and committees;

5) Collaboration with the designated SEED Data Coordinating Center and Central Laboratory and Biorepository; and

6) Data analysis and dissemination of findings.

Maintaining the same basic study design and overall protocol integrity will ensure that data pooling can be achieved across SEED phases.

A copy of the complete SEED 3 protocol is available upon request see Section VII. Agency Contacts, Scientific / Research Contact(s) Michael A. Brown to obtain a copy of the SEED 3 protocol.

This protocol is very similar to the SEED 2 protocol. However, some enhancements have been added to increase response rates and better understand response bias. These include language encouraging sites to work closely with their local data sources to develop mechanisms to increase response to the initial invitation mailing and obtain the necessary permissions to implement these mechanisms. The exact mechanism will vary by site but incorporating some type of active follow-up of non-responders via telephone calls, email messages, or both is strongly encouraged.

The second enhancement added to the SEED 3 protocol is language that sites are strongly encouraged to develop a mechanism and obtain necessary permissions to allow for linkage of limited birth certificate data on all participants (ASD, DD, and POP groups) invited including those who are never successfully contacted, those who refuse contact, and those contacted but found to be ineligible such that SEED investigators will be able to directly assess characteristics of respondents vs. non-respondents.

The exact plan for data linkage can vary across sites. Some sites will have access to the full birth records and are thus able to perform linkages between children invited from the ASD and DD source lists directly and retain all of the data onsite. Other sites might obtain more limited access. While individual-level data is preferred, aggregate data with distributions of aforementioned key variables will also be helpful in assessing potential response bias.

There are no other additions to the SEED 3 protocol. However, there are some reductions; the SEED 3 data collection protocol is a more streamlined version of the SEED 2 data collection protocol.

A summary of the main components of the SEED 3 protocol is described below and also can be found in the Tables included in Appendix A.

SEED 3 Study Design and Recruitment:

The SEED case-control design, including an ASD case group and DD and POP comparison groups at a 1:1 ratio of the ASD case group to the DD comparison group and a 1:1 ratio of the ASD case group to the POP comparison group, will be retained.

SEED’s original multi-source, population-based ascertainment approach for potential ASD and DD participants, including use of the “broad diagnostic net” to ensure both previously diagnosed and undiagnosed cases are identified, as well as random sampling of birth certificates for ascertaining potential POP participants will be retained.

Potential ASD and DD children will be identified through sources serving or evaluating children with…