and Human Services (HHS)
ADMINISTRATIVE SUPPLEMENTS TO SHARE RESEARCH RESOURCES FOR GENETIC STUDIES ON
AUTISM
RELEASE DATE: June 30, 2003
NOTICE: NOT-MH-03-006
National Institute of Mental Health (NIMH)
(http://www.nimh.nih.gov/)
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov/)
National Institute on Deafness and Other Communication Disorders (NIDCD)
(http://www.nidcd.nih.gov/)
National Institute of Child Health and Human Development (NICHD)
(http://www.nichd.nih.gov/)
RECEIPT DATE: September 1, 2003
PURPOSE
The National Institute of Mental Health (NIMH), the National Institute of
Neurological Disorders and Stroke (NINDS), the National Institute on Deafness
and Other Communication Disorders (NIDCD), and the National Institute of Child
Health and Human Development (NICHD) announce an administrative supplement
program for currently funded NIH research projects, in order to encourage the
collection and timely sharing of research resources for genetic studies on
autism through the NIMH Center for Genetic Studies ("the Center")
(http://zork.wustl.edu/nimh/). The Center allows receipt, storage,
maintenance, standardization, quality control, and equitable, ethical
distribution to the broader scientific community of DNA, clinical information,
genotyping data and other resources important for genetic studies of autism.
It is NIH's intent to include in this program all eligible research groups
worldwide who have collected data that could be utilized in genetic research
on autism.
RESEARCH OBJECTIVES
Background
The sharing of data is critical for the rapid progress of research investigating
the genetic basis of human disease. It is particularly important for disorders
like autism and other mental disorders that are genetically complex and
clinically heterogeneous. For such disorders, large sample sizes are often
essential for achieving adequate statistical power for genetic analysis. Other
scientific advantages of sharing data and research resources include:
facilitating the rapid replication of new findings, stimulating
multidisciplinary research among clinical and basic scientists, providing
needed clinical resources to promising young investigators, clarifying
discrepancies in results obtained from multiple data sets, avoiding duplicative
data collection efforts and laboratory work, and facilitating the rapid
application of state-of-the-art genomic technologies and analytic methods to
clinical data sets.
This administrative supplement program is open to all researchers who are
working on an ongoing NIH project in which autism samples have already been
collected. Funds will be provided to support the collection of blood and data
and related activities necessary for future genetic studies. This effort
ultimately will facilitate genetic research on autism and related disorders by
the broader scientific community. Cell lines, DNA, diagnostic information, and
other clinical data from subjects targeted under this program will be included
in the NIMH Human Genetics Initiative
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html) and
will be widely distributed to the scientific community. Successful
applications will focus on previously ascertained pedigrees containing multiple
affected individuals that were collected for a family-genetic or linkage study
in an outbred population, or a linkage disequilibrium mapping study in a
genetically isolated population. This includes small nuclear families
(affected individuals and their parents). Applications may also include a
large sample of well-characterized unrelated affected subjects for inclusion
in future case-control association studies. If such an application were to be
funded under this program, the supplement will exclusively support collection
of cases and will not support collection of control subjects.
Areas of Supplemental Support
The supplement will provide funds to defray the added costs of collecting blood
for submission to the Center, and other related activities (see below). Costs
associated with the actual clinical research project are not part of this
supplement program. Funds will not be used to support the ascertainment of new
pedigrees or of new samples of affected subjects for clinical studies.
There will be an anticipated maximum award for 1 year of $200,000 (DIRECT COSTS)
per data collection effort. Some NIH research projects may include multiple
data collection efforts by different investigators supported under subcontracts
or other mechanisms ("clinical sites"), as part of the funded NIH project.
Each clinical site may request up to $200,000 (direct costs); in such cases,
the aggregate requested direct costs for the NIH research project likely would
exceed $200,000.
Some clinical sites supported in part or wholly under NIH grant awards to
domestic institutions may have collected autism samples in countries other than
the United States. Inclusion of these clinical sites in applications to this
program is strongly encouraged. Before an award can be made under this
supplement program to support the activities of such a clinical site, NIH will
require written assurance that shipments of blood and data from the country in
question to the Center will be in strict accordance with that country's
existing laws and regulations. Funding under this program is contingent on
approval of written documentation by an appropriate government official.
This program will provide funds to support the following activities, which will
become conditions of the award:
o Contact or re-contact of autistic probands and relatives in pedigrees
(including small nuclear families) currently being studied or followed as part
of an NIH-funded research project, regardless of whether NIH supported the
initial pedigree ascertainment.
o Contact or re-contact of unrelated autistic subjects currently being studied
or followed as part of an NIH-funded research project, regardless of whether
NIH supported the initial subject ascertainment.
o Re-consent of affected individuals and relatives with a consent form
template, utilized in the NIMH Human Genetics Initiative and developed with
input from the National Human Genome Research Institute's Ethical, Legal, and
Social Implications Research Program and the Department of Health and Human
Services' Office for Human Research Protection, that explicitly discloses
participation in genetic research and acknowledges data sharing and maintenance
of DNA and data as national resources for studying the genetic basis of autism.
This template is available at
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html).
Funds provided under this program may be used to support activities (such as
personnel time) required of project staff when working with their local
institution, including the local Institutional Review Board, to obtain approval
of the consent form and to implement it in the project protocol.
o The drawing of viable blood samples and submission of these samples to the
Center, which will create high-quality lymphoblastoid cell lines to establish
an infinitely renewable source of DNA for subsequent genetic analyses.
Successful applicants shall ship blood samples in accordance with a blood
shipment protocol available from the Center
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html) so as
to minimize trauma, i.e., excessive heating or freezing. Funds provided under
this program may be used to support activities (such as personnel time) needed
to ensure that blood drawing procedures meet Center requirements for submission.
Also, funds may be used to recover all phlebotomy costs. All samples submitted
must be accompanied by required clinical and diagnostic data (see below).
o Electronic transfer at regular intervals of clinical, diagnostic, family
structure and other data to the Center, on all subjects for whom a blood sample
is submitted. Funds provided under this program may be used to support
activities (such as personnel time) needed to ensure that data are transmitted
in an expeditious fashion to the Center.
o Implementation of adequate quality assurance/quality control procedures to
ensure high quality of all data provided to the Center. Funds provided under
this program may be used to support activities (such as personnel time) needed
to ensure that high-quality data are transmitted to the Center.
The amount of award will be based on the number of subjects for whom both blood
samples and data are submitted to the Center. An initial award will be made to
cover the anticipated costs over 3 months of collecting and submitting data and
blood samples on the number of "sample units" (see below) anticipated during
this period, based on the proposed data collection milestones specified in the
application. Funds will then be released at subsequent 3-month intervals based
on the number of samples units proposed in the next 3-month period and the
success rate realized in the preceding 3-month period. It typically is not
feasible for all samples from a sample unit to be submitted to the Center at a
single time; therefore, single submissions will be accepted by the Center and
tracked until the minimum number required to complete the unit is met.
There are four types of possible sample unit submissions:
o Affected sib pairs. Two or more affected full siblings from the same family
with a diagnosis of autism (not an autism spectrum disorder) constitute a sample
unit in this context. This type of sample will be reimbursed at a rate per
affected (concordant) sib pair stipulated by the PI in the application. If only
these samples units are targeted, a minimum of 10 affected sib pairs is required
per clinical site, with a minimum of 20 affected sib pairs in aggregate per
research project. Samples submitted in addition to the required minimum number
are strongly encouraged. Incurred costs will only be justified for
reimbursement per sib pair when data and blood samples from both members of the
pair are provided to the Center.
o Extended pedigrees. Multigenerational, extended pedigrees that contain at
least four affected individuals (at least two of which are diagnosed with
autism and not an autism spectrum disorder) constitute a sample unit in this
context. This type of sample will be reimbursed at a rate per extended
pedigree stipulated by the PI in the application. If only these sample units
are targeted, a minimum of two extended pedigrees is required per clinical site,
with a minimum of four extended pedigrees in aggregate per research project.
Samples submitted in addition to the required minimum number are strongly
encouraged. Incurred costs will only be justified for reimbursement per
extended pedigree after data and blood samples from all pedigree members are
provided to the Center.
o Affected individuals and their two parents (trios). For such sample units,
only subjects diagnosed with autism (and not an autism spectrum disorder) are
to be included. Each sample unit of this type will be reimbursed at a rate per
trio stipulated by the PI in the application. If only these samples units are
targeted, a minimum of 10 trios is required per clinical site, with a minimum
of 20 trios in aggregate per research project. Samples submitted in addition
to the required minimum number are strongly encouraged. Incurred costs will
only be justified for reimbursement per trio when data and blood samples from
all members of the trio are provided to the Center.
o Unrelated affected individuals. For such sample units, only subjects
diagnosed with autism (and not an autism spectrum disorder) are to be included.
Applications may be submitted for funding under this supplement program that
propose a large collection of at least 200 unrelated affected individuals for
use in future case-control association studies. Such applications will be
assigned a lower funding priority than applications that specify pedigree data
collection. Each sample unit of this type will be reimbursed at a rate
stipulated by the PI in the application per affected subject. A minimum of
100 affected subjects is required per clinical site, with a minimum of 200
affected subjects in aggregate per research project. Samples submitted in
addition to the required minimum number are strongly encouraged. Incurred
costs per affected individual will only be justified for reimbursement when
data and blood samples from the subject are provided to the Center.
Collections from a single investigator may include one or a combination of
several sample unit types. In applications where there is a mixture of sample
units, minimum sample units as stated above need not be met for the purpose of
establishing milestones for data collection or reimbursement, but the aggregate
must exceed a given threshold. Please contact the NIH staff listed under
INQUIRES to discuss the threshold, given the sample unit mixture proposed for
collection. The following types of sample submissions will NOT be accepted by
the Center:
o Existing pedigrees currently included in the NIMH Human Genetics Initiative.
o Pedigrees or affected subjects included in the NIH Studies to Advance Autism
Research and Treatment (STAART) Centers Program.
o Samples other than whole blood (such as brain tissue, buccal swabs or
cerebrospinal fluid).
o Samples without accompanying clinical and diagnostic data.
Applications submitted for funding under this program need to include a detailed
description of each of the following, which will be incorporated in the terms
and conditions of award (after negotiation with the applicant when necessary):
o Targeted number and type of sample units from which data and blood samples
will be submitted to the Center, as well as a timeline for submission.
o Rates of reimbursement per affected sib pair, extended pedigree, trio, and
affected individual (case-control sample).
o Structured diagnostic criteria to establish a final best estimate lifetime
diagnosis. PIs are expected to employ state-of-the-art methods to synthesize
information collected from multiple sources, e.g., a structured diagnostic
interview, standardized intelligence testing, medical records, and multiple
family informants.
o Comprehensive clinical characterization through use of a standardized
intelligence test and a highly reliable diagnostic instrument, e.g., Autism
Diagnostic Interview Revised (ADI-R) and the Autism Diagnostic Observation
Schedule Generic (ADOS-G).
o A highly operable computerized database of diagnostic and clinical
information, which will permit rapid electronic uploads to the Center. This
should include a description of the time intervals at which data will be
electronically transmitted to the Center. This is not the same as the timeline
for release of these data to the wider scientific community, which is specified
in the data sharing plan (see below).
o A data sharing plan that permits broad sharing of clinical, diagnostic,
pedigree structure and other information, according to a specific distribution
timeline. The plan is expected to stipulate acceptance of existing NIMH
mechanisms and policies for data release, as already established in the NIMH
Human Genetics Initiative. [Note: NIMH policies and mechanisms do not specify
a specific distribution timeline.] These mechanisms allow for wide
distribution by the Center of all information (e.g., demographic, diagnostic,
clinical, genotypic, family structure data) and biomaterials (cell lines, DNA
samples) to qualified investigators in the scientific community. These
mechanisms further specify that NIMH determines to whom and in what format such
data and biomaterials are distributed.
o Adequate informed consent procedures. The consent form template described
above is expected to be utilized, in which the following are addressed:
(1) disclosure that biomaterials (DNA, cell lines) and clinical data will be
stored at the Center, as part of a national resource of data and biomaterials
distributed by NIMH for the genetic analysis of the disease under investigation;
(2) assurance that such data will be provided to the Center without personal
identifiers; (3) disclosure that analyses of these data will be conducted by
other scientists currently not included within the current research team; and
(4) disclosure that there is no plan to provide subjects with any financial
benefits from commercial products derived from the data. All samples must be
collected under an IRB-approved protocol. IRB approval must be documented, and
a copy of the IRB approved consent form to be utilized must be submitted prior
to funding. Funding under this program is contingent on NIMH approval of
consent forms. The Center is not a covered health-care entity according to
HIPAA guidelines, but if it were, it would be fully HIPAA-compliant.
Applicants should consider applying for a certificate of confidentiality for
sample collection done under this supplement.
o A request for a specific quantity of DNA or cell lines, to be used for
research conducted under the aegis of the PI's NIH research project. NIMH will
provide these biomaterials to the PIs at no cost, as a benefit of participation
in this administrative supplement program. Prior to shipment, the PI will
complete and execute a distribution agreement, available at
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html).
FUNDS AVAILABLE
The NIH institutes named on the notice plan to collectively commit $2.25
million in FY 2003 to fund applications for supplements to existing NIH-
supported grants in response to this Notice. Direct costs will be awarded in
modules of $25,000, less any overlap and other administrative adjustments.
Because the nature and scope of the data collection efforts may vary, it is
anticipated that the size of each award will also vary. There will be an
anticipated maximum award for 1 year (DIRECT COSTS) of $200,000 for any of the
above mechanisms per clinical site. Some NIH research projects may include
multiple clinical sites overseen by different investigators supported under
subcontracts or other mechanisms as part of the funded activities. In such
cases, each clinical site may request a direct cost award of up to $200,000; in
such cases, the aggregate requested direct costs for the NIH research project
likely would exceed $200,000. For such applications, please contact NIH
program staff listed below under INQUIRIES. Although the financial plans of
the NIH provide support for this program, supplements awarded as a result of
this Notice are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
ELIGIBILITY
Those eligible to apply are NIH Principal Investigators (PIs) with a clinical
study in which autism subjects were recruited under any of the following
mechanisms: Research Project (R01), Education Project (R25), Program Project
(P01), Research Program (Cooperative Agreement) (U19), Specialized Center (P50),
Research Project (Cooperative Agreement) (U01), Cooperative Clinical Research
(Cooperative Agreement) (U10) Specialized Center (Cooperative Agreement) (U54),
Research Scientist Development Award Research & Training (K01), Clinical
Investigator Award (K08), or Mentored Patient-Oriented Research Career
Development Award (K23) grants. To be eligible, projects must be ongoing at
the start of the supplement start date (studies ongoing under a no-cost
extension are eligible).
REQUIREMENTS FOR SHARING RESEARCH RESOURCES
The sharing of clinical data and biomaterials in a timely manner is an important
element in progress toward understanding the neurobiological basis of autism.
This administrative supplement program is responsive to the NIH Grants Policy
Statement requiring investigators to provide prompt and effective access to
unique research resources generated by NIH funds
(http://grants.nih.gov/grants/policy/nihgps_2001/part_iia_6.htm - _Toc504811860).
As described above, applications must include a data sharing plan. Data and
biomaterials from subjects included in projects funded by these administrative
supplements will be made available and distributed through the NIMH Human
Genetics Initiative to the broader scientific community.
HUMAN SUBJECTS
All applicable regulations that govern human subjects protection from research
risk must be addressed. The definition of human subjects in Title 45 CFR Part
46, the Department of Health and Human Services regulations for the protection
of human subjects applies, i.e., "Human subject means a living individual about
whom an investigator (whether professional or student) conducting research
obtains (1) data through intervention or interaction with the individual, or
(2) identifiable private information." These regulations specifically address
the protection of human subjects from research risks. It should be noted that
there are research areas (Exemptions 1-6) that are exempt from these
regulations. However, under these guidelines, NIH-supported biomedical and
behavioral research projects involving human subjects, whether of not exempt
from the human subjects regulations must still address the inclusion of women
and minorities in their study design
(http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm,
and children http://grants.nih.gov/grants/guide/notice-files/not98-024.html).
Thus, all biomedical and behavioral research projects involving human subjects
will be evaluated for compliance with this policy. Research involving the
collection or study of existing data, documents, records, pathological
specimens, diagnostic specimens, or tissues that are individually identifiable
also is included within the term "research involving human subjects."
APPLICATION PROCEDURES
1) Fill out a face page, including appropriate signatures, from Grant
Application Form PHS 398 (Revised May, 2001), found at
(http://grants.nih.gov/grants/funding/phs398/phs398.html .) Include the
title and grant number of the parent grant on line 1 and enter Notice MH-03-006,
"Administrative Supplements To Share Research Resources For Genetic Studies On
Autism" on line 2.
2) Prepare a project description (6-page limit), including the following:
o Performance site(s)
o Key personnel
o Targeted sample
o Targeted number of affected sib pairs, extended pedigrees, trios, and
affected subjects (if a case-control sample unit is included) for whom a blood
sample and data will be submitted to the Center
o Data collection timeline
o Structured diagnostic criteria
o Phenotypic assessments, e.g., ADOS-G
o Information regarding the computerized database
o Data quality assurance/quality control procedures
o Which data will be electronically transmitted to the Center, and at what
time interval
o Request for specific quantity of DNA per subject and/or cell lines
o Data sharing plan
o Rates of reimbursement per affected sib pair, extended pedigree, trio, and
affected individual (case-control sample)
3) The abstract and specific aims of the parent grant (2-page limit).
4) An itemized proposed budget and budget justification entered on the budget
pages from Grant Application Form PHS 398. Supplements should be requested in
modules of $25,000 in DIRECT COSTS, up to a maximum of $200,000 per clinical
site. Projects with multiple independent clinical sites may request an
aggregate direct cost budget for the NIH research project that exceeds $200,000.
5) Letters indicating approval and commitment of resources from collaborating
institutions.
6) IRB approval of a consent form containing key elements described above
related to data sharing, or agreement to obtain such approval prior to funding.
7) Written agreement to electronically submit to the Center data on all subjects
for whom a blood sample is sent to the Center.
8) Written agreement to ship blood samples in accordance with existing Center
protocols.
9) Written acceptance of existing NIMH mechanisms and policies for data release,
as already established in the NIMH Human Genetics Initiative.
10) Written assurance for foreign clinical sites that shipments of blood and
data from the country in question to the Center are in strict accordance with
that country's existing laws and regulations, or agreement that such written
assurance will be obtained prior to funding.
11) The original and two copies of the entire application package must be sent
directly to Dr. Steven Moldin at the address listed under INQUIRIES.
12) Applications must be received by September 1, 2003.
13) The supplemental award will be made prior to September 30, 2003, after
favorable evaluation and approval by NIH staff.
ADMINISTRATIVE REVIEW CONSIDERATIONS
Applications for submission will be evaluated administratively by NIH staff.
All funding decisions are final and are not subject to appeal. Applicants
should provide the following information for consideration in the
administrative review:
o How the proposed activities will be incorporated into the parent project;
o Size of available pedigree or case-control sample;
o Number and diagnoses of expected sample units (affected sib pairs, extended
pedigrees, trios, affected individuals for a case-control sample) and total
number of affected and unaffected subjects for which a blood sample and data
are to be provided to the Center;
o Feasibility of obtaining targeted number of sample units;
o Quality of diagnostic and other clinical assessments;
o Open operability of the computerized database, to permit electronic
transmission of data to the Center;
o Data quality assurance/quality control procedures;
o Rate of reimbursement per affected sib pair, extended pedigree, trio, and
affected individual (case-control sample).
INQUIRIES
Inquiries concerning this Notice are encouraged. The opportunity to clarify
any issues or answer questions from potential applicants is welcome.
o Direct inquiries regarding programmatic issues to:
Steven O. Moldin, Ph.D.
Office of Human Genetics and Genomic Resources
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7189, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-2037
FAX: (301) 443-9890
Email: [email protected]
o Direct inquiries regarding fiscal matters to:
Carol J. Robinson
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-3858
FAX: (301) 443-6885
Email: [email protected]
Weekly TOC for this Announcement
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