RESEARCH ON AUTISM AND AUTISM SPECTRUM DISORDERS

Release Date:  September 24, 1998

PA NUMBER:  PA-98-108

P.T.

National Institute of Mental Health
National Institute of Child Health and Human Development
National Institute on Deafness and Other Communication Disorders
National Institute of Neurological Disorders and Stroke

PURPOSE

The purpose of this program announcement is to encourage grant applications for
the support of research designed to elucidate the diagnosis, epidemiology,
etiology, genetics, treatment, and optimal means of service delivery in relation
to Autistic Disorder ("autism") and autism spectrum disorders (Rett's Disorder,
Childhood Disintegrative Disorder, Asperger's Disorder, Pervasive Developmental
Disorder-Not Otherwise Specified, or "Atypical Autism").

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Research on Autism and Autism
Spectrum Disorders, is related to the priority area of mental health, maternal
and fetal health, and chronic disabling conditions.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-
512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit organizations,
public and private, such as universities, colleges, hospitals, laboratories,
units of state and local governments, and eligible agencies of the Federal
government.  Foreign institutions are not eligible for program project (P01)
awards.  Racial/ethnic minority individuals, women, and persons with disabilities
are encouraged to apply as principal investigators.

Collecting clinically well-characterized samples of sufficient size may in some
instances require or be facilitated by the establishment of international
consortia.  For example, sufficient power with which to detect susceptibility
loci for autism spectrum disorders may be facilitated through international
consortia.  Thus, full collaborations between U.S. scientists and scientists at
foreign institutions are encouraged when scientifically appropriate.

MECHANISM OF SUPPORT

Support mechanisms for this program are the individual research project grant
(R01), investigator-initiated interactive research project grant (IRPG)(R01), and
program projects (P01).  Applicants are encouraged to consult with program staff
listed under INQUIRIES prior to submission concerning these mechanisms and their
requirements.  Additional information on the IRPG mechanism is available in PA-
96-001, NIH Guide for Grants and Contracts, Vol. 24, No. 35, October 6, 1995,
http://www.nih.gov/grants/guide/pa-files/PA-96-001.html

An applicant planning to submit an investigator-initiated grant application
requesting $500,000 or more in direct costs for any year is advised that he or
she must contact Institute program staff (see INQUIRIES, below) before submitting
the application, i.e., as plans for the study are being developed.  Furthermore,
the applicant must obtain agreement from Institute staff that the Institute will
accept the application for consideration for award.  Finally, the applicant must
identify, in the cover letter that is sent with the application, the staff member
and Institute who agreed to accept assignment of the application.  Refer to the
NIH Guide for Grants and Contracts, March 20, 1998 available at:
http://www.nih.gov/grants/guide/notice-files/not98-030.html

RESEARCH OBJECTIVES

Although it has long been recognized that the pervasive developmental disorders,
including autism, are highly variable in their clinical manifestations and likely
the result of multiple etiologies, only recently have efforts been directed
toward a meaningful subtyping of this group of disorders.  Current classification
systems (e.g., DSM-IV) include five separate diagnoses under the pervasive
developmental disorders: Autistic Disorder, Rett's Disorder, Childhood
Disintegrative Disorder, Asperger's Disorder and Pervasive Developmental Disorder
Not Otherwise Specified (also called "Atypical Autism").

Autistic disorder, or "autism," is considered the most classic of the pervasive
developmental disorders in that it was the first of these disorders to be
recognized as a distinct disorder.  These disorders share a cluster of
impairments in reciprocal social interaction and communication and/or the
presence of stereotyped behavior, interests and activities.  These complex
disorders are of lifelong duration and affect multiple aspects of development,
learning, and adaptation in the community, and thus represent a pressing public
health need. The etiologies of these disorders are poorly understood, but are
thought to include genetic, metabolic, immunologic, neurophysiological, and
infectious or other environmental causes.

Such complex disorders require well integrated, multi-disciplinary,
methodologically-rigorous scientific approaches and access to a sufficient number
of well-characterized patients with these disorders.

Basic research into the pathophysiology of autism and autism spectrum disorders,
including research on brain mechanisms and genetics, is of special interest. 
Also of interest are clinical and applied investigations that may lead to the
development of diagnostic research instruments, treatments, and intervention
strategies.  Specific areas of interest thus include epidemiology, early
identification and diagnosis, genetic studies, brain mechanisms, communication
skills, cognitive neuroscience, psychosocial (behavioral) interventions,
pharmacological and other medical interventions, and services.

Methodological Considerations

The range of appropriate research methodologies is broad and includes a variety
of laboratory studies, the use of animal models, neuroimaging, population and
molecular genetic techniques, naturalistic and observational field studies, and
survey research.  However, regardless of topic or method, the following
considerations are relevant:

o Given the expected heterogeneity in this area, research need to apply a strict
set of diagnostic criteria for the inclusion and exclusion of subjects.  Whenever
possible, standardized diagnostic and assessment methods should be used.

o Subjects should be diagnosed using DSM-IV criteria or later diagnostic
classifications.

o Subjects' levels of verbal and nonverbal functioning need to be described at
least minimally, such as with verbal and performance or nonverbal, IQ measures. 
Description of other clinical features is encouraged.

o Methodologies for studies in all of the above areas should be state-of the-art.

o Applicants proposing studies of psychosocial interventions or pharmacotherapy
should attend to additional methodological considerations.  Standardized
intervention protocols should be used when possible.  Attention should be given
to random assignment and the choice of control groups (i.e., matching for
relevant variables, use of multiple control groups).  Pilot data assessing
feasibility are encouraged.

Epidemiology

Prevalence estimates for autism spectrum disorders for the United States are
unavailable.  However, recent studies from Canada and Japan indicate that autism
spectrum disorders may not be as rare as heretofore assumed.  Studies from those
countries indicate that prevalence rates are greater than ten per 10,000.  There
is a need to increase research efforts in epidemiology in order to understand
etiologic factors, rigorously characterize high-risk groups, identify comorbid
conditions, clarify the relationships between disorders (e.g., Asperger's
syndrome and autism) and document their broad range of expression.  Of particular
interest are developmentally-focused, longitudinal epidemiological studies that
follow children and families over time.  Areas of interest include, but need not
be limited to, the following:

o Development of new screening tools for use in a variety of settings;

o Research on the expression of the full range of autism spectrum disorders;

o Studies on their developmental course;

o Studies that characterize the range of expression within families;

o Research on co-occurring features;

o Studies of risk assessment;

Early Identification and Diagnosis

Of critical importance is research that examines existing diagnostic criteria as
they apply to very young children.  There is a need for progress in nomenclature,
definitions, and diagnosis.  Developmentally sensitive studies in early
identification and diagnosis can lead to better delineation of the course of
these disorders, aid in projecting clinical outcomes, and help determine optimal
clinical interventions at various ages.  Areas of investigation include, but need
not be limited to, the following:

o Key diagnostic features associated with various stages of development;

o  Assessment of comorbid features including hyperactivity, attentional 
dysfunctions, and obsessive and compulsive symptoms;

o Assessment and further differentiation of subtypes of autistic spectrum
disorders including Autistic Disorder, Asperger's Disorder, Rett's Disorder, and
Childhood Disintegrative Disorder;

o Developmental factors relevant to reliable and valid diagnosis.

Genetic Studies

A consensus among researchers that genetic factors play a major role in autism
has led to several large-scale national and international efforts to identify
genes that contribute to the susceptibility to autism.  Given the size and scope
of these efforts, this PA seeks applications for interdisciplinary neuroscience
on the genetic basis of autism spectrum disorders in humans.  Applications for
interdisciplinary neuroscience research on the genetic basis of behavior in model
organisms or on the genetic basis of any aspect of neural functioning
(neuroendocrine and neuroimmunologic systems, neurodevelopment, Circadian
rhythms) may have as a focus either autism or autism spectrum disorders.

Given the major public health implications of identifying genes responsible for
these disorders, the information and resources generated by human genetic studies
funded under this PA will be substantial, and the interest in having access to
them is widespread.  In accordance with evolving NIH policies for data sharing
and access to data and materials collected in human genetic research, applicants
proposing human genetic studies are required to include with their applications
under this PA a detailed plan and timetable for the rapid release of these data
and materials to qualified scientific investigators.  NIH staff will consider the
adequacy of this plan as one of the criteria for award.  The proposed sharing
plan, after negotiation with the applicant when necessary, will be made a
condition of the award.

One resource currently available to applicants is the Center for Inherited
Disease Research (CIDR), a centralized facility established to provide high-
throughput genotyping and statistical genetics services for investigators seeking
to identify genes that contribute to human disease.  CIDR was established in 1996
as a joint effort of eight NIH Institutes and is supported through a contract to
Johns Hopkins University.  CIDR utilizes automated fluorescent microsatellite
analysis using a standard marker set (Weber Screening Set 8) consisting of 387
primer pairs spaced approximately 10 CentiMorgans throughout the genome.  Its
current capacity is approximately 120,000 genotypes per month.

CIDR is available to all investigators through competitive peer review.  Given
that NIMH, NINDS, NICHD, and NIDCD are supporting NIH Institutes, research
projects funded under this PA are eligible for CIDR's special introductory rate
of no-cost genotyping.  To obtain an approval letter from CIDR's Access Committee
for inclusion in their application, investigators need to submit a request to
CIDR for one of the following three receipt dates:  March 1, July 1 or November
1.  Additional information about CIDR is available at http://www.cidr.jhmi.edu.

Applicants who wish to conduct a whole genome scan in the genetic analysis of
autism spectrum disorders are strongly encouraged to request access to CIDR. 
Although utilization of CIDR is not required, applicants who do not use it must
demonstrate that they will conduct genotyping and statistical analyses comparable
to that achieved at CIDR with respect to genotyping costs and completion time for
a genomic scan.

Specific areas of needed investigation include, but are not limited to, the
following:

o  Large-scale linkage studies of affected relative pairs or extended pedigrees
to identify chromosomal regions harboring disease susceptibility genes;

o  Family-based association analysis and other linkage disequilibrium  approaches
that aim to identify a specific susceptibility gene;

o  High-resolution mapping and positional cloning studies;

o  Resolution of locus heterogeneity;

o  Analysis of gene-environment interactions;

o  Identification of genes that influence comparable behaviors in mice, through
the use of gene targeting and selectively bred, recombinant  inbred and
transgenic strains;

o  Regulation at different developmental stages of genes expressed in neural
cells believed to be involved in the pathogenesis of autism or autism spectrum
disorders;

o  Characterization of transcription elements (e.g., promotors, enhancers) that
regulate genes showing tissue-specific expression patterns in brain regions
implicated in autism or autism spectrum disorders;

o  Studies of the control and regulation of genes of unknown function that are
expressed in and isolated from brain regions implicated in autism or autism
spectrum disorders.

Brain Mechanisms

There is a compelling need to increase research efforts in understanding
neurodevelopmental factors involved in autism and autism spectrum disorders.
Research studies in pathophysiology have been encouraging, as they provide
accumulating evidence for functional and structural abnormalities in several
brain regions in persons with autism. The data indicate abnormalities in limbic
structures (e.g., amygdala, hippocampus, septum, mammillary bodies) and the
cerebellum.  Multiple structures at multiple levels of the neuraxis are
implicated in the disorder.  Areas of needed investigation include, but are not
limited to, the following:

o  Studies of brain mechanisms underlying the development, regulation, and
modulation of behaviors characterizing autism and autism spectrum disorders,
particularly those mechanisms involving communication and social interaction;

o  Studies of brain mechanisms and biological factors underlying autistic
regression, or the loss of previously acquired skills;

o  Studies of brain mechanisms involved in the development of abnormal
electroencephalograms and epilepsy and studies to clarify the subtypes of
seizures and seizure disorders in autism;

o  Studies to define the neurobiological basis of neurological abnormalities and
neuropsychiatric symptoms, including motor stereotypies, gait abnormalities,
akinesias, dyskinesias, obsessive/compulsive traits, and the exacerbation of
these symptoms, including the role of neuroimmune/autoimmune factors;

o  Studies that seek to define basic processing deficits using neuropsychological
and cognitive neuroscience techniques;

o  Studies designed to develop and test interventions directed toward specific
processing deficits, thereby potentially providing further confirmation or
disconfirmation concerning the nature of core processing deficits and their
relationship to overall behavioral functioning and social adaptation;

o  Studies combining neuropsychological and cognitive neuroscience techniques
with structural and functional imaging;

o  Longitudinal studies to identify structural and functional alterations in
neural circuitry occurring with development.

Communication Skills

Autism and many of the autism spectrum disorders are characterized by significant
impairment in both verbal and nonverbal communication, deficits in emotional
understanding and expression, difficulties in initiating and maintaining verbal
interaction, and a limited behavioral repertoire with restricted interests and
activities.  Longitudinal data are limited, so the course of communicative,
social and emotional development in children with these disorders is poorly
understood.  Longitudinal studies of communication combined with techniques such
as neurochemistry and/or neuroimaging are needed to elucidate their underlying
biology and the interplay between biological and environmental influences on the
course of lifespan communicative competence.  Areas of research may include, but
are not limited to:

o  Longitudinal, developmental studies of behaviors that are precursors to later
communication (e.g., imitation, joint attention, early vocalization) and their
emergence in children with autism and autistic spectrum disorders;

o  Sensory, motor and social-cognitive impairments that impact upon interaction
and communication;

o  Predictors of loss of or regression in expressive language abilities;

o  The nature of severe spoken language deficits when other areas of function,
such as written language skills, are relatively preserved;

o  Interventions designed to remediate communication and related deficits.

Cognitive Neuroscience

At their core, autism and autism spectrum disorders involve complex social and
cognitive deficits.  From a developmental perspective, greater research efforts
are needed to study the complex deficits implicated in these disorders.  Areas
of investigation may include, but need not be limited to, the following:

o  Developmental studies of relevant behaviors during infancy including attention
to social and nonsocial stimuli, affective behavior, gaze, vocalization,
imitation, initiative, reciprocity, attachment, play, compliance, and self-
recognition and their emergence in children with autism and autistic spectrum
disorders;

o  Research on the delays and deviations in social behavior and cognition during
preschool and middle school, including empathy, receptive social cognitive
deficits (i.e., difficulties understanding others), and expressive difficulties;

o  Studies leading to more sophisticated tests of higher cognitive functioning,
especially in social, communicative, reasoning, and problem-solving areas, as
well as tests of basic attentional, emotional and cognitive deficits that may
underlie these deficits or be precursors to them;

o  Studies of theory of mind, of unconventional verbal behaviors, and of the
sensory-motor factors involved in relevant social cognition;

o  The development, validation and refinement of interventions designed to
address deficits in complex social and cognitive abilities or their developmental
precursors.

Psychosocial Interventions

Autism and autism spectrum disorders can be helped through interventions of
various types including behavioral treatments.  There is a need for research to
assess various interventions and to provide rigorous scientific testing of their
effectiveness.  Emphasis will be given to studies that utilize experimental and
longitudinal designs to evaluate and compare various approaches to treatment.
Also encouraged are collaborative treatment projects incorporating
multidisciplinary approaches. Needs include, but are not limited to, the
following:

o  Studies developing new treatments (e.g., behavioral, cognitive-behavioral) and
studies validating, refining and comparing approaches to the treatment of autism
and autism spectrum disorders, as well as studies that analyze and define the
critical features of effective intervention;

o  Studies that relate characteristics of individuals (or diagnostic subtypes)
to treatment outcomes;

o  Research on relevant contextual factors including physical environments,
parent-child and sibling-child relationship factors, and peer-child interactions;

o  Studies addressing generalization or the transfer of learning from one setting
to another.

Pharmacological/Medical Intervention

Currently, no pharmacological treatments are available for the core symptoms of
autism and autism spectrum disorders.  Based mainly on limited data, medications
are often used, however, to treat a variety of symptoms commonly associated with
autism (e.g., impulsivity, aggression, hyperactivity, self-injury, obsessive-
compulsive symptoms).  There is a need for rigorous evaluation of the
effectiveness of currently available medical approaches to treatment.  Also
needed are studies combining pharmacotherapy with psychosocial and other
interventions.  Investigation may include, but need not be limited to, the
following:

o  Studies aimed at developing and testing the efficacy and safety of 
pharmacological agents that specifically target the core features of autism and
autistic spectrum disorders;

o  Studies of the efficacy and safety of pharmacological and combined treatments
for the most common and impairing psychopathology associated with autism (e.g.,
hyperactivity, impulsivity, aggression, self-injury, and obsessive-compulsive
symptoms);

o  New approaches to treatment that build on advances in neuroscience, genetics,
immunology, and other neurobiologic fields;

o  Focused interventions that test specific theories or hypotheses regarding
possible neuropathogenesis;

o  Studies that address the benefits of combined drug and psychosocial
interventions.

Services

Studies of services for individuals (children and adults) with autism and
autistic spectrum disorders have documented the gap between needs and service
availability and use.  However, few studies have documented the precise social,
environmental, or economic factors that affect access to care and its
availability and use.  Studies directed toward these factors are important for
systematic planning of service delivery.  In addition, studies of the
effectiveness of services in mitigating negative outcomes are particularly
needed.  These kinds of studies, coupled with attention to the involvement of
families in treatment planning, can further the goal of improving outcomes for
individuals with these disorders and their families.  Areas of particular
interest include, but are not limited to, the following:

o  Studies of fiscal, policy, or organizational factors affecting access,
availability, quality, use or outcomes of care;

o  Studies of the effectiveness of interventions delivered in naturalistic
settings, especially integrated services that target two or more primary settings
(e.g., school, home, community, work, etc.);

o  Studies of the impact of family involvement in treatment planning and
delivery;

o  Studies of the cost-effectiveness of various treatments and service delivery
models.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS  PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://www.nih.gov/grants/guide/notice-files/not98-024.html.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD  20892-7910, telephone (301) 710-0267; FAX: (301) 480-0525; Email:  [email protected].  The title and number
of this program announcement must be typed in Section 2 on the face page of
the application.

It is conceivable that one or more participating applications in an IRPG
package may be continuations of currently funded R10s, IRPGs, or separate
(i.e., previously non-collaborative) grants, with others being new (Type 1)
R01s, all seeking support to come under the umbrella of the IRPG program.  In
such cases, the competing renewal (Type 2) applications will keep the same
grant number as usual.

Separate applications must be prepared by each participating institution.  It
is crucial that all applications comprising the IRPG cite this program
announcement title and number in section 2 on the application face page.

Applicants applying under the IRPG mechanism must adhere to the application
procedures identified in PA-96-001 http://www.nih.gov/grants/guide/pa-files/PA-96-001.html

The completed original application and five legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/express service)

Revised IRPG applications must include an Introduction and highlight the
changes made in the Research Plan in response to the previous critique and
describe in item (I) how the delay in initiating the collaboration will be
managed.  This is particularly important if some projects in a collaborative
IRPG group were awarded and research on those projects has already begun.

Because each research project is an independent application, it must be
prepared with the same detail and thoroughness required of any R01
application.  Each project must stand on its own scientifically and could be
accomplished independently.  For example, one project must not be dependent on
another project in the IRPG group for a critical chemical or reagent, testing
or processing of key samples, or interpretation of data.

If there is a question about the appropriateness of a set of applications for
an IRPG group, applicants are encouraged to discuss the issues with one of the
NIH staff contacts listed under INQUIRIES.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Incomplete applications will be returned to the applicant without
review.  Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in accordance
with the standard NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique and undergo a process
in which only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council or board.

Review Criteria for R01s

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.  Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score.  For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

(1) Significance.  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

(2) Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation.  Does the project employ novel concepts, approaches or
methods?  Are the aims original and innovative?  Does the project challenge
existing paradigms or develop new methodologies or technologies?

(4) Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

(5) Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

(6) Appropriateness of the proposed budget and duration in relation to the
proposed research;

(7) Adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research.  Plans
for the recruitment and retention of subjects will also be evaluated.

(8) For genetic studies, adequacy of data sharing plan.

The initial review group will also examine the provisions for the protection
of human and animal subjects, the safety of the research environment.

In addition, an Interactive Research Project Grant will also be evaluated on:

o  the intended IRPG interactions.

In an administrative note, the reviewers will indicate the effectiveness and
feasibility of the proposed IRPG group interactions, whether or not they
enhance the prospects for reaching the stated objectives of the group, and the
extent of the synergy among the various projects.  The appropriate national
advisory council or board and institute or center program staff will consider
these comments when making award decisions.

The criteria for the initial review of the shared resources requested for the
IRPG group, which are reviewed independently from the research project, are
the following:

o  qualifications of key personnel;

o  adequacy of approaches, methods, and facilities;

o  appropriateness for the IRPG group; and

o  use by component IRPGs.

o  Procedures to ensure access to data, sharing of data and resources (both
within and outside a collaborative group), publication rights, and means of
arbitrating and resolving publication disagreements among the participating
investigators.

The reviewers may also make recommendations about the shared
resource(s) and the reasonableness of the budget request.  These
recommendations will be considered when funding decisions are made by the
awarding institute or center.  The amount awarded for shared resources may
depend on the number of component projects awarded.

Review Criteria for P01s:

Review criteria are based on the objectives and goals of the application. The
Review Committee will evaluate applications for impact, approach, and
feasibility using the standard NIH review criteria, and additional review
criteria specific to this initiative and specific to either preclinical or
clinical studies, as follows:

IMPACT:  The extent to which the project, if successfully completed, will make
an original and important contribution to biomedical science.  Specifically:

A.  The scientific, technical or medical significance, and originality of the
project.

B.  The likelihood that, if successfully executed, this research will open a
new direction in the treatment of autism (e.g., the innovativeness and
uniqueness of the proposed strategy), demonstrate a capacity to be reduced to
clinical practice, or merit evaluation in clinical studies for safety and
proof-of-concept.

C.  For previously funded preclinical applications: evidence of significant
progress in the previous award (e.g. design, formulation, or development of
therapeutic entities/strategies that merit clinical evaluation).

D.  For previously funded clinical applications: demonstrate that the concept
proposed is new, substantially improved, or represents a new direction from
that evaluated in the preceding funding period.

APPROACH:  the extent to which the conceptual framework, design (including
selection of appropriate subject populations or animal models), methods, and
analyses are properly developed, well integrated, and appropriate to the
objectives of the project. Specifically:

A.  Appropriateness and adequacy of the experimental approach, the development
plan, and the methodology proposed to carry out the research.

B.  Scientific and technical merit of the approach as a whole, and the
relationship and contribution of each project and core to the central focus of
the overall program.

C.  Cohesiveness, multi-disciplinary and multifaceted scope of the program and
the coordination and interdependence of the individual projects and core(s);
plans for effective intra-Group communication.

D.  For applications focusing on preclinical research: choice of the
therapeutic target or strategy, its contribution to the diversity of potential
therapeutics, and the likelihood that the target/strategy can be developed
during the award period.

E.  For applications proposing clinical research: adequacy and validity of the
proposed milestones for determining the readiness of the Group to transition
to clinical research (if applicable); iterative nature of clinical/laboratory
research plan to develop and optimize the proposed treatment strategy;
protocol design (clinical and scientific), short and long term development
plans, and contingency plans addressing the specific objectives set forth in
the therapeutic strategy; and provisions to obtain the required institutional
and regulatory approvals to conduct the clinical study.

FEASIBILITY:  the likelihood that the proposed work can be accomplished by the
investigators, given their documented experience and expertise, past progress,
preliminary data, requested and available resources, institutional commitment,
and (if appropriate) documented access to special reagents or technologies and
adequate plans for the recruitment and retention of subjects.  Specifically:

A.  Leadership, scientific ability, and administrative competence of the PI
for the development and management of a comprehensive research program.

B.  Qualifications and experience of each Project Leader (PL) or Core Leader
in relation to his/her proposed contribution to the program.

C.  The commitment of the PI and the PL to devote substantial time and effort
to the program.  [Due to the complexity and time required to maintain a well-
coordinated and productive research effort, a minimum 20% (time) commitment by
the PI and PLs is strongly suggested unless there are compelling arguments to
the contrary.]

D.  The academic, clinical, and physical environment in which the research
will be conducted; the potential for interaction with scientists from other
departments and/or institutions in relevant disciplines.

E.  For applications proposing clinical research: experience of the PI and PLs
in the planning, design, and conduct of small clinical studies in patients
with autism.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions:
quality of the proposed research project as determined by peer review,
availability of funds, and program priority for all of the above areas of
research and, in addition, for genetic studies, the data sharing plan.

INQUIRIES

Inquiries are encouraged.  Questions and discussion of programmatic issues
from potential applicants may be addressed to:

Judith M. Rumsey, Ph.D.
National Institute of Mental Health
5600 Fishers Lane, Room 18C-17
Rockville, MD  20857
Telephone:  (301) 443-9264
FAX:  (301) 480-4415
Email:  [email protected]

Marie Bristol, Ph.D.
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B09
Bethesda, MD  20892
Telephone:  (301) 496-1383
FAX:  (301) 496-3791
Email:  [email protected]

Judith Cooper, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400C-11 - MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 496-5061
FAX:  (301) 402-6251
Email:  [email protected]

Giovanna Spinella, M.D.
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-5821
FAX:  (301) 402-0887
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Diana Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-3065
FAX:  (301) 443-6885
Email:  [email protected]

Edgar D. Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17 - MSC 7150
Bethesda, MD  20892
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  [email protected]

Sharon Hunt
Grants Management Office
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, EPS-400-B MSC-7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758
Email:  [email protected]

Karen Shields
Grants Management Office
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242, 93.865, 93.173, and 93.853.  Awards are made under authorization of
the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency Review.  Awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy Statement
(April 1, 1994).

PHS strongly encourages all grant and contract recipients to provide a smoke-
free work place and promote the non-use of all tobacco products. In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)