This Program Announcement expires on December 21, 2004.


Release Date:  December 11, 2001

PA NUMBER:  PA-02-034 (This PA has been reissued, see PA-05-030)

Office of Research on Women's Health
Office of Dietary Supplements
Office of Behavioral and Social Science Research
National Center for Complementary and Alternative Medicine
National Institute on Alcohol Abuse and Alcoholism
National Institute of Allergy and Infectious Disease
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Child Health and Human Development
National Heart, Lung and Blood Institute
National Institute of Environmental Health Sciences
National Institute of Nursing Research



The Office of Research on Women's Health (ORWH) and cosponsoring 
Institutes and Offices (IC) of the National Institutes of Health (NIH) 
invite submission of investigator-initiated research grant applications 
to support research on the pathophysiology and treatment of chronic 
fatigue syndrome (CFS) in diverse groups and across the life span.  
Applications that address novel hypotheses, heterogeneous population 
groups, research gaps and common mediators influencing the actions 
among and between various bodily systems are encouraged. The NIH is 
interested in funding research that will improve the diagnosis, 
treatment and quality of life of all persons with this disease.


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 Program 
Announcement (PA) is related to several priority areas, including 
chronic disabling diseases.  Potential applicants may obtain a copy of 
"Healthy People 2010" at


Applications may be submitted by domestic and foreign, for-profit and 
non-profit organizations, public and private, such as universities, 
colleges, hospitals, and laboratories, units of State and local 
governments, and eligible agencies of the Federal government. 
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.  


Traditional project research grant (R01) applications may be submitted 
in response to this program announcement.  Funds and time requested 
should be appropriate to the research proposed. Applicants will be 
solely responsible for the planning, direction, and execution of the 
proposed project, which is not to exceed a period of 5 years. 
Applicants from institutions that have a General Clinical Research 
Center (GCRC) funded by the National Center for Research Resources 
(NCRR) may wish to identify the GCRC as a resource for conducting the 
proposed research. 



Chronic fatigue syndrome (CFS) is a debilitating and complex syndrome 
that may involve multiple bodily systems and is characterized by 
profound fatigue, which is not improved by bed rest and may be 
exacerbated or re-kindled by physical or mental activity. Persons with 
CFS most often function at substantially lower levels of activity from 
their pre-onset capacities.  In addition to these defining 
characteristics, CFS is also associated with a diverse array of 
symptoms including, for example, cognitive difficulties, impaired 
sleep, myalgia, arthralgia, headache, gastrointestinal symptoms, and 
tender lymph nodes.  Neither a specific cause(s) nor any specific 
diagnostic test(s) has yet been identified for this illness.  The range 
of symptoms, however, suggests there may be subtle perturbations in 
multiple physiological pathways that may have been triggered by diverse 
causes, for example infection, stress, brain structure abnormalities, 
hormone levels, proinflammatory cytokines, etc.  Epidemiological 
evidence is also limited and requires further study.  However, it 
suggests that CFS occurs 3 to 4 times more frequently among women than 
among men and 10 times more often in white Americans than in Americans 
of other racial/ethnic groups.  A more recent study disputes these 
numbers and would narrow the gap between the sexes as well as among 
racial/ethnic population subgroups. 

Research Objectives and Experimental Approaches

Well designed studies are needed to provide a better understanding of 
both CFS pathogenesis and pathophysiology with the goal of developing 
improved diagnostic and intervention strategies.  Studies should test 
biologically rational hypotheses. In clinical studies, selection 
criteria and procedures for CFS case and comparison groups should be 
carefully delineated and appropriate for the hypothesis under study. 
The heterogeneity of CFS population should be considered; thus both sub 
group analysis and collaborative, multidisciplinary research within or 
across scientific disciplines and institutions are encouraged. Human 
studies should include appropriate sample sizes to allow for analysis 
of sex, age /developmental period and racial/ethnic group differences. 

Applicants are encouraged to review recommendations from a NIH 
sponsored CFS science summit held in October 2000 at Arlington, VA.  
This may be found at  They may 
also wish to consider the  "Agenda for Research on Women's Health for 
the 21st Century, volume 2"(NIH Publication No 99-4386. as well as  "Exploring the Biological 
Contributions to Human Health.  Does Sex Matter" (National Academy 
Press, Washington DC. to ensure responsivity to all 
aims of this Program Announcement.  

Examples of multisystemic factors that may explain or have an impact on 
CFS pathogenesis and pathophysiology, and that are of interest to the 
NIH have been arbitrarily sorted into crosscutting categories that 
include all interested disciplines.  Areas in which such scientific 
opportunities exist include but are not limited to:


o Define the extent of the problem and identify appropriate subgroups 
o Identify the antecedent or triggering events that precipitate CFS, 
including their biologic correlates
o Identify environmental/geographic and other precipitants of CFS
o Prospectively study the natural history of incident cases
o Explore whether pathogenesis and pathophysiology differ as a function 
of age, sex, developmental period and racial/ethnic background 
o Compare the diagnostic criteria and symptomatology of CFS in children 
and adolescents with those for adults
o Investigate long term mental, social and physical health outcomes in 
children and adolescents with CFS
o Conduct case-control comparisons of CFS and syndromes with similar or 
overlapping symptomatology
o Identify the frequency and severity of primary or secondary sleep 
loss, impaired sleep and daytime sleepiness


o Develop/refine objective measures for fatigue, severity of associated 
symptoms and degree of disability that do not rely heavily on self-
o Explore multi-systemic factors as precipitants to CFS symptoms
o Develop/refine technologies to improve the identification and 
measurement of these precipitating factors   
o Develop novel and objective biological markers for the diagnosis of 
o Conduct longitudinal studies and studies with multiple sampling 
points to capture the changing nature of CFS symptomatology
o Explore the role of neuroimaging modalities in the diagnosis, 
treatment, and natural progression of CFS
o Conduct genetic epidemiological studies leading to new insights 
regarding potential genetic risk factors

Basic Scientific Understanding of Symptoms and Disrupted Physiologic 

o Study the role of neuroendocrine and neuroimmune functions in CFS 
pathogenesis and pathophysiology
o Study the role of neuro-cardiovascular regulation in the loss of the 
normal control of blood pressure, heart rate and contractility in CFS 
o Study the nature of psychiatric comorbidity in CFS patients
o Elucidate the factors/mechanisms involved in explaining cognitive 
difficulties, sleep disturbances, pain and inability to sustain 
physical exertion in CFS patients
o Elucidate the factors/mechanisms involved in altered sleep state or 
circadian regulation or other causes of impaired or ineffective sleep
o Study the role of cytokines, in interaction with physiological 
systems other than the immune, in CFS pathogenesis and pathophysiology
o Study the manner and consequences of dysregulation in the major 
physiologic control systems to better understand the diverse symptom 
complexes among CFS patients

Treatment, Quality of Life

o Conduct clinical trials to determine the efficacy in CFS patients of 
reliable and valid strategies that are used to improve quality of life 
in other chronic diseases 
o Conduct definitive trials to determine the effectiveness of currently 
prescribed pharmacologic, behavioral and other treatments used in CFS 
o Develop and test new pharmacologic and nonpharmacologic strategies 
for ameliorating symptoms common to CFS that impair quality of life
o Study perceptions, attitudes, and behaviors that influence both the 
course of CFS and the quality of care provided to CFS patients
o Examine the role of self-medication with alcohol, illicit and 
prescription drugs in CFS patients. 
o Examine the use of complementary and alternative therapies, including 
dietary supplements, in CFS patients

Applications for small studies that explore new ideas or investigative 
techniques are also encouraged and could provide the basis for 
submission of a subsequent larger grant application


Multidisciplinary studies and collaboration among investigators with 
expertise in appropriate disciplines are encouraged.  When 
investigators are at different institutions, individual R01 
applications may include consortium arrangements.

Collaborative arrangements with ongoing studies that provide patient 
populations, specimens and data are encouraged.  Such arrangements 
should be clearly delineated in the application.

The hypotheses to be tested should be clearly stated. The constructs 
and measurements to be used operationally to obtain biologically and 
statistically meaningful data should be clearly defined and enumerated. 
Personnel involved in data collection and statistical/epidemiological 
analyses should be described.  The statistical methods used for 
analysis of the data should be described and evident in the design of 
the study. 

Methods and procedures used in selecting patients or their specimens 
should be precisely defined and described in detail.  Care should be 
given to the criteria used for case definition and the manner in which 
the criteria are applied.  Similar care should be given to descriptions 
of procedures and methods for enrolling subjects in comparison groups.  
Investigators are encouraged to use the CFS case definition as 
presented in Fukuda, et al. Annals of Internal Medicine 1994; 121: 953-
9.  If other case definitions are proposed, they should be clearly 
defined and the rationale for the alternative choice clearly 
delineated. Similar care should be given to definition of subgroupings 
for CFS patients, if you chose to consider them.  

Sample sizes should reflect the study design and degree of precision 
needed for statistically and biologically meaningful results. If 
multiple comparisons and interaction terms are of interest, this must 
be considered.

The reliability and validity of all measures used, be they behavioral, 
physiological, or technical, for addressing quantitative aspects of the 
relevant populations should be demonstrated. It is important that 
applicants clearly define the measures to be used, the rationale for 
those choices, and the methodology for validation/accuracy. Methods of 
collection, processing and storing of sample specimens and data must be 
clearly described.  When conflicting results have been reported in the 
literature, applicants should provide putative explanations for the 
variability and indicate how the methodological approach used might 
resolve the issue.


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 AMENDMENT 
"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 
a complete copy of the updated Guidelines are available at  
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.


It is the policy of the 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

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


NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  This policy announcement is found 
in the NIH Guide for Grants and Contracts Announcement dated June 5, 
2000, at the following website:


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:

Applicants may wish to place data collected under this PA 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.


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


The PHS 398 research grant application instructions and forms (rev. 
5/2001) at must 
be used in applying for these grants and will be accepted at the 
standard application deadlines ( 
as indicated in the application kit.  This version of the PHS 398 is 
available in an interactive, searchable format. Beginning January 10, 
2002, however, the NIH will return applications that are not submitted 
on the 5/2001 version.  For further assistance contact Grants Info, 
Telephone 301/710-0267, Email:

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any 
amended/revised version of the preceding grant application types 
requesting $500,000 or more in direct costs for any year are advised 
that he or she must contact the Institute or Center (IC) program staff 
before submitting the application, i.e., as plans for the study are 
being developed.  Furthermore, the application must obtain agreement 
from the IC staff that the IC will accept the application for 
consideration for award.  Finally, the applicant must identify, in a 
cover letter sent with the application, the staff member and Institute 
or Center who agreed to accept assignment of the application.  

This policy requires an applicant to obtain agreement for acceptance of 
both any such application and any such subsequent amendment.  Refer to 
the NIH Guide for Grants and Contracts, March 20, 1998 at


The modular grant concept establishes specific modules in which direct 
costs may be requested as well as a maximum level for requested 
budgets. Only limited budgetary information is required under this 
approach.  The just-in-time concept allows applicants to submit certain 
information only when there is a possibility for an award. It is 
anticipated that these changes will reduce the administrative burden 
for the applicants, reviewers and NIH staff.  The research grant 
application form PHS 398 (rev. 5/2001) at is to be used 
in applying for these grants, with modular budget instructions provided 
in Section C of the application instructions.

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

Submit a signed, typewritten original of the application, including the 
checklist, and five signed photocopies in one package to:

6701 ROCKLEDGE DRIVE, ROOM, 1040, MSC 7710
BETHESDA MD  20892-7710
BETHESDA MD  20817 (for express/courier service)


Upon receipt applications will be reviewed for completeness by the CSR.  
Incomplete applications will be returned without further consideration.  
Applications that are complete and responsive to this PA will be 
assigned on the basis of established NIH referral guidelines. An 
appropriate scientific review group convened in accordance with 
standard NIH peer review procedures will evaluate applications for 
scientific and technical merit.  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 board(s).


The goals of NIH supported research are to advance our understanding of 
biological systems, improve 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 need not 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 an important work that by its nature is not 
innovative but is essential to move the 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 each 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 
method? Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 
(4) Investigator:  Is the investigator appropriately trained and well 
suited to carry out this work? Is the work 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) In accordance with NIH policy, applications will also be reviewed 
with respect to
a. The adequacy of plans to include, in numbers sufficient for 
meaningful analysis, subjects of both sexes, minorities and their 
subgroups, and children as appropriate. 
b. The adequacy of plans for recruitment and retention of subjects.
c. The adequacy of proposed protections for humans, animals and/or the 
environment to the extent that they may be adversely affected by the 
project proposed in the application.
d. The reasonableness of the proposed budget and duration in relation 
to the proposed research.


Applications will compete for available funds with all other 
recommended applications.  The following will be considered in making 
funding decisions: Quality of the proposed project as determined by 
peer review, availability of funds, and program priority.


Written and telephone inquiries are welcome.  Potential applicants are 
encouraged to avail themselves of the opportunity to clarify any issues.

Direct inquiries regarding programmatic issues to:

Dr. Eleanor Hanna
Senior Advisor to the Director
Office for Research on Women's Health
National Institutes of Health
Shannon Building, Room 201
Bethesda, MD  20892
Phone:  (301) 402-1770
Fax:  (301) 492-1798

Dr. Stephen M. Drigotas
Office of Behavioral and Social Science Research
Office of the Director
National Institutes of Health
Shannon Building, Room 236
Bethesda, MD  20892
Phone:  (301) 402-1146
Fax:  (301)  402-1150

Dr, Rebecca B. Costello
Deputy Director
Office of Dietary Supplements
National Institutes of Health
31 Center Drive, Room 1B29
Bethesda, MD  20892-2086
Phone:  (301) 435-2920
Fax:  (301) 480-1845

Dr. Christine Goertz
National Center for Complimentary and Alternative Medicine
National Institutes of Health
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475
Phone:  (301) 402-1030
Fax:  (301) 480-3621

Dr. Stephen S. Goldman
Division of Heart and Vascular Diseases
National Heart, Lung, Blood Institute, NIH
6701 Rockledge Drive, Suite 10193, MSC 7956
Bethesda, MD  20892-7920
Phone:  301-435-0560
Fax:  301-480-2858

Dr. Denise Russo
National Institute on Alcohol Abuse and Alcoholism
Division of Basic Research
Willco Building, Suite 402
6000 Executive Boulevard
Rockville, MD  20952
Phone:  (301) 402-9403
Fax:  (301) 594-0673

Dr. Catherine Laughlin
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room 3258
6700B Rockledge Drive
Bethesda, MD  20892-7630
Phone:  (301) 496-7453
Fax:  (301) 402-0659

Deborah N. Ader, Ph.D.
Director, Behavioral and Prevention Research Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Building 45, Room 5A19H
Bethesda, MD  20892-6500
Phone:  (301) 594-5032
Fax:  (301) 480-4543 

Dr. Lynne M. Haverkos
Director, Behavioral Pediatrics and Health Promotion Research Program
National Institute of Child Health and Development
6100 Executive Blvd, Room 4B05B
Bethesda, MD  20892-7510
Phone:  (301) 435-6881
Fax:  (301) 480-7773

Dr. Annette Kirshner
Division of Extramural Research and Training
National Institute of Environmental Health Science
Box 12233, MD EC-23
Research Traingle Park, NC  27709
Phone:  919-541-0488
Fax:  919-541-5064

Hilary D. Sigmon, Ph.D., R.N.
Program Director
National Institute of Nursing Research
45 Center Drive MSC 6300
Bethesda, Maryland  20892-6300
Phone:  301-594-5970
Fax:  301-480-8260

Although not a formal sponsor of this program announcement, the 
National Institute if Mental Health (NIMH) accepts applications on 
mental health disorders that are co-morbid with chronic fatigue 
syndrome. The NIMH accepts applications if they have explicit relevance 
to mental disorders, symptoms, or related disability as reflected in 
the title, abstract, theoretical framework, specific aims, measures and 
analyses.  For more information and pre-application technical 
assistance, please contact: Peter Muehrer, Ph.D., Health and Behavior 
Science Research Branch, National Institute on Mental Health, National 
Institutes of Health, 6001 Executive Boulevard, Room 6189, MSC9615, 
Bethesda, MD 20892-9615.  Telephone: (301) 443-4708, 

Direct Inquiries regarding fiscal matters to:

Victoria Carper
National Center for Complimentary and Alternative Medicine
National Institutes of Health
6707 Democracy Blvd., Suite 106
Bethesda, MD  20892-5475
Phone:  (301) 594-9102
Fax:  (301) 480-3621

Judy Fox Simons
Acting Grants Management Officer
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Blvd.MSC7003
Bethesda MD  20892-7003
Phone:  (301)443-2434
Fax:  (301)443-3891

Melinda B. Nelson
Chief Grants Management Officer
45 Center Drive, Room 5As49
Bethesda, MD  20892-6500
Fax:  (301) 480-4543

Mary E. Daley
Lead Grants Management Specialist
National Institute of Child Health
 and Human Development
Bldg. 6100, Rm. 8A17 MSC 7510
Bethesda, MD  20892-7510
Phone:  301-496-1305
Fax:  301-402-0915

Laura Williams-Boyd
Grants Management Specialist
Division of Extramural Research and Training
National Institute of Environmental Health Science
Box 12233, MD EC-22
Research Triangle Park, NC  27709
Phone:  919-541-7629
Fax:  919-541-22860

Tara Mowery
Grants Management Specialist
National Institute of Nursing Research
45 Center Drive MSC 6300
Bethesda, Maryland  20892-6300
Phone:  301-594-5979
Fax:  301-480-8260


This program is described in the Catalog of Federal Domestic Assistance 
No. 93.121. Awards are made under authorization of sections 301 and 405 
of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 
52 and 45 CFR Parts 74 and 92. The Office of Dietary Supplements (ODS) 
was established in 1994 under the Dietary Supplement Health and 
Education Act (DSHEA), Public Law 103-417, Section 3a  to establish 
standards with respect to dietary supplements. This program is not 
subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.
The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace 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, and 
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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
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9000 Rockville Pike
Bethesda, Maryland 20892
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