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/archive/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:  smoldin@mail.nih.gov

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:  crobinso@mail.nih.gov


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