GENETICS AND PATHOBIOLOGY OF VASCULAR COGNITIVE IMPAIRMENT

RELEASE DATE: August 20, 2004

PA NUMBER:  PAS-04-149

The R01 portion of this funding opportunity has been replaced by PAS-07-194,
which now uses the electronic SF424 (R&R) application for February 5, 2007 
submission dates and beyond.

March 2, 2006 (NOT-OD-06-046)   Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. 
A replacement R21 (PAS-06-265) funding opportunity announcement has been issued 
for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:  
National Institutes of Health (NIH)
(http://www.nih.gov/) 

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov/)
National Institute on Aging (NIA)
(http://www.nia.nih.gov/)
National Heart, Lung and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  NINDS 93.853, NIA 93.866, 
NHLBI 93.837, 93.838

THIS PAS CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PAS
o Research Objectives
o Mechanism(s) of Support
o Funds available 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PAS

The purpose of this Program Announcement with set-aside funds (PAS) is to 
invite applications to study the biological basis of vascular cognitive 
impairment (VCI).  VCI causes a burden of illness similar to that caused by 
Alzheimer’s disease (AD), but has been far less well-studied.  Recently, 
however, some important strides have been made in understanding the etiology 
of VCI.  These include the discovery of a monogenic form of vascular 
dementia, CADASIL, and identification of the causative gene as Notch 3.  In 
addition, MRI and other pathological data have provided a clearer delineation 
of the various clinical subtypes of VCI, and awareness of the synergistic 
interaction between vascular and classical Alzheimer’s pathologies in 
producing cognitive impairment.  The goal of this PAS is to build on these 
first critical achievements to obtain a better understanding of the cellular 
and molecular mechanisms causing vascular, neural, and glial dysfunction in 
human VCI and animal models of VCI.

RESEARCH OBJECTIVES

The number of people affected by dementia in the US is expected to increase 
three-fold in the next 50 years, to a total of over 13 million.  The best-
known form of dementia is AD, whose definitive diagnostic sign is the 
presence of plaques and tangles in brain neurons upon autopsy.  However, a 
large proportion of dementia cases in the aged population are not due to AD, 
but rather to cerebrovascular disease.  Dementia due to cerebrovascular 
disease is referred to as  vascular dementia , and can occur in the absence 
of Alzheimer’s pathology.  In addition to this so-called  pure  vascular 
dementia, there are also cases of  mixed  dementia in which cerebrovascular 
and Alzheimer’s pathologies coexist.  Recent studies suggest that pure 
vascular dementia and mixed dementia together comprise the majority of 
dementia cases in some populations.  

Vascular dementia can arise from any of several cerebrovascular disease 
conditions, but its two major causes are focal ischemic infarcts (i.e., 
strokes) and subcortical ischemic vascular disease.  Focal ischemic infarcts 
result from occlusion of large vessels, in either cortical or subcortical 
locations, and are accompanied by acute clinical signs of neurological 
impairment.  (Dementia arising from large infarcts is also sometimes referred 
to as  multi-infarct dementia .)  Subcortical ischemic vascular disease, on 
the other hand, results from occlusion of small vessels, and creates 
widespread small lesions(lacunae) and/or areas of demyelination.  The areas 
affected are generally subcortical, including the basal ganglia, cerebral 
white matter and brainstem. This form of vascular disease generally does not 
produce sudden, acute symptoms, but rather causes longer-term, insidious 
changes in neurological function.  In a significant portion of cases, this 
disease can even remain clinically silent for the life of the individual.  
Subcortical small vessel disease can be diagnosed by imaging even in cases 
where it is clinically silent.

In recent years, the term  vascular dementia  has been replaced by the term 
 vascular cognitive impairment (VCI) .  This change reflects the realization 
that cerebrovascular disease can cause significant cognitive and functional 
decline in the absence of dementia as defined by standard criteria.  In 
addition, there is increasing evidence that VCI differs from AD in terms of 
precise range of cognitive defects associated with each disease.  AD is 
characterized primarily by episodic memory loss due to loss of cholinergic 
basal forebrain neurons and their projections to the hippocampus.  In 
contrast, VCI in its purest forms seems to be characterized more by loss of 
executive function and attentional mechanisms associated with prefrontal 
circuitry.  However, the spectrums of defects seen in VCI and AD overlap 
substantially.  This fact, together with the frequent coexistence of vascular 
and Alzheimer’s pathologies within individual patients, renders it difficult 
to provide definitive diagnoses based strictly on cognitive tests.

Despite the enormous prevalence of VCI, the biological basis of this disease 
has been much less well studied than that of AD.  This lack has been due in 
part to the clinical heterogeneity of the disease, and also to poor 
understanding of its pathology at the cellular level.  Recently, however, 
research in VCI has taken some critical first steps forward.  A genetic form 
of vascular dementia, CADASIL, has been discovered, and the mutant gene 
identified as Notch 3.  Previous research in animal models had shown Notch 3 
to be important in early neural and vascular development. The finding that 
mutation of Notch 3 leads to stroke and dementia (both seen in CADASIL) 
suggests that the gene also plays an important role in the function or 
maintenance of vascular and/or neural cells in the adult.  Consistent with 
this possibility, a transgenic mouse carrying the mutant form of Notch 3 has 
now been generated which shows degeneration of smooth muscle cells similar to 
that seen in human patients.  These findings provide an important foothold 
for understanding the cell biology as well as the genetics of VCI.  Moreover, 
the known interaction of Notch with the presenilin proteins suggests a 
juncture in the disease pathways underlying VCI and AD, which also could be 
further explored in mouse models.

Another major area ripe for exploration concerns the genes and other risk 
factors that link vascular pathology to neural pathology:  eg., that render 
individuals susceptible to neuronal damage and cognitive impairment in 
response to cerebrovascular disease.  Some progress has been made in recent 
years in defining genes that predispose individuals to stroke and 
cerebrovascular disease per se, but no studies have yet examined genes that 
control the ability of neural tissue to recover from ischemic injury.  
Identifying such genes would provide clear paths both to understanding the 
cell biology of VCI, and also to the design of protective agents and 
therapeutics.

Research areas appropriate for this announcement would include, but are not 
limited by the following examples:

o Genetics of VCI, in both animal models and humans;  in particular, 
identification of genes that render individuals susceptible to cognitive 
impairment secondary to cerebrovascular disease

o Analysis of cellular and molecular changes occurring in vascular, neuronal, 
and glial cells during the development of VCI in human patients, and 
correlation of these with MRI signs and changes in cognitive function

o Studies of cellular and molecular pathological processes occurring in 
vascular, neuronal, and glial cells in animal models of VCI, such as mouse 
lines carrying mutant forms of Notch 3 or the stroke-prone spontaneously 
hypertensive rat

o Studies of Notch 3 function in the maintenance and repair of vascular, 
neuronal, and glial cells in normal adult animals;  studies of the cellular 
and molecular bases of the pathogenic actions of mutant Notch 3

o Studies of the cellular and molecular bases of the interaction between the 
VCI and AD pathways (for example, studies of vascular function and pathology 
in animal models of AD)

o Development and characterization of new animal models for the study of VCI, 
and of the interaction between VCI and AD pathogenic mechanisms

o Analysis of cognitive function in animal models of VCI, and correlation of 
changes in cognitive function with cellular and molecular pathologies

o Studies on the cellular and molecular effects of hypertension, diabetes, 
hyperlipidemia, coagulant and anticoagulant proteins, inflammatory cytokines, 
and complement proteins on the vessel wall in appropriate animal models for 
VCI

MECHANISM(S) OF SUPPORT 

This PAS will use the NIH R01 and R21 award mechanism(s).  As an applicant, 
you will be solely responsible for planning, directing, and executing the 
proposed project.  The proposed project period during which the research will 
be conducted should adequately reflect the time required to accomplish the 
stated goals  The R21 mechanism (see 
http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to 
encourage exploratory and developmental research projects by providing support 
for the early and conceptual stages of these projects.  These one-time awards 
support innovative, high impact research projects that 1) assess the feasibility 
of a novel area of investigation or a new experimental system, 2) include 
the unique and innovative use of an existing methodology to explore a new 
scientific area, 3) involve considerable risk but may lead to a breakthrough 
in a particular area, or 4) develop new technology or methodology that could have 
major impact in a specific research area.  Applications for R21 awards should 
describe projects distinct from those supported through the traditional R01 
mechanism.  For example, long-term projects, or projects designed to increase 
knowledge in a well-established area will not be considered for R21 awards.  
Applications submitted under this mechanism should be exploratory and novel.  
These studies should break new ground or extend previous discoveries toward 
new directions or applications.

R21 applications may request a project period of up to two years with a 
combined budget for direct costs of up to $275,000 for the two year period.  
For example, you may request $100,000 in the first year and $175,000 in the 
second year.  The request should be tailored to the needs of your project.  
Normally, no more than $200,000 may be requested in any single year.  For 
further information on the R21 mechanism, including Institute-specific 
information, see 
http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.

This PAS uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  

FUNDS AVAILABLE

NINDS has set aside a total of $2,250,000, in addition to funds available for 
applications sent in response to this program announcement that score within 
the NINDS payline (see NINDS Funding Strategy 
http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on 
the overall scientific merit of the applications and the availability of 
funds throughout the duration of this solicitation (3 years).  NIA has set 
aside a total of $300,000, and NHLBI has set aside a total of $350,000.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.

SPECIAL REQUIREMENTS 

Plans for Dissemination of Data and Biomaterials

PHS policy requires that investigators make unique research resources 
available for research purposes to qualified individuals within the 
scientific community when they have been published (see the NIH Grants Policy 
Statement at http://grants.nih.gov/grants/guide/notice-files/not96-184.html).  
In addition, NIH recently released a statement on the sharing of research 
data that applies to all investigator-initiated applications with direct 
costs greater than $500,000 in any single year 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html).  

All applicants who respond to this PAS must propose plans for sharing data 
and biomaterials generated through the grant.  Applicants should explain how 
funds for the storage and distribution of data and biomaterials will be 
obtained, and may request such funds in the budget of the application.  It is 
expected that the data to be shared will be clinical, diagnostic, and 
pedigree structure information, and information about the genetic backgrounds 
and phenotypes of mutant or transgenic animal strains.  Biomaterials to be 
shared will include patient DNAs and cell lines, and mutant or transgenic 
animal strains. When possible, data and biomaterials should be placed in 
databases or repositories that will permit their efficient distribution to 
investigators throughout the scientific community.  An example of such a 
facility is the NINDS Human Genetics Resource Center 
(http://locus.umdnj.edu/ninds).

The Initial Review Group will evaluate the proposed sharing plan and comment 
on its adequacy in an administrative note in the summary statement. Reviewers 
will not factor the proposed data-sharing plan into the determination of 
scientific merit or priority score.  The adequacy of the plan will be 
considered by NIH staff in determining whether the grant shall be awarded. 
The sharing plan as approved, after negotiation with the applicant when 
necessary, will be a condition of the award.

Phenotyping Issues

Our understanding of pathogenic mechanisms in VCI would benefit tremendously 
from the use of standardized criteria for diagnosing this condition, 
including standardized methods for measuring cognitive function.  NINDS plans 
to encourage and coordinate the use of a minimal diagnostic dataset in 
studies funded by this PAS.  Until such a dataset is defined, applicants to 
this PAS should provide detailed descriptions of the patient data to be 
collected, including methods for independently assessing (1) the presence and 
type of cerebrovascular disease, and (2) levels of cognitive function.  
Rationale for choice of specific cognitive test(s) should be included.  In 
addition, plans should be included for entry of disease and cognitive 
phenotypic data into a computerized database that may be easily shared with 
other researchers.  

Attendance at Meetings

Applicants to be funded under this PAS will be expected to travel to NIH in 
once a year to share progress with NIH program staff, other investigators 
funded under this PAS, and additional advisers as deemed necessary by NIH 
program staff.  Applicants should include funds to support one trip per year 
to Bethesda, MD (for the principal investigator and co-principal 
investigators only).

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PAS and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Gabrielle G. Leblanc, Ph.D.
Program Director, Neurogenetics
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Suite 2136, MSC 9537
Bethesda, MD  20892
Telephone:  (301) 496-5745
FAX:  (301) 402-1501
Email: leblancg@ninds.nih.gov

Creighton H. Phelps, Ph.D.
Director 
Alzheimer's Disease Centers Program
Neuroscience and Neuropsychology of Aging 
National Institute on Aging
National Institutes of Health
7201 Wisconsin Ave., Suite 350
Bethesda, MD, 20892
Telephone: (301)496-9350
FAX:(301)496-1494
Email: phelpsc@nia.nih.gov

Stephen S. Goldman, Ph.D.
Vascular Biology Research Program
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10192, MSC 7956
Bethesda, MD 20892
Telephone: (301) 435-0560
FAX: (301) 480-2858
Email: goldmans@nhlbi.nih.gov

o Direct your questions about financial or grants management matters to:

Aaron Kinchen  
Grants Management Specialist  
National Institute of Neurological Disorders and Stroke  
6001 Executive Boulevard  
Room 3271 MSC 9537  
Bethesda, MD  20892-9537  
Telephone:  (301) 496-7386 
FAX: (301) 402-0219 
Email: kinchena@ninds.nih.gov

Deborah Stauffer
Grants and Contracts Management Office 
National Institute on Aging 
7201 Wisconsin Avenue
Suite 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: stauffed@nia.nih.gov

Beckie Chamberlin
Grants Management Specialist
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7144, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0174
FAX:  (301) 480-1948
Email:  chamberr@nhlbi.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements.  The D&B number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/.  The D&B number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be checked.

SUPPLEMENTARY INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) 
must be followed, with these exceptions:

o   Research Plan

For R21 applications only, items a   d of the Research Plan (Specific Aims, 
Background and Significance, Preliminary Studies, and Research Design and 
Methods) may not exceed a total of 15 pages.  No preliminary data is required 
for R21 proposals, but may be included if it is available.  Please note that 
a Progress Report is not needed for R21 awards; competing continuation 
applications for an exploratory/developmental grant will not be accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 
except that for R21 applications, no more than 5 manuscripts, previously 
accepted for publication, may be included.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
   
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: APPLICATION PROCESSING: Applications must be mailed 
on or before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PAS that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an unfunded version of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PAS will be assigned on the basis of 
established PHS referral guidelines.  Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council 
or board  

REVIEW CRITERIA

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 evaluate application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 
application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
   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.

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?

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?

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?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS

Sharing Research Data 

Applicants requesting $500,000 or more in direct costs in any year of the 
proposed research are expected to include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, 
reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score. 
(http://grants.nih.gov/grants/policy/data_sharing)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PAS will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities
o Adequacy of proposed data and biomaterials sharing plans

REQUIRED FEDERAL CITATIONS 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN:  Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.  (NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing.  Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
.
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy 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. 

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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PAS in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the  Standards for Privacy of Individually Identifiable Health Information , 
the  Privacy Rule,  on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on  Am I a covered 
entity?   Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This 
PAS is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 awards are 
subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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