GAO

United States General Accounting Office

Report to the Honorable

Harry Reid, U.S. Senate

June 2000 CHRONIC FATIGUE

SYNDROME

CDC and NIH

Research Activities

Are Diverse, but

Agency Coordination

Is Limited

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Contents

Letter 3

Appendixes Appendix I: Background on Chronic Fatigue Syndrome 30

Appendix II: Accounting Issues at CDC 34

Appendix III: CDC Research Efforts and Publications 37

Appendix IV: NIH Research Efforts and Grants 44

Appendix V: Congressionally Requested CFS Activities for CDC

and NIH 54

Appendix VI: External Review Recommendations to CDC and NIH 59

Appendix VII: NIH Expenditures on CFS Research, by Institute and

Center 64

Appendix VIII:NIH Activities in Support of CFS Research 65

Appendix IX: Comments From the Department of Health and

Human Services 69

Tables Table 1: U.S. Studies of CFS Prevalence Based on Clinical

Evaluation of Samples of Local Populations 32

Table 2: NIH Disposition of Projects Identified by CRISP From 1997

Through 1999 Not Included in NIH’s List 47

Table 3: NIH-Funded R01 (Research Project) Grants Related to CFS 48

Table 4: NIH-Funded Intramural Research Projects Related to CFS 49

Table 5: NIH-Funded Grants and Projects Not Including R01

(Research Project) Grants and Intramural Projects Related

to CFS 50

Table 6: NIAID Cooperative Research Center Projects Related to

CFS 52

Table 7: Congressionally Requested CFS Activities for CDC 54

Table 8: Congressionally Requested CFS Activities for NIH 57

Table 9: Recommendations From CDC’s 1996 Peer Review and

Agency Response 59

Table 10: Recommendations From CDC’s 1999 Peer Review, Board of

Scientific Counselor Review, and Meeting With Patient

Advocates, and Agency Response 61
Contents

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Figures Figure 1: CDC Funding, Fiscal Years 1988 Through 1999 14

Figure 2: NIH Expenditures, Fiscal Years 1988 Through 1999 16

Figure 3: Proportion of CFS Funds Retained at Each Level of

CDC, Fiscal Years 1998 Through 1999 19

Figure 4: CDC Publications 39

Abbreviations

CDC Centers for Disease Control and Prevention

CFS chronic fatigue syndrome

CFSCC CFS Coordinating Committee

CRISP Computer Retrieval of Information on Scientific Projects

FDA Food and Drug Administration

HHS Department of Health and Human Services

NCI National Cancer Institute

NCRR National Center for Research Resources

NHLBI National Heart, Lung, and Blood Institute

NIAID National Institute of Allergy and Infectious Diseases

NIAMS National Institute of Arthritis and Musculoskeletal and Skin

Diseases

NICHD National Institute of Child Health and Human Development

NIH National Institutes of Health

NIMH National Institute of Mental Health

NINDS National Institute of Neurological Disorders and Stroke
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United States General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services

B-283171 Letr

June 2, 2000

The Honorable Harry Reid

United States Senate

Dear Senator Reid:

Chronic fatigue syndrome (CFS) is a debilitating and complex disorder that

potentially affects more than 800,000 Americans—yet it has no known

cause or cure. CFS is defined by profound fatigue that is not improved by

bed rest and other symptoms, such as weakness, muscle pain, cognitive

difficulties, and problems with sleep. CFS is diagnosed only by excluding

other possible causes of the fatigue and only after the fatigue has persisted

for at least 6 months.

Since fiscal year 1988, congressional appropriations committee reports

have asked the Centers for Disease Control and Prevention (CDC) and the

National Institutes of Health (NIH) to initiate investigations and projects

related to CFS, a disorder each agency began investigating in the mid1980s. The goals of their work have included defining CFS and determining

its prevalence and cause or causes. CDC and NIH research to date has

focused largely on estimating prevalence, investigating suspected clusters

of CFS, and examining possible causes. In 1996, the Secretary of the

Department of Health and Human Services (HHS) established a committee

of representatives from CDC, NIH, and other federal agencies; scientists;

and patient advocates largely for the purpose of coordinating federal

research efforts on CFS.

Since fiscal year 1987, NIH has devoted approximately $57.6 million to the

study of CFS through intramural and extramural CFS grants. The

committee reports indicated a level of funding to support CFS work at CDC
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totaling $44.7 million through fiscal year 1998.1 For fiscal years 1995

through 1998, the committees recommended that CDC spend $23.4 million

on the study of CFS. However, in 1999, the Inspector General of HHS

reported that CDC had expended $8.8 million on activities unrelated to CFS

and $4.1 million on inadequately documented indirect costs—as much as

half of the funds the committees recommended for CFS. Because of

concerns related to the redirection of CFS funds at CDC and questions

raised by patient advocates about the lack of research progress, you asked

us to (1) identify the CFS research activities that CDC and NIH have

supported, (2) determine the funds and resources CDC and NIH have

devoted to CFS research, and (3) describe how CDC and NIH coordinate

research and involve patient organizations and external researchers in

developing their CFS research programs.

For this study, we reviewed documents from CDC and NIH and talked with

agency officials; reviewed minutes of and attended meetings of HHS’ CFS

Coordinating Committee (CFSCC); and talked with current and past

federal, patient advocate, and scientific members of the chartered

committee. We reviewed work in the years that each agency devoted

funding to CFS research: for CDC, fiscal years 1988 through 1999; for NIH,

fiscal years 1987 through 1999. We did not evaluate the quality of the

research conducted. We conducted our work between July 1999 and May

2000 in accordance with generally accepted government auditing

standards.

Results in Brief For approximately the last 12 years, both CDC and NIH have conducted a

broad range of activities related to CFS. CDC has focused largely on

prevalence and disease causes, including the search for infectious and

immunological abnormalities. NIH has focused primarily on CFS’ effects on

bodily systems and possible causal agents. Both agencies’ work has

generally been consistent with their missions, and both have initiated most

1

The Congress did not make a line item appropriation to the CFS program. Rather, the

appropriations committees expressed their funding expectations for the CFS program in

reports that accompanied the annual “lump sum” appropriation to CDC. See, for example,

H.R. Rep. No. 103-156, at 44 (1994); S. Rep. No. 103-143, at 69 (1994); and H.R. Conf. Rep. No.

105-825, at 1270 (1998). Because the Congress did not use a line item appropriation to fund

the CFS program, the CDC director had latitude in determining whether funds would be

allocated in strict accordance with the CFS program funding guidance expressed by the

Congress.
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of the projects that have been requested in appropriations report language

and the projects defined in their program plans.

Funds for CFS research have increased at both CDC and NIH since 1987.

Much of the increase occurred in the first few years; over the past 4 years,

funds have generally not increased. At CDC, the lengthy and uncertain

process for allocating CFS funds to the branch responsible for most of the

CFS work has resulted in delays in undertaking particular projects. Further,

CDC’s redirection of funds has resulted in reductions in CFS resources that

have impeded the agency’s CFS research. However, CDC has begun a

process to restore all redirected CFS funds. NIH has taken a number of

steps to facilitate the funding of CFS projects, including issuing program

announcements, establishing a special emphasis panel to review CFS grant

applications, and using a discretionary program to fund additional studies.

NIH has also supported a number of research centers on CFS.

Coordination between CDC and NIH and their use of input from external

researchers and patient advocates in developing agency research programs

have been limited. CDC and NIH have not jointly conducted research,

although CDC’s advisory panel and external peer reviewers have

recommended that CDC undertake such a collaboration. CFSCC, chartered

to encourage federal coordination, has helped to facilitate some

interagency communication, but it has not provided an effective forum for

developing coordinated research programs. Certain shortcomings in how

CFSCC conducts its work may have limited its usefulness, although the

committee has made recent efforts to improve its effectiveness.

HHS commented on a draft of this report and generally agreed with our

findings, particularly that CFSCC could be more effective.

Background Because there is currently no known biological way to differentiate cases

of CFS from other conditions, researchers use clinical descriptions of

symptoms to define CFS. To date, CFS has had two different case

definitions. The first case definition, developed in 1988, required that, in

addition to fatigue, patients had to meet 8 of 14 symptom or physical

criteria. In 1994, the definition was revised to include only four of eight

symptoms in addition to fatigue. An additional revision of the case

definition is being considered. In addition, other terms have been used to

describe the illness—such as chronic fatigue and immune dysfunction

syndrome and myalgic encephalomyelitis—and other definitions of CFS

are used in other countries. Estimates of CFS prevalence in the United
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States have varied from 2.0 to 7.3 per 100,000 under the first definition to

238 to 422 per 100,000 under the revised case definition. This last estimate

translates to about 836,000 Americans. (For a more detailed discussion of

CFS case definition, prevalence estimates, and research on possible

causes, see app. I.)

Evidence to support many of the hypothesized causes of CFS has been

insufficient, but other hypotheses continue to be developed. And while CFS

has no known cause or cure, there are some therapies for CFS that are

directed at relieving patient symptoms.2

Federal CFS Research

Through CDC and NIH

CDC’s CFS work is performed largely in the Viral Exanthems and

Herpesvirus Branch within the Division of Viral and Rickettsial Diseases

under the National Center for Infectious Diseases. CFS work is assigned to

this branch because early hypotheses about the causes of CFS included

viruses covered by the branch, such as Epstein-Barr virus and herpes

viruses. CDC allocates funds budgeted for CFS to the branch through the

center and the division. Annually, each branch of the Division of Viral and

Rickettsial Diseases presents a review of its program activities, plans, and

accomplishments. Most of CDC’s CFS research is conducted extramurally,

primarily through research contracts. Intramural work is planned by

individual branch chiefs and reported in these reviews as part of the

branches’ plans. In 1998, it was alleged that in fiscal years 1995 through

1998, CDC had spent funds that had been budgeted for CFS on other

programs and had misled the Congress about how it had spent these funds.

At CDC’s request, HHS’ Inspector General conducted an audit of the CFS

program for these years and found that about one-third of the funds ($8.8

million) had been spent on non-CFS-related activities. An additional onefifth ($4.1 million) of funds were indirect costs not adequately documented

to determine applicability to CFS. While the Inspector General noted that

CDC was not legally prohibited from spending funds this way, the Inspector

General found that these discrepancies resulted from deficiencies in CDC’s

internal control system for handling direct and indirect costs. (See app. II.)

2

These have included pharmacological therapies, such as medications to improve sleep or

relieve pain, and nonpharmacological therapies, such as acupuncture, chiropractic

manipulation, massage, and yoga. Certain psychotherapies, such as cognitive behavior

therapy, have also been used in efforts to help patients cope and alleviate some of the

symptoms associated with CFS. In addition, some consider that modest regular exercise to

avoid deconditioning is important.
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NIH’s CFS research is conducted by both intramural scientists employed by

NIH as well as extramural scientists who are awarded grants or contracts

for their work. The largest portion of NIH’s CFS work has been performed

within the National Institute of Allergy and Infectious Diseases (NIAID).

Other NIH institutes and centers that have funded CFS research include the

National Institute of Mental Health; the National Institute of Neurological

Disorders and Stroke; the National Center for Research Resources; the

National Cancer Institute; the National Heart, Lung, and Blood Institute; the

National Institute of Arthritis and Musculoskeletal and Skin Diseases; and

the National Institute on Child Health and Human Development. Four

additional NIH institutes and centers have joined the solicitation for grant

applications for work on CFS; but, to date, none have been funded by these

units.3 External grant applications are reviewed by special emphasis panels

of external scientists who rate the merit of each application. Final

decisions about the merit of grants are subsequently made by the relevant

institute’s external advisory council, which meets three times each year.

Every 4 years, each laboratory in the intramural research program is

reviewed by its institute’s board of scientific counselors. Recently, NIH

moved the responsibility for coordinating efforts on CFS from NIAID to the

Office of the NIH Director. NIH officials told us this was to centralize these

efforts at NIH.

Role of CFSCC To help ensure coordination of federal research efforts related to CFS,

HHS’ Assistant Secretary for Health in 1990 assembled a group of federal

researchers—adding nonfederal scientists and patient advocates as

consultants in 1994—to form an interagency committee. Then in 1996, the

Secretary of HHS chartered CFSCC, in part, to ensure coordination and

communication regarding CFS. The committee consists of seven members,

appointed by the Secretary, and five ex-officio members. Of the seven

appointed members, three are biomedical research scientists; two have

expertise in health care services or disability issues or represent private

health care services insurers; and two represent voluntary organizations

that serve people with CFS. Members are invited to serve for overlapping 4-

year terms. The ex-officio members are representatives from CDC, NIH, the

Food and Drug Administration (FDA), the Health Resources and Services

3

The four additional institutes and centers are the National Institute of Environmental

Health Sciences, the National Institute of Nursing Research, the National Institute of

Diabetes and Digestive and Kidney Diseases, and the Office on Research on Women’s

Health.
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Administration, and the Social Security Administration.4 The Assistant

Secretary for Health chairs the committee. CFSCC management and

support services are provided on a 2-year rotating basis between NIH and

CDC, and the ex-officio representative from that agency serves as cochair.

Meetings are held approximately two times a year and are open to the

public.

CFSCC membership is different from that of all other HHS advisory

committees. For nearly all of HHS’ 12 other similar advisory committees,

the federal members serve in an ex-officio capacity and are nonvoting.

CFSCC is the only committee chaired by federal representatives when

there are nonfederal members of the committee. All other committees with

nonfederal members have a nonfederal member as the chair of the

committee.

CDC and NIH Research

Activities Are Diverse

While researchers and advocates have expressed concerns about the

breadth of CFS research at CDC and NIH, we found the agencies have

conducted a broad range of activities related to CFS. The agencies have

also undertaken efforts to educate patients and physicians. These activities

and efforts have generally been consistent with what would be expected

based on the agencies’ mission statements. Further, both agencies initiated

the majority of studies and activities that were requested in appropriations

committee reports. Finally, the agencies generally conducted activities

mentioned in their own program plans and responded to recommendations

of external expert reviewers.

CDC and NIH Conduct a

Broad Range of CFS

Activities Consistent With

Their Missions

CDC has conducted activities in most areas of its recent mission

statements for its CFS program. For example, CDC has led efforts to

develop a rigorous case definition for CFS, which is necessary to evaluate

whether CFS is a single disease or a set of symptoms that could have

multiple causes. The agency has also conducted a number of surveillance

studies to determine the prevalence of CFS, starting with a study using

4

Federal agencies other than CDC and NIH have the following roles related to CFS: new

CFS-related products or advertising require review by FDA; the Health Resources and

Services Administration generally translates research findings into practice and addresses

issues related to the training of health professionals; and the Social Security Administration

tracks medicine and science behind disorders like CFS so that their policies reflect the

clinical world, especially related to rulings on CFS disability claims.
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physician referrals to identify possible CFS patients and later shifting to a

more active community-based approach. In addition, CDC has examined a

number of possible CFS risk factors, including viral and immunological

ones, and has relied on data collected from its surveillance studies to

describe the natural history of CFS. To date, however, the agency has not

identified any cause or causes for CFS.

As part of its CFS mission, CDC has also undertaken a variety of efforts to

educate practitioners, professionals, and the public, including scientific

publications, a web site, a toll-free hot line, and a booklet about CFS.

Because there have been so few objective findings to date, it has not been

possible for CDC to develop control strategies. (See app. III for more

details on CDC’s research efforts and a list of its CFS-related publications.)

With CDC’s direction of an additional $12.9 million to its CFS program over

4 years—to compensate for redirected funds in prior years—work has been

planned in a number of additional areas, including a national survey to

estimate prevalence, a national patient registry, a workshop to determine if

the current case definition for CFS should be revised, endocrine and sleep

studies, and genetic tests of tissue samples. For example, in May 2000, CDC

held a 3-day workshop to assess current clinical and empirical knowledge

concerning the definition of CFS. Participants agreed that it was premature

to revise the case definition and that future revisions should be based on

data-driven research rather than consensus clinical opinion.

While CDC has conducted research in a broad range of areas, the agency

has been criticized by researchers and patient advocates about the lack of

openness of its efforts. For example, because CDC sometimes does not

release findings from its studies until they are published in a professional

journal, the latest information may not always be immediately available.

However, this is a common practice among scientific researchers, and

obtaining peer review prior to publication is used to ensure the integrity of

the communication. Further, CDC officials reported that the agency follows

its normal procedures in releasing results of its CFS studies. We also found

that CDC has periodically presented preliminary results from its

surveillance studies at scientific conferences and regularly reviews the

current status of its research at CFSCC meetings.

Within NIH, NIAID’s intramural and extramural research programs have

been responsible for most of NIH’s work on CFS, and the institute has

supported work on causes, prevalence, origin and development of diseases,

diagnosis, and treatment. NIH has funded investigations of a number of
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possible causes, including immunologic, neuropsychologic,

neuroendocrinologic, brain wave, and infectious aspects of CFS. However,

NIH, like CDC, has not yet been able to identify a single cause or group of

causes for CFS. NIAID has supported a number of attempts to estimate the

prevalence of CFS, particularly a large epidemiological project in Chicago

to study the socioeconomic and ethnic variability of CFS. Early work to

identify the origin and development of the disease focused on the possible

role of the Epstein-Barr virus and of immune system deficiencies. Recent

efforts involve postinfectious fatigue and blood pressure irregularities in

CFS patients. Some agency efforts to develop diagnostic methods focus on

the intensity of the symptoms and new measurement tools to evaluate CFS

patients. NIH has also supported several projects with possible application

to treatment, including modulating brain chemistry, developing individually

tailored exercise programs, trials of pharmacologic agents, and studies of

nonpharmacologic treatments. Given the limited understanding of the

causes of CFS, work on NIAID’s goal of furthering prevention has not been

undertaken. Additional details about NIH’s CFS research efforts and lists of

the grants and projects funded by NIH are in appendix IV.

Some patient advocates have voiced concern that NIH has not funded

specific kinds of CFS research, such as research on mycoplasma and its

possible connection to CFS. However, we found no evidence that a grant

proposal on mycoplasma had ever been submitted. Patient advocates have

also criticized the types of CFS research that NIH has funded—in

particular, psychiatric research. Some believe that NIH has

disproportionately funded research of this type, but we found no such

evidence. The National Institute for Mental Health’s funding reported for

CFS is artificially high because it includes funds for a large grant, of which

only a small portion was related to CFS.

CDC and NIH Initiated Most

Activities Requested by the

Congress

Congressional interest in CFS research was first expressed in fiscal year

1988.5 Since then, congressional report language, directed at both CDC and

NIH, has indicated areas of research that the appropriations committees

thought should be pursued. Both CDC and NIH have undertaken efforts in

nearly all these areas. (A list of requested activities and their status is in

app. V.)

5

See H.R. Rep. No. 100-256, at 50 (1988); and S. Rep. No. 100-189, at 69 and 110 (1988).
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Appropriations committees have requested in reports 33 distinct activities

for CDC, including development and implementation of a surveillance

network, continued tests related to specific suspected causes, and public

information and training initiatives. CDC has initiated work on most of

these. For the four areas where CDC did not initiate work, the agency

reported that the work was inappropriate or not feasible for them to

pursue.

NIH has also been largely responsive to congressional committee direction,

appointing a CFS coordinator, ensuring appropriate representation to

advisory committees and boards, and encouraging studies of risk factors

and immunology. In report language, the appropriations committees have

requested NIH work in 34 areas. All but five activities have been pursued;

NIH considers some of those that have not been pursued infeasible.

CDC and NIH Initiated Most

CFS-Related Activities in

the Agencies’ Own Program

Plans and Responded to

Recommendations of

External Reviewers

CDC and NIH produced annual reports outlining their activities and plans

for future work on CFS. For the most part, both agencies completed the

work in those plans. To help the agencies stay focused on their goals, the

agencies’ review boards periodically examined the CFS program. At CDC,

the CFS program has undergone a number of reviews. In 1991, CDC

conducted an internal peer review of the CFS program by scientists from

other CDC areas and programs. In 1993, there was an external peer review

of the Viral Exanthems and Herpesvirus Branch, which included the CFS

program. The CFS program underwent peer reviews in 1996 and 1999 as

well as a review by CDC’s Board of Scientific Counselors in 1999. At NIH,

the National Advisory Allergy and Infectious Diseases Council discussed

the CFS program in 1995, although components of the program were

discussed at other meetings as well.

Scientists involved in the 1991 internal CDC peer review expressed

concerns in four areas: (1) the limited sample size proposed for a case

control study of CFS risk factors, (2) the statistical power of the case

control study to detect real differences, (3) the lack of representativeness

of the sample of patients referred by physicians in the surveillance study

designed to estimate prevalence, and (4) the extensiveness of the factors to

be evaluated in an exploratory study. The 1993 branch review suggested

two specific additions to CDC’s study of possible causes of CFS. They also

recommended that CDC scientists contact those at NIH where a relevant

study was under way. Agency officials reported that there was no official

agency response to either review.
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CDC’s 1996 peer review, conducted by four scientists and two patient

advocates, made 18 recommendations; for the most part, CDC has

undertaken activities in response to these recommendations. CDC received

a consistent message from both the 1999 peer review and the review of its

Board of Scientific Counselors that they should look for more

opportunities to collaborate with other researchers, including possibly

those at NIH. There were a number of other recommendations from these

recent reviews, and CDC officials have reported many activities planned to

address these recommendations. (See app. VI.)

NIAID’s National Advisory Allergy and Infectious Diseases Council has also

occasionally made recommendations about CFS research efforts. The

council has advocated that the agency support specific studies suggested

by findings from case demographics, encouraged continuing and

expanding the CFS Cooperative Research Centers program, and

determined at a fall 1995 CFS program review that NIAID should retain

overall leadership of NIH’s CFS efforts but that a multidisciplinary research

approach involving other institutes should also continue, where

appropriate. A subcommittee of the council also recommended the agency

develop work in a number of areas. NIH has conducted investigations in all

but two of these areas (studies of patients with shorter duration of illness

and issues related to pregnancy). (See app. VI.)

CDC’s Funding

Practices Have

Impeded CFS Research

in Contrast to NIH’s

Researchers and patient advocates have expressed concerns about CDC’s

and NIH’s resources (funding and staffing) and funding mechanisms for

CFS research, and their potential effects on the agencies’ ability to plan and

carry out research. Although CDC and NIH funds have increased over time,

stabilizing in recent years, their funding data may not fully reflect their CFS

expenditures due to each agency’s process for tracking CFS funds. Staffing

directly related to CFS has increased in recent years at CDC, but it has

declined at NIH. We found that the processes and timing for distributing

funds within CDC impeded CFS research and may reflect inadequate

control on the part of the agency. Conversely, NIH has used a number of

mechanisms to facilitate the support of CFS research, including program

announcements, the formation of a special review panel for CFS grant

applications, and support of research centers.
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CDC and NIH Resources for

CFS Research Have

Increased, but These Levels

Have Been Flat Over the

Past 4 Years

Since 1988, the congressional committee reports accompanying CDC’s

annual appropriation act have expressed an expectation that specific funds

would be used for CFS research and other CFS projects. Although CDC has

generally requested each year the same level of funding for CFS as was

received the prior year, the committee reports suggest increasingly larger

sums. The amount of funds suggested in these reports has increased from

$407,000 in fiscal year 1988 to $6,497,000 in fiscal year 1999.6 (See fig. 1.)

However, since fiscal year 1995, the level of suggested funding increased

only a total of $455,000. Moreover, the HHS Inspector General review found

that over one-third of the funds ($8.8 million) in fiscal years 1995 through

1998 was spent on activities unrelated to CFS and another $4.1 million in

indirect costs was not adequately documented to determine applicability to

CFS . Regardless, CDC officials reported only one study—a survey of

adolescents—that it did not initiate because of insufficient funds, and the

agency has since determined that this study was not feasible for

methodological reasons.

6

For CDC, we refer only to funds budgeted for CFS research because the HHS Inspector

General review of the CFS program at CDC found that CDC had been unable to clearly

identify funds actually spent on CFS.
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Figure 1: CDC Funding, Fiscal Years 1988 Through 1999

CDC indicated that it has increased the number of staff working on CFS.7

Prior to 1996, permanent staff working on CFS filled approximately 5 to 8

positions; since then, the number of positions has increased to 13 to 15.

During these same periods, the staff has also changed from mostly

permanent employees to mostly temporary employees. The temporary staff

have typically been predoctoral or postdoctoral students or laboratory

technicians.

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Actual Dollars

Adjusted for Constant

Fiscal Year 1999 Dollars

Funding (Dollars in Thousands)

7

The staffing levels represent only those who work directly for CDC on CFS, although much

of CDC’s work on CFS is conducted extramurally, as is most of CDC work in general.
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NIH expenditures for both intramural and extramural CFS projects

increased from $782,000 in fiscal year 1987 to $6,892,000 in fiscal year

1999,8 although these expenditures declined slightly over the last 4 years.

(See fig. 2.) Further, while NIAID was the only institute to fund CFS

research in the first 2 years (fiscal years 1987 through 1988), with minimal

support from one other institute during the next 2 years, six institutes

funded CFS research in fiscal year 1999. (See app. VII.) It is important to

note that these figures may not accurately reflect expenditures for CFS.

For the National Institute of Mental Health, expenditures are likely

overestimated because projects are included even when only a small

portion is relevant to CFS. For other institutes, expenditures may be

underestimated for at least two reasons. First, if the institute or center has

$250,000 or less in total funding for a disease, it is not required to report

spending for that disease. Second, projects that are peripherally related to

CFS may not have been included in NIH’s funding figures.

8

For NIH, we refer to expenditures—that is, funds that were spent on grants (extramural),

projects (intramural), and cooperative agreements.
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Figure 2: NIH Expenditures, Fiscal Years 1988 Through 1999

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Actual Dollars

Adjusted for Constant

Fiscal Year 1999 Dollars

Expenditures (Dollars in Thousands)
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While NIH expenditures for CFS research have remained fairly stable over

recent years, staffing levels at NIAID, the only institute for which we have

data, have decreased.9 Between 1988 and 1996, the number of full-timeequivalent intramural staff increased from 2.5 to 3.25 staff. Since 1997,

however, the number of intramural full-time-equivalent staff at NIAID

working on CFS decreased from 2 in 1997 to less than 1 in 1999. Most of the

intramural staff working on CFS in NIAID specialized in either nursing or

internal medicine. In addition to the intramural staff, NIAID has a program

officer assigned to the Virology Branch (which is responsible for the

extramural CFS work at NIAID). Over the years, the amount of time

devoted by the program officer to CFS work versus other work has ranged

from 20 to 60 percent.10

9

The staffing levels represent only those scientists who work directly for NIH on CFS,

although much of NIH’s work on CFS is conducted extramurally, as is most of NIH work in

general.

10According to agency officials, other staff—such as the division director, branch chief,

committee management staff, and budget staff—also devote time to work on CFS at NIH.
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CDC’s Processes and Timing

for Allocating Funds Has

Impeded CFS Research

Concerns have been raised by patient advocates that funding practices at

CDC may create barriers to planning and carrying out CFS research.

Specific issues raised are that indirect costs charged to the CFS program

are inordinately high and that the distribution of CFS funds is not timely.

We found that, from fiscal years 1988 through 1999, an average of 45

percent of CFS funds at CDC covered indirect costs, with funds being taken

from budgeted allocations at the agency (20 percent), center (13 percent),

and division levels (12 percent) prior to being distributed to the Viral

Exanthems and Herpesvirus Branch.11 (See fig. 3.) These set percentages

were taken from budgeted allocations without consideration for variability

in use of services across different programs. CDC officials told us that the

agency recently changed the way it calculates indirect costs at the agency

level and that these changes were made in a manner consistent with

recommendations in the Inspector General audit. In recent years (1998

through 1999), therefore, total indirect costs have been closer to 37.5

percent. Changes in methods for calculating indirect costs have not been

implemented at the center level or below.12 Regardless, CDC officials told

us that other programs within the Division of Viral and Rickettsial Diseases

had similar proportions of funds deducted for indirect costs, so these

percentages are not unique to CFS funds.

11Agency-level indirect costs pay for, among other things, all offices of program support,

three facilities offices, design, construction, maintenance, a financial management office,

human resources management, information resources management, utilities, a procurement

and grants office, a management analysis and services office, and mail. Center-level indirect

costs are used to support the Office of the Director and the Scientific Resources Program.

The Scientific Resources Program covers lab program services for all of the divisions and

branches, including glassware, animal work, infrastructure, chemicals, and the making of

reagents. The division portion of indirect costs has been used for, among other things,

support of maintenance agreements on all equipment, telephones, hardware support of

computers, and equipment for the Office of the Director (such as facsimiles and

photocopiers).

12The agency continues to develop its procedures for calculating indirect costs and expects

to have them finalized by fiscal year 2001. Each center is also developing procedures for

calculating indirect costs, though these are not expected to be implemented until after the

agency procedures are implemented. Accordingly, the National Center for Infectious

Diseases has requested an external review of its indirect cost methodology. Further,

divisions will not begin similar work until after the centers have implemented their

procedures.
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Figure 3: Proportion of CFS Funds Retained at Each Level of CDC, Fiscal Years 1998

Through 1999

The HHS Inspector General review of CFS found that the distribution of

indirect costs agencywide may have been arbitrary and inconsistent, with

some programs being significantly overcharged while other programs were

charged far less than their fair share. The Inspector General also concluded

that the various centers and divisions within CDC were able to arbitrarily

determine the indirect costs for some or all of their programs, with no

assurance that those charges would be reasonable and consistent. Further,

the Inspector General found that the CFS program’s indirect costs were

largely undocumented and generally excessive in relation to those of other

programs.

19%

Centers for Disease

Control and Prevention

13%

National Center for 

Infectious Diseases

12%

Division of Viral and

Rickettsial Diseases

56%

Viral Exanthems and

Herpesvirus Branch
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Although improvements in fund allocation have been made since 1998, the

allocations of funds at CDC have typically been received late in the fiscal

year—on average, more than 9 months into the fiscal year—which can

adversely affect the ability to plan research programs. Moreover, funding

allocations for the Viral Exanthems and Herpesvirus Branch have

frequently not included explicit funding amounts for CFS. The National

Center for Infectious Diseases has generally not received its final allocation

from CDC until mid to late spring for the fiscal year that began the prior

October.13 The center then typically provided an allocation to the Division

of Viral and Rickettsial Diseases 1 month later and the Division provided

final allocation memorandums to the branches approximately 1 to 2

months after that. These timelines are typical across CDC. In fiscal years

1997 and 1998, the Viral Exanthems and Herpesvirus Branch received its

allocation on July 7 or later—more than 9 months into the fiscal year.14

Traditionally, the branch chiefs have been told to expect their budget to be

about what it had been the previous year for planning purposes. However,

uncertainties in funding levels have meant that the branch has planned only

limited new work related to CFS each year.

The branch’s allocation memorandums for fiscal years 1994, 1996, 1997,

and 1998 did not include an allocation for CFS research.15 That is, the

allocation forms, received more than 9 months into the fiscal year, did not

include any information about the level of funding available for the CFS

program. For fiscal year 1998, final clarification about funds for CFS was

not made until 9 days before the end of the fiscal year. Therefore, some CFS

funds were not obligated by the end of the fiscal year and some program

elements had to be suspended until the next fiscal year. However, in fiscal

year 1999, the allocation memorandum to the branch chief clearly outlined

the CFS funds available to the branch. This improvement may have been

due to changes CDC had instituted in response to the 1999 HHS Inspector

General review.

13Officials have said that CDC has recently improved this process. For example, agency

officials reported that tentative ceilings were provided to the center within 30 calendar days

of passage of its appropriations bill for fiscal year 1999 and within 17 calendar days for fiscal

year 2000.

14Prior to fiscal year 1997, the Viral Exanthems and Herpesvirus Branch did not have an

administrative officer, and budget allocations to the branch prior to that time did not

indicate a date for the allocation.

15CDC was unable to provide allocation memorandums for any fiscal years prior to fiscal

year 1994 or for fiscal year 1995.
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Finally, the Inspector General review reported that CDC said it could not

complete its adolescent study or hire a neuroendocrinologist because of a

lack of available funds.16 Nevertheless, the Inspector General found that,

while program components were not implemented, more than $850,000 of

fiscal year 1998 funds were never made available to the CFS program.

NIH Has Used a Number of

Mechanisms to Facilitate

Support of CFS Research

NIH develops extramural research on diseases, including CFS, primarily by

creating program announcements for grant applications. The agency then

relies on external researchers to decide what topics they want to pursue

and funds meritorious applications up to the level of funds available. In

addition to using program announcements to encourage extramural

applications on CFS, NIH has created a special emphasis panel to review

those applications, used selective payment, and established CFS

cooperative research centers. NIH has also funded intramural

investigations on CFS. Intramural research is determined by individual

researchers and reviewed retrospectively. (See app. VIII for a more detailed

description of these efforts.)

Since 1987, NIH has issued four program announcements to stimulate

research on CFS. The first two program announcements were supported by

NIAID only; the first, in 1987, focused on epidemiology; the second, in 1992,

focused on exercise-induced fatigue and disease origin and development.

In 1994, NIH issued its first joint program announcement, involving three

institutes, which focused on studies of the causes, natural history, and

origin and development of CFS. The most recent program announcement,

issued in 1996, involves eight different units within NIH and supports

studies on the effects of CFS on the body.

NIH established the CFS Special Emphasis Panel to review CFS grant

applications. Agency officials reported that NIH did so to demonstrate the

agency’s commitment to CFS research because CFS is so little understood

and so few applications for CFS were being received. The panels were

designed to help facilitate the consideration and scoring of CFS grant

applications that might otherwise not receive scores favorable enough to

be funded if reviewed by the regular review panels. To date, a total of 30

extramural grants (or investigator-initiated research projects) reviewed by

16CDC has since initiated the hiring process of a neuroendocrinologist. We were told that the

lengthy delay in hiring was due to a lack of an appropriate candidate, not a lack of funds.

The adolescent study was later found not to be feasible for methodological reasons.
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the panel have been funded. During the years that CFS grants have been

funded (fiscal years 1988 through 1999), the funding rate for CFS was about

24 percent versus about 28 percent for all grants across the same institutes

that fund CFS research. Officials at NIH have told us that, in their view, all

meritorious CFS applications have been funded and that review by the

special emphasis panel improves the chances that a CFS grant application

will get a score that qualifies it for funding.

NIH has also used selective payment to facilitate the funding of CFS

research. Selective payment is designed to provide funding to a small

number of applications that are programmatically important but not rated

favorably enough to receive funding otherwise. From 1992 through 1996,

six CFS applications were funded through this process—all by NIAID;

however, none have been funded through selective payment since 1996.

NIH describes the selective payment process as designed to support

applications that received scores just beyond the funding cut-off. However,

it appears that NIAID made extra efforts to fund some CFS research

because CFS applications funded through the selective payment process

were ranked well beyond the funding cut-off.17

Since 1991, NIH has also issued three separate requests for applications for

CFS cooperative research centers, supported with funds set aside for this

purpose. The centers are designed to augment the existing grant program

and to provide a sustained multidisciplinary approach to CFS research. The

intent is to advance the field by bridging basic science and clinical research

and facilitating confirmatory testing and follow-up of new hypotheses and

observations. An NIH official told us that, each year, the agency plans to

spend a certain amount on CFS. In fiscal year 1999, when NIH was unable

to spend these funds on grants (because few were approved for funding),

the agency chose to spend these funds on a third center, though only two

had been initially planned for.

17The percentile rankings of all CFS applications funded under the selective payment

program ranged from 53.7 to 75, well above what would be expected with just over 28

percent of the applications being funded overall. A high percentile ranking is assigned to

applications with poor scores, and a low percentile ranking is assigned to those with good

scores.
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In addition to these sources of support for extramural work on CFS, NIH

has also supported intramural work on CFS, most of it at NIAID. Intramural

research activities have included studies of chronic viral infections and

immunologic and endocrine systems. NIAID’s intramural scientists have

also been involved in a number of other collaborative activities.18 Despite

its varied efforts, the intramural program on CFS in NIAID is currently

inactive. NIAID’s primary CFS investigator has recently moved elsewhere

in the agency, and we were told that no one else has yet indicated an

interest in developing work in this area.

Limited Coordination

Through Agency

Efforts or CFSCC

Researchers and patient advocates have also expressed concerns about the

extent to which the agencies obtain and use their input in developing

research programs and about how CFSCC functions to coordinate agency

efforts. While there has been interagency communication, coordination

between CDC and NIH and involvement of patient advocates and external

researchers have been limited. CFSCC has also had limited success in

ensuring a coordinated research effort.

CDC and NIH Coordination

and Involvement of Patient

Advocates and External

Researchers Limited

Although CDC and NIH officials reported frequent informal contacts, there

are few formal mechanisms for interagency coordination. The director of

the National Center for Infectious Diseases is an ex-officio member of

NIAID’s National Advisory Allergy and Infectious Diseases Council, and

NIAID’s Director of the Division of Microbiology and Infectious Diseases is

an ex-officio member of the National Center for Infectious Diseases’ Board

of Scientific Counselors. Both advisory groups cover all areas of infectious

disease—not just CFS. Officials at both CDC and NIH claimed that

interagency coordination occurs through frequent and regular

communication about CFS across the two agencies. We were also told that

these communication efforts have been helpful and the quality of

interagency communication has improved in recent years.

18NIAID intramural scientists collaborated with other NIH scientists on studies of the

neuroendocrine system, seasonal variations in CFS patients, diagnosis and treatment of

CFS, the measurement of fatigue, the characteristics of patients with CFS, memory function,

and the relationships between CFS and induced episodes of illness and of fatigue. NIAID

intramural scientists also collaborated with extramural researchers on a study of a therapy

for neurally mediated hypotension. Neurally mediated hypotension is a disturbance in the

autonomic nervous system’s regulation of blood pressure and pulse, characterized by

abnormally low blood pressure under certain circumstances.
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However, there is little evidence of coordination between CDC and NIH on

CFS research. While the missions of the two agencies are somewhat

distinct, we identified no specific efforts to ensure that CFS research does

not overlap or leave important gaps. For example, while CDC and NIHfunded researchers have shared preliminary manuscripts of their

surveillance studies, both agencies have separately funded communitybased surveillance research. We also identified no activities intended to

build on the results of studies at the other agency, beyond generally reading

the scientific literature.

Further, there have been no joint CFS research projects undertaken by

CDC and NIH scientists. While CDC’s peer review and Board of Scientific

Counselors both recommended that there be more collaboration, projects

of this type have not been initiated to date. CDC has indicated that it will

share blood and serum samples with NIH intramural and extramural

scientists when appropriate.

The agencies have used a number of mechanisms for soliciting the input of

external researchers and patient advocates. CDC included CFS patient

advocates on its two most recent CFS peer review teams, and NIH selected

a CFS patient advocate to serve 4 years on its National Advisory Allergy

and Infectious Diseases Council. Also, in 1998, patient advocates reviewed

and commented on CDC’s revised patient brochure, and in 1999, CDC

convened a meeting of CFS patient advocacy group representatives to

comment on various aspects of the CFS program. Further, external experts

comprise NIH’s CFS Special Emphasis Panel, reviewing grant applications.
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However, the agencies have not always sought the input of patient

advocates and external researchers when there have been appropriate

planning opportunities. For example, NIH officials responsible for what

was initially intended to be a state-of-the-science meeting for CFSCC did

not involve the patient advocate and scientific members of the committee

in the planning process. This occurred despite the expressed interest of

patient advocates and researchers who had a number of specific concerns

about the selection of panelists.19

CFSCC Has Provided a

Forum for Communication

but Has Not Ensured a

Coordinated Research

Effort

While CFSCC has addressed a number of issues since it was chartered in

1996, it has made only limited progress in meeting its goals aimed at

improving agencies’ coordination of CFS research activities, programs, and

education efforts.20 Shortcomings in how the committee has functioned

have hampered its progress; some of these shortcomings are beginning to

be addressed.

Some CFSCC efforts have helped facilitate communication—particularly

among representatives from FDA, the Health Resources and Services

Administration, and the Social Security Administration—about CFS

activities that are being carried out across HHS. For example, FDA used the

CFS prevalence rates cited by CDC to determine whether a product would

qualify for orphan drug designation.21 To help address some research and

educational needs, CFSCC identified gaps in knowledge and, in

conjunction with their meetings, scheduled scientific discussion around

19Among the concerns patient advocates raised over the proposed list of participants are the

following: (1) the list did not include any broad-based CFS experts, such as one of the past

or present NIH CFS Cooperative Research Center directors; (2) the list did not include

anyone who regularly saw CFS patients to draw on clinical experience; (3) two participants

were included who are known for promoting psychiatric approaches to CFS and cognitive

behavioral therapy research; and (4) an NIH scientist was asked to provide an overview of

CFS research for the meeting, despite the scientist’s no longer being actively involved in

CFS research.

20CFSCC’s five goals are (1) provide advice to the Secretary of HHS and others to ensure

interagency coordination and communication regarding CFS research and other related

issues, (2) develop complementary research programs that minimize overlap, (3) facilitate

increased department and agency awareness of CFS research and educational needs, (4)

identify collaborative and coordination opportunities in research and education, and (5)

develop informed responses to constituency groups regarding agency efforts and progress.

21A product used to treat a rare disease affecting fewer than 200,000 Americans may be

designated as an orphan drug and thereby qualifies the manufacturer for exclusive

marketing for 7 years and tax incentives.
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these topics, including adolescent CFS issues and physician education.

CDC officials also reported that the agency provides funding to HHS’

Health Resources and Services Administration and a patient advocacy

organization to develop CFS educational materials. One CFSCC effort,

currently under way, addresses patient advocates’ concerns regarding the

term “chronic fatigue syndrome,” which they believe does not accurately

reflect the nature of the disorder and stigmatizes individuals diagnosed

with CFS. To address this issue, CFSCC has surveyed physicians,

researchers, and patients and has formed a work group, with the

involvement of the Assistant Surgeon General and the support of the

Assistant Secretary of Health. CFSCC has also established a separate work

group to review CFS’ placement in the International Classification of

Diseases, an international manual for classifying diseases. Committee

consensus on this issue has not yet been reached.

Overall, however, CFSCC has made only limited progress in meeting the

goals established by the Secretary to better coordinate CFS efforts. For

example, CFSCC has not been a particularly useful forum for developing

complementary research programs. At each of the committee’s biannual

meetings, representatives from each agency have described their recent

CFS activities, but there has been little discussion about how to coordinate

these activities. Moreover, according to agency officials, the meetings have

had no effect on the direction of research at either CDC or NIH. However,

agency officials stated that a change in the direction of research generally

occurs as a result of relevant scientific or technical breakthroughs.

In addition, CFSCC has made only three recommendations to HHS’

Secretary—and none have focused on interagency coordination. The first

recommendation asked that HHS examine opportunities to combine

existing data from various sources to better understand prevalence and

epidemiology; the second asked the Secretary to help develop some

clinically useful instruments that could be linked to other CFS information;

and the third asked that the Secretary make more money available for CFS

research to attract more researchers to the field. Regardless of the focus of

these recommendations, the Secretary has not responded to any of them.

Patient advocates serving on CFSCC have voiced their dissatisfaction with

the committee’s ability to get information from the agencies. Specifically,

they have been unable to obtain timely information from CDC and NIH

necessary to carry out their advisory function and to be responsive to

constituents. According to some of the patient advocate members, they

repeatedly requested from each agency, over separate time periods,
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information on funding and research activities but did not receive the

information in a timely fashion.

Based on our discussions with agency officials and CFSCC members, as

well as a review of meeting transcripts, we found a number of

shortcomings in the way the committee functions that may be limiting its

effectiveness. Committee members cited a failure to

• discuss issues raised in agency reports and public testimony,

• develop recommendations for action, and

• develop continuity in the leadership of the committee because the

cochair alternates between CDC and NIH every 2 years.

Much of the committee’s meeting time is spent presenting reports from

each agency on recent CFS activities. Minutes from the meetings show that,

during CDC and NIH agency updates, the agencies’ representatives rarely, if

ever, questioned or discussed information in each other’s updates. Meeting

minutes also reflect no discussion of the issues raised during the public

testimony portion of the meeting.

There are indications, however, that some of these shortcomings are

beginning to be addressed. NIH changed its committee representative—

who currently serves as cochair—from an official of NIAID to an official of

NIH’s Office of the Director. CFSCC members cited this as a positive

development, viewing the centralized placement as more appropriate for

facilitating cross-institute communication. In addition, CFSCC, during its

February 2000 meeting, took steps to develop a new state-of-the-science

meeting, establishing a planning committee chaired by a scientific member.

This group will work between regular CFSCC meetings to facilitate more

rapid progress on developing the state-of-the-science meeting; it should

also provide greater committee control over the participants and agenda

for this meeting. Finally, the cochair has invited all committee members to

submit suggested format changes to make the meetings more productive.

Some members of the committee believe that format changes will provide

for greater discussion and progress and, therefore, coordination.

Conclusions CDC has pursued avenues of research in a number of areas, in accordance

with the agency’s mission and congressional report language, including

work on the case definition, surveillance, and risk factors for CFS.

However, CDC’s funding practices and redirection of CFS funds have

delayed its research—evidenced by the agency’s proposal to initiate an
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array of CFS projects, funded with the money it plans to restore. NIH has

used a number of mechanisms to ensure that CFS research was funded.

The development of program announcements, creation of the special

emphasis panel, the use of selective payment, and support of cooperative

research centers seem to demonstrate NIH’s commitment to CFS research.

CFSCC has not been successful in meeting its goal: to ensure interagency

coordination. While the committee has been useful in keeping both federal

agencies and the public informed of current developments at the agencies

and allowing the public an opportunity to raise issues that the committee

might want to consider, it has yet to stimulate much discussion about how

CDC and NIH could coordinate their programs. Recent actions within

CFSCC to improve the structure of the meetings should help the committee

move toward achieving its goals.

Agency Comments We provided HHS the opportunity to comment on a draft of this report.

HHS generally agreed with our findings and said that the report accurately

conveyed the department’s efforts on CFS. HHS specifically agreed that

CFSCC could function more effectively as a coherent body with focus and

direction. The department also provided technical comments, which we

incorporated where appropriate. HHS’ comments are reprinted in appendix

IX.
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As agreed with your office, unless you publicly announce the report’s

contents earlier, we plan no further distribution until 30 days from the date

of this letter. We will then send copies to the Honorable Donna E. Shalala,

Secretary of HHS; the Honorable Jeffrey P. Koplan, Director of CDC; the

Honorable Ruth Kirschstein, Acting Director of NIH; and others who are

interested. If you have any questions or would like additional information,

please call me at (202) 512-7114. Marcia Crosse, Carolyn Feis, and Donald

Keller made major contributions to this report.

Sincerely yours,

Janet Heinrich

Associate Director, Health Financing and

Public Health Issues
Page 30 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix I

Background on Chronic Fatigue Syndrome ApApenednxidexiIs

CFS Case Definition Under the first U.S. CFS case definition, developed in 1988, a case had to

fulfill 2 major criteria and at least 8 of the 11 symptom criteria or at least 6

of those symptom criteria and 2 of 3 physical criteria. One major criterion

was that there be a “new onset of persistent or relapsing, debilitating

fatigue or easy fatigability in a person who has no previous history of

similar symptoms, that does not resolve with bed rest, and that is severe

enough to produce or impair average daily activity below 50 percent of the

patient’s premorbid activity level, for a period of at least 6 months.”1 The

other major criterion was that other clinical conditions capable of causing

similar symptoms had to be absent upon a thorough clinical evaluation.

The list of the other conditions included over a dozen broad categories of

disease, such as malignancy, autoimmune disease, chronic psychiatric

disease, and chronic cardiac disease. The symptom criteria, which also had

to persist or recur over at least 6 months, were specifically defined levels

and/or kinds of fever, sore throat, sore lymph nodes, muscle weakness,

muscle discomfort, prolonged fatigue induced by exercise, headaches, joint

pain, neuropsychologic complaints, sleep disturbance, and development of

the symptom complex over a period of a few hours to a few days (not a

symptom but a criterion treated like the symptom criteria for purposes of

the case definition). The physical criteria were specific, documented levels

of fever, sore throat, and palpable or tender lymph nodes.

This first CFS case definition caused many difficulties for researchers. For

example, the definition did not appear to distinguish CFS from other types

of unexplained fatigue or define a distinct group of cases. As a result,

another CDC consensus panel revised the U.S. definition of CFS in 1994.

According to this second definition, in order to receive a diagnosis of CFS,

a patient case must satisfy two criteria: (1) severe chronic fatigue of 6

months or longer duration with other known medical conditions excluded

by clinical diagnosis and (2) four or more of the following symptoms

concurrently: substantial impairment in short-term memory or

concentration; sore throat; tender lymph nodes; muscle pain; pain in

multiple joints without swelling or redness; headaches of a new type,

pattern, or severity; unrefreshing sleep; and postexertional malaise lasting

more than 24 hours. The symptoms must have persisted or recurred during

6 or more consecutive months of illness and must not have predated the

fatigue. There are currently no laboratory tests to diagnose CFS, and there

1

G. P. Holmes and others, “Chronic Fatigue Syndrome: A Working Case Definition,” Annals

of Internal Medicine, Vol. 108 (1988), pp. 387-9.
Appendix I

Background on Chronic Fatigue Syndrome

Page 31 GAO/HEHS-00-98 Chronic Fatigue Syndrome

are a number of other illnesses that have a spectrum of symptoms similar

to CFS, such as fibromyalgia, myalgic encephalomyelitis, neurasthenia,

multiple chemical sensitivities, and chronic mononucleosis. Further, there

are a large number of other illnesses that can result in fatigue, the diagnosis

of which would preclude a diagnosis of CFS, such as major depressive

disorders, hypothyroidism, cancer, and others.

Estimates of CFS

Prevalence

CFS does not appear to be as rare as was originally suggested. Table 1

shows that estimates of CFS prevalence have increased over time as new

data have been obtained and the definition of CFS has been modified. The

estimates described here are based on data from samples of geographically

defined populations, as opposed to individual clinics or health groups, and

are based on patients who have been clinically evaluated relative to the

case definition—not on patients’ self-identification of chronic fatigue. Early

CDC estimates—derived from data provided by physicians in four cities

(Atlanta, Georgia; Wichita, Kansas; Grand Rapids, Michigan; and Reno,

Nevada) who referred patients with CFS—were minimum prevalence rates,

over a 2-year period, ranging across cities from 2.0 to 7.3 per 100,000.2 A

subsequent report based on more data from the same sources yielded age-,

sex-, and race-adjusted rates over a 4-year period, ranging across cities

from 4.0 to 8.7 per 100,000.3 A more recent CDC study that looked only at

persons aged 18 to 69 in Wichita used a more valid community sampling

procedure to find cases, and had additional refinements of study design

and data analysis yielded an adjusted prevalence rate for 1997 of 183 per

100,000.4

2

W. J. Gunn and others, “Epidemiology of Chronic Fatigue Syndrome: The Centers for

Disease Control Study,” Ciba Foundation Symposium, Vol. 173 (1993), pp. 83-101.

3

M. Reyes and others, “Surveillance for Chronic Fatigue Syndrome—Four U.S. Cities,

September 1989 Through August 1993,” Morbidity and Mortality Weekly Report, Vol. 46

(SS-2) (Feb. 21, 1997), p. 1-13.

4

M. Reyes and others, “Random-Digit-Dialing Survey of Fatiguing Illness in Sedgwick

County, Kansas (Wichita).” Paper presented at the American Association for Chronic

Fatigue Syndrome International Research Conference (Boston, Mass., Oct. 10, 1998).
Appendix I

Background on Chronic Fatigue Syndrome

Page 32 GAO/HEHS-00-98 Chronic Fatigue Syndrome

When CDC reanalyzed the data from Wichita and included for the first time

complete data from certain participants whose data were initially

incomplete, the adjusted prevalence rate was reported to be 238 per

100,000.5 The research team that conducted a population-based study in

Chicago, funded by NIH, reported an overall estimated prevalence rate of

422 per 100,000.6 The estimated rate for women was reported to be even

higher: 522 per 100,000.

Table 1: U.S. Studies of CFS Prevalence Based on Clinical Evaluation of Samples of Local Populations

a

Adjusted for age, sex, and race, where indicated.

Research on Possible

Causes of CFS

There have been many hypotheses about the cause or causes of CFS. One

possibility is that an infectious agent, such as the Epstein-Barr virus, is the

cause of CFS, but a systematic association between CFS and Epstein-Barr

virus has not been found.7 Similarly, many known human infectious agents,

including other viruses and nonviral pathogens have been studied as

possible causes of CFS.8 So far, none of the infectious agents studied have

been found to be significantly associated with CFS. It is possible, however,

5

W. Reeves at meeting of Chronic Fatigue Syndrome Coordinating Committee (Washington,

D.C., Apr. 22, 1999).

6

L. A. Jason and others, “A Community-Based Study of Chronic Fatigue Syndrome,”

Archives of Internal Medicine, Vol. 159 (1999), pp. 2129-37.

Study Methoda Rates (per 100,000)

Estimated number of people

with CFS in U.S. population

Gunn and others (1993), four cities 2-year prevalence 2.0-7.3 4,000-14,000

Reyes and others (1997), four cities 4-year prevalence, adjusted 4.0-8.7 8,000-17,000

Reyes and others (1998), Wichita Prevalence, adjusted 183 363,000

Reeves (1999), Wichita Prevalence, adjusted 238 471,000

Jason and others (1999), Chicago Prevalence 422 836,000

7

Epstein-Barr virus has been implicated in a number of medical conditions, including

mononucleosis, and the similarity of CFS to chronic mononucleosis led to the hypothesis

that CFS was due to chronic Epstein-Barr infection.

8

Causes that have been studied include, for example, human retroviruses, human

herpesvirus 6, enteroviruses, rubella, Borna disease viruses, Candida albicans, and

mycoplasma.
Appendix I

Background on Chronic Fatigue Syndrome

Page 33 GAO/HEHS-00-98 Chronic Fatigue Syndrome

that an unknown or rarely studied infectious agent is the cause, or that CFS

has many different infectious causes, each one of which is responsible for

only a subset of CFS cases. Further, viral infection is one of many

conditions proposed, along with other transient traumatic conditions,

stress, and toxins, to trigger, but not necessarily sustain, the development

of CFS.

Another vigorously pursued possibility is that CFS is caused by an

immunologic dysfunction, such as lower numbers of the immune system

components called “natural killer cells” or an inappropriate production of

the natural body chemicals known as “cytokines.” Several immune system

abnormalities and histories of allergies have been observed in CFS

patients, but none of them consistently. Moreover, CFS patients have not

been shown to have the tissue damage found in autoimmune diseases, such

as rheumatoid arthritis. Nor do they typically manifest the susceptibility to

opportunistic infections or increased cancer risk so often found in persons

with deficient or suppressed immune systems, such as AIDS patients. It is

also possible that if there are immune system abnormalities in patients with

CFS, the abnormalities are themselves caused by infectious agents, other

specific kinds of exposure, or stress. There has been no empirical support

for any of these specific hypotheses involving an immunologic cause, but it

is possible that immunologic dysfunction plays a role, perhaps a complex

one, in the development of some or all cases of CFS.

The infectious and immunologic etiological hypotheses are not the only

ones that have been explored for CFS. Two hypotheses related to the

nervous system have also generated considerable research. First, it has

been observed that CFS patients secrete lower than normal levels of the

hormone cortisol in response to physical or emotional stress. The

hypothesis that has resulted from this observation is that the

neuroendocrine system, which is involved in these secretions via the

hypothalamus and pituitary gland of the brain (the hypothalamic-pituitaryadrenal axis), has an important role in CFS. However, the difference in

cortisol levels between patients and healthy control subjects does not

appear great enough to account for CFS. Second, it has been hypothesized

that disturbances in the autonomic nervous system’s regulation of blood

pressure and pulse, characterized by abnormally low blood pressure under

certain circumstances, play an important role in CFS. This condition is

known as neurally mediated hypotension. As in the cases of the infectious

and immune system hypotheses, conclusive support for the involvement of

either the hypothalamic-pituitary-adrenal axis or neurally mediated

hypotension in all or most cases of CFS has not been found.
Page 34 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix II

Accounting Issues at CDC ApendxiI

In 1998, a CDC employee alleged that CDC had diverted CFS funds to other

programs and had provided erroneous information to the Congress

regarding the scope and costs of CFS research. At the request of CDC, HHS’

Inspector General conducted an audit to determine whether costs charged

to the CFS program from fiscal years 1995 through 1998 were actually

incurred for that program in accordance with applicable laws, regulations,

and accounting standards. CDC is not legally prohibited from spending

funds budgeted for CFS on other programs because the Congress did not

make specific line item appropriations to that program. However, it is clear

from Senate, House, and Conference report language that CDC was

expected to spend the amount budgeted for CFS only on CFS.

HHS’ Inspector General found that a significant portion of CFS funds were

spent on other programs and activities and that CDC failed to adequately

document the relevance of other costs charged to CFS. The Inspector

General accepted 43 percent of the expenditures as actually incurred for

program purposes, could not accept 39 percent because they were incurred

for non-CFS-related activities, and could not determine the applicability of

18 percent of indirect costs because of insufficient documentation. The

Inspector General found that the questionable charges resulted from

deficiencies in CDC’s internal control system for handling direct and

indirect costs. The Inspector General also found that, as a result, CDC

officials provided inaccurate information to the Congress.

The Inspector General further determined that CDC did not have adequate

controls to ensure that direct costs charged at the program activity level

are based on the actual efforts of involved personnel. As a result, the

Director of the Division of Viral and Rickettsial Diseases was able to

transfer to CFS unrelated costs without appropriate analysis,

documentation, or justification. Similarly, the Inspector General

determined that CDC had inadequate controls to ensure that indirect costs

from all organizational levels were properly identified and consistently

allocated.

In response to the Inspector General report, CDC will restore $12.9 million

in funding to the CFS program over 4 years. This is identical to the sum of

funds the Inspector General did not accept as related to CFS ($8.8 million)

and was questionable ($4.1 million). CDC also promised a number of

corrections:

• A public apology to the Congress from the Director of CDC and other

senior staff.
Appendix II

Accounting Issues at CDC

Page 35 GAO/HEHS-00-98 Chronic Fatigue Syndrome

• Probationary status for the Division of Viral and Rickettsial Diseases

with regard to budget execution until January 2001.

• Separate apportionment of CFS funds from the Office of Management

and Budget with the accompanying requirement that an operating plan

be submitted to the Congress. Accordingly, quarterly reports will be

submitted to the Congress regarding the budgetary execution of this

plan.

• Mandatory training for all CDC managers and staff responsible for

budget and accounting functions to ensure complete knowledge of

statutory and regulatory requirements for the use of federal funds.

• Establishment of an internal review capacity to conduct regular

assessments of CDC’s fiscal policies, procedures, practices, and

controls.

• Development and implementation of a new system for allocation of

CDC-wide indirect program support costs.

• Reinvigoration of CDC’s efforts to better understand CFS by

establishing a long-term research and program agenda with in-depth

advice from the research and advocacy communities.

A subsequent accounting analysis of fiscal year 1999 CFS expenditures,

conducted by PricewaterhouseCoopers, an independent auditing firm,

found that 99.2 percent of the fiscal year 1999 funds reported by CDC as

CFS obligations were in fact related to CFS program activities. They also

found that CDC adequately addressed the concerns raised by the Inspector

General report for the CFS program for fiscal year 1999.

In February 2000, there were public reports that similar accounting

difficulties extended beyond the CFS program. Specifically, it had been

reported that CDC also spent funds intended for the study of hantavirus on

other diseases. The PricewaterhouseCoopers analysis of fiscal year 1999

CFS expenditures also recommended that the CDC strongly consider

conducting an accounting analysis of the obligations reported for the

hantavirus program for fiscal years 1995 through 1998. In response to these

concerns, CDC made management changes at the level of the Director of

the Division of Viral and Rickettsial Diseases, responsible for both the CFS

and hantavirus programs. In addition, the Secretary of HHS, in consultation

with the Director of CDC, told the Congress that a number of additional

corrective actions were under way:

• HHS’ Chief Financial Officer will take such actions as necessary to

certify all financial obligations made by the National Center for

Infectious Diseases for the remainder of fiscal year 2000.
Appendix II

Accounting Issues at CDC

Page 36 GAO/HEHS-00-98 Chronic Fatigue Syndrome

• HHS’ Chief Financial Officer will work with the Director of CDC to

ensure that all senior decisionmakers in the National Center for

Infectious Diseases receive certified budget execution training.

• CDC is commissioning an external review of the agency’s fiscal

management practices. The review is to be completed by September

2000. The results of the analysis will be communicated to the Congress

as soon as the review is complete.

• CDC program managers will conduct a top-to-bottom examination of

CDC’s programs and projects to make sure there are no other areas of

concern. During the 90-day period, CDC managers will be able to fully

and openly identify any area for which there may be a discrepancy

between actual expenditures and the information provided to the

Congress. CDC will share these findings with the Congress.

• CDC has commissioned PricewaterhouseCoopers to thoroughly

examine the hantavirus expenditures. The results will be communicated

to the Chair of the Senate Subcommittee on Labor, Health and Human

Services, Education and Related Agencies, Committee on

Appropriations, immediately upon completion. When the audit is

complete, CDC will expand the effort to the entire National Center for

Infectious Diseases.
Page 37 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix III

CDC Research Efforts and Publications ApendxiI

CDC, with others, developed the first case definition of CFS in 1988 and the

second definition in 1994. These case definitions reflect clinical judgment

gathered from experience with patients sick enough and with sufficient

resources to seek medical care. Neither of the case definitions has been

derived from quantitative clinical data, such as lab results, because there

are no known markers for infection and, consequently, no laboratory tests

available. CDC recently met to consider the need for another revision of the

case definition, which may change the number of people who could be

diagnosed with CFS, as occurred when the definition was broadened in

1994 and more people met the revised definition’s criteria. While higher

prevalence estimates can be helpful to research by potentially attracting

more funding and more research interest, it can also mask possible

research findings—that is, if the population now defined as having CFS is

heterogeneous, it may be more difficult to identify causes.

CDC has conducted a number of surveillance studies to determine the

prevalence of CFS, including a four-city study using physician referrals to

identify possible CFS patients. CDC was criticized for using physician

referrals because patient frustration over physicians who do not

understand CFS or over insurance difficulties may result in CFS patients

not being in the health care system. A CDC official offered many

justifications for this approach, including its past use for other diseases, the

participation of most primary care physicians in the areas studied, and the

ability to gather data annually. Further, we were told that the study was the

most rigorous that could be performed with the funds that were available

to the agency at that time and that the prevalence estimates could be used

to estimate the burden of CFS on the health care system.

CDC shifted from this passive surveillance approach to a more active

approach when it conducted a pilot study of randomly selected individuals

in San Francisco, California. Based on this pilot, the agency began a largescale study in Wichita, Kansas. Here, almost 7,000 subjects are being

followed annually for 3 years. However, because most participants in the

Wichita sample are white, the sample may not be adequate for studying the

prevalence of CFS in racial and ethnic minorities. Regardless, a CDC

official told us that Wichita was chosen because it is representative of the

United States with respect to its racial and ethnic makeup. Further, the

population of Wichita is relatively stable, allowing for the long-term followup called for by the study. CDC uses interview and clinical data from

participants in these studies to describe the epidemiology of fatiguing

illnesses. For example, blood and other specimens are collected from those

enrolled in the clinical evaluation component of the study to be used in
Appendix III

CDC Research Efforts and Publications

Page 38 GAO/HEHS-00-98 Chronic Fatigue Syndrome

laboratory studies to identify risk factors and diagnostic markers. CDC is

also taking additional steps to estimate prevalence. The agency is currently

developing a national study to estimate sex-, age-, race/ethnic-, and

socioeconomic-specific prevalence of CFS. Finally, late in fiscal year 2000,

CDC plans to begin developing a national CFS patient registry where

patients will be followed yearly.

To date, CDC studies of risk factors and diagnostic markers associated with

CFS have not identified consistently strong and significant associations

between CFS and exposure to infectious agents or abnormalities in

immune function.1 In efforts to understand the physiological basis of CFS,

CDC established a group to examine genetic issues in CFS and further

identify risk factors and diagnostic markers. CDC also has investigated

suspected clusters of CFS in seven different locations but was unable to

confirm any clusters in these areas.

CDC has presented only limited data on the natural course of the disease,

relying on data collected from their longitudinal surveillance studies, which

have taken years to conduct. Further, CDC has acknowledged the

limitations in the data it has published from its four-city physician-based

study. CDC has noted that the study was limited because most patients had

been ill for many years and no clinical data were gathered to further

support the symptoms described by patients, observed by providers, or

both. To supplement this work, CDC continues to gather data from the

Wichita area that include baseline and annual follow-ups for 3 years.

CDC has undertaken a variety of efforts to educate practitioners,

professionals, and the public. Scientists from CDC have published

numerous articles describing their work, and a CDC official reported that

peer-reviewed publications, listed in figure 4, were the cornerstone of their

education efforts for physicians.

1

For example, CDC has looked at the association of CFS with chronic enteroviral infections;

associated viral infections and immunological abnormalities; viruses like human T-cell

lymphotropic virus type II; retroviruses; Borna disease virus; physical, behavioral, and

psychological risk factors; strain differences in common viral infections; and

neuroendocrine function. Laboratory work has involved immune function assays, including

lymphocyte markers, cytokines, natural killer cell dysfunction, serum Ig levels, complement

levels, and immune complexes. CDC also cultured specimens in attempts to isolate

herpesvirus 6 and 7.
Appendix III

CDC Research Efforts and Publications

Page 39 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Figure 4: CDC Publications
Appendix III

CDC Research Efforts and Publications

Page 40 GAO/HEHS-00-98 Chronic Fatigue Syndrome
Appendix III

CDC Research Efforts and Publications

Page 41 GAO/HEHS-00-98 Chronic Fatigue Syndrome
Appendix III

CDC Research Efforts and Publications

Page 42 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Source: CDC.

In addition, CDC has established a web site devoted to CFS containing

hundreds of pages of materials, has maintained a toll-free hot line, and has

developed a booklet about CFS, which has been revised twice. Further,
Appendix III

CDC Research Efforts and Publications

Page 43 GAO/HEHS-00-98 Chronic Fatigue Syndrome

CDC has presented information at conferences for CFS patient support

groups and other professional associations. CDC acknowledges that some

physicians might not recognize CFS as a distinct illness. As a result, CDC

plans to add a medical education specialist to its staff in fiscal year 2000 to

develop a more rounded and aggressive medical education program aimed

at health care providers, public health officials at the state and local levels,

health maintenance organizations, and insurance providers.

CDC has been criticized for delays in releasing the findings of its studies

and for the breadth of its research. CDC sometimes does not release

findings from its studies until they are published in a professional journal.

The publication process can take months or years, meaning that the latest

information may not always be immediately available. However, CDC

officials told us they use professional journals to communicate with the

medical community—the generally accepted way to disseminate results

from scientific studies. Further, the peer review that is often required prior

to publication can serve to validate its findings. Second, some scientists

feel that certain areas of research have not been adequately or

appropriately pursued. For example, some were concerned that valuable

data would be lost when CDC proposed selecting new patients for future

work, rather than continuing to work with those patients who had been

part of the Wichita study for 3 years. In addition, it has been suggested that

CDC’s efforts to replicate findings on certain types of viruses did not use

the same methodology as in the original study and, therefore, CDC’s failure

to replicate the findings was based on a flawed design. CDC officials stated

that the agency plans to continue working with patients identified during

the Wichita study as part of future clinical and laboratory investigations.

CDC officials also reported that the agency uses the most current and

appropriate methods to identify infectious agents. According to agency

officials, where these differ from those in an original study, it is because

CDC has determined new or better methods exist.
Page 44 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix IV

NIH Research Efforts and Grants ApendxiIV

NIH Research Efforts The National Institute of Allergy and Infectious Diseases (NIAID) has

pursued the goal of studying the causes of CFS, including the search for

risk factors and diagnostic markers, more extensively than any of its other

CFS-related goals. A number of the other institutes have supported

collaborative or complementary work on causes. NIH has funded

investigations of immunologic, neuropsychologic, neuroendocrinologic,

brain wave, and infectious aspects of CFS, any of which might have

implications for understanding causes.1 Studies of subtypes of CFS have

also been conducted.

Although CDC has taken the lead in efforts to estimate the prevalence of

CFS, NIAID has also supported a number of attempts to establish the

magnitude of the problem. In the early 1990s, it funded research in Seattle

and Boston estimating CFS prevalence in primary care settings. In 1995, it

began funding a large epidemiological project in Chicago to study the

socioeconomic and ethnic variability of CFS. This project has generated

population-based prevalence estimates for the overall population and for

racial and other subgroups, such as women.

NIH has supported research on the origins and development of CFS. Early

work focused on the possible role of Epstein-Barr virus in CFS and on

certain immune system deficiencies thought to occur in CFS. The two most

recent efforts involve a model of postinfectious fatigue, which may provide

insight into what happens when a person contracts CFS after an infection,

and blood pressure irregularities in CFS patients.

NIH has supported some efforts to develop clinically useful diagnostic

methods. The early work in this area involved distinguishing chronic, active

Epstein-Barr infection from diagnosed CFS. More recently, NIH has

supported a study of the effective diagnosis of chronic fatigue and its

intensity and a study of the feasibility of using specific measurement tools

to evaluate CFS patients.

1

NIH funded a number of studies comparing CFS patients and healthy controls with respect

to potential laboratory markers and risk factors, including sleep patterns and various

neurologic, virologic, and immunologic features. Some additional etiological hypotheses

that were tested include those implicating orthostatic intolerance, other aspects of cardiac

regulation, hypothalamic dysfunction, autoantibody responses, allergies, and the

dysregulation of specific antiviral pathways.
Appendix IV

NIH Research Efforts and Grants

Page 45 GAO/HEHS-00-98 Chronic Fatigue Syndrome

NIH has supported several projects with possible application to treatment.

These include modulating brain chemistry and developing individually

tailored exercise programs. Other efforts have included trials of

pharmacologic agents and studies of nonpharmacologic treatments.

Work on NIAID’s goal of furthering prevention would be premature given

the limited understanding of the causes of CFS, and NIH has not supported

efforts in this direction. However, NIH has supported a number of relevant

efforts not explicitly linked to any of its stated goals, such as activities

contributing to the education of researchers—chiefly workshops and other

kinds of meetings—and to a lesser extent, the education of practitioners

and the public, chiefly pamphlets about CFS.

Researchers and patient advocates have criticized NIH’s efforts on CFS

research. Some have suggested that studies in certain areas have not been

adequately investigated. In at least one situation, it has been speculated

that NIH investigators did not pursue a particular finding because the

finding was possibly contrary to what was expected. We were also told that

prominent researchers have been turned down for funding, discouraging

them from staying in the field. Some patient advocates have argued that

NIH is increasingly funding research on mental health and its relation to

CFS, but the evidence does not support this assertion. While it appears that

the National Institute of Mental Health has spent more funds on CFS

research than any institute other than NIAID, this is an artifact of the data

management system at NIH. The majority of these funds were allocated to

a study encompassing a range of work, only a small portion of which was

related to CFS. In fact, National Institute of Mental Health officials told us

that they do not consider CFS to be a mental disorder and that CFS is not

listed in the diagnostic manual used in psychiatry and psychology. They

further do not consider themselves to have an ongoing program on CFS;

rather they occasionally study CFS because of interest in certain relevant

hypotheses. Nevertheless, these concerns are indicative of the doubt and

mistrust that both researchers and patient advocates expressed.

NIH-Funded Grants

and Projects Related to

CFS

Due to concerns we heard about inconsistencies between CFS grants listed

in NIH reports and grants listed in NIH’s Computer Retrieval of Information

on Scientific Projects (CRISP), we conducted our own search of CRISP.

Using only the key phrase “chronic fatigue syndrome” for years 1997

through 1999, we searched CRISP and found a number of studies that were

not included in the lists of grants originally provided to us by NIH.
Appendix IV

NIH Research Efforts and Grants

Page 46 GAO/HEHS-00-98 Chronic Fatigue Syndrome

NIH officials explained this discrepancy. Projects identified through CRISP

are based on text word searching and, as such, are not verified as

rigorously as are projects for budget and research reporting, including the

CFS grant tables provided to us. Due to the indexing terms used for CRISP

and the search logic employed, it is not unusual to observe differences

between CRISP-generated lists (which are designed for public access) and

formal agency reporting related to fiscal responsibility. According to

agency officials, the primary reason for differences between the list of

projects found through CRISP and the list of projects reported by the

institutes is that the methods used to compile the lists are different.

Entering a set of key words in CRISP will generate a list of projects based

on the grant application. The institutes may use CRISP as a starting point,

but the institutes have procedures to ensure that they report to the budget

office only actually funded projects or subprojects. For example, in a large

center grant, the CRISP database may include a number of subprojects.

Some, but not all, of these subprojects may be related to the specific

disease area in question. Occasionally, a planned subproject will not be

funded. Such a subproject would not be included in the list of projects

generated by the institute but could remain in the CRISP database (see

table 2).
Appendix IV

NIH Research Efforts and Grants

Page 47 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Table 2: NIH Disposition of Projects Identified by CRISP From 1997 Through 1999 Not Included in NIH’s List

Tables 3 through 6 list all CFS-related NIH-funded grants and projects,

which are administered through the following institutes:

• National Cancer Institute (NCI),

• National Center for Research Resources (NCRR),

• National Heart, Lung, and Blood Institute (NHLBI),

• National Institute of Allergy and Infectious Diseases (NIAID),

• National Institute of Arthritis and Musculoskeletal and Skin Diseases

(NIAMS),

• National Institute of Child Health and Human Development (NICHD),

• National Institute of Mental Health (NIMH), and

• National Institute of Neurological Disorders and Stroke (NINDS).

NIH disposition Number

Projects should have been included

Small business innovative research grants (grants were not included in NIH’s search for CFS grants) 1

Grants funded for a year in addition to that included on the list of projects provided by NIH 1

Subproject of a general clinical research centers grant 4

Subproject of a biomedical resource grant 1

Grants inadvertently not included in NIH list, identified by NIH prior to this request 1

Projects were appropriately not included

CFS was not the primary focus of the grant 6

Subproject of a grant, funding of subproject reported in funding of overall project 1

Cooperative Research Center (subproject reported in CRISP by a different title than by NIH) 6

Project in CRISP had a different title than that on list provided by NIH 2

Project number duplicated an earlier grant 1

Project was not funded during one of the years for which it was listed in CRISP 1
Appendix IV

NIH Research Efforts and Grants

Page 48 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Table 3: NIH-Funded R01 (Research Project) Grants Related to CFS

Fiscal year(s) Institute Grant title

Total funding in

dollars

1987-1990 NIAID Definition of the Chronic Epstein-Barr Virus Syndrome $540,220

1989-1991 NIAID Prevalence of CFS 930,285

1990-1992 NIAID Neuroimmunologic Studies of CFS 871,215

1992-1994 NIAID Chronic Fatigue in Lyme Disease 744,236

1992-1994 NIMH Predictors of Recovery From Acute Viral Infectiona 716,106

1993-1997 NIAID Human JHK Virusb 769,203

1993-1995 NIAID Exertion-Induced Cytokines in CFSb 536,958

1993-1995,

1997-1999

NIAID Motor Control and Cytokines in CFS (later retitled Motor Control in CFS)b 970,696

1993-1995 NIAID Exercise Intolerance in CFS 454,121

1993-1999 NIMH Research Center on the Psychobiology of Ethnicityc 6,978,751

1993 NIAID Virology Assessment of CFS Patientsd 6,910

1993-1996 NIAID Antigens of Human Herpesvirus-6 521,694

1994-1996 NIAID Virology and Immunology of CFSb 497,473

1994-1996,

1998-1999

NIAID Mechanisms of Immunologically Mediated Fatigue 1,008,464

1995-1999 NIAID Estimating Rates of CFS in a Community Sample 2,714,041

1995 NCI Transforming Domain of Human Herpesvirus-6 That Transactivates HIV 1 207,000

1995 NCI Epidemiologic Study of Pediatric HIV-Related Lymphomas 55,000

1995 NCI Molecular Studies on Bovine Immunodeficiency Virus and Bovine Herpes

Virus Interactions

21,000

1996-1998 NIMH Cognitive Dysfunction in CFS 275,836

1996-1999 NIAID Dysregulated 2-5A Synthetase/RNase L/PKR Pathways in CFSe 1,086,909

1996-1998 NIAID A Trial of Fludrocortisone for CFSb 748,132

1997-1999 NIAID Autoantibodies to Cellular Matrix Antigens in CFS 1,063,378

1997-1999 NIAID Mechanisms of Rhinitis in CFS 508,806

1998-1999 NIAID A Model for Induction of CFS 641,607

1998-1999 NHLBI Circulatory Control in Young People with Chronic Fatigue 859,156

1998-1999 NHLBI Investigation of Orthostatic Intolerance in CFS 639,674

1998-1999 NIAMS HPA Axis Dysregulation in Fibromyalgia 385,015

1999 NIMH Auditory Working Memory in CFS: A Functional Magnetic Resonance Imaging

Study

135,152

1999 NHLBI Muscle Blood Flow and CFS 114,359

1999 NINDS Motor Learning in CFS: Implications for Neural Dysfunction 160,665

Total funds $25,162,062
Appendix IV

NIH Research Efforts and Grants

Page 49 GAO/HEHS-00-98 Chronic Fatigue Syndrome

a

This NIMH grant was funded prior to the time when NIMH was a part of NIH, but the project extended

into the period after which NIMH was a part of NIH. Therefore it is included.

b

Grant funded through selective pay program.

c This NIMH project studies a range of issues and only a small portion of the funds are spent on CFSrelated activities.

d

From 1991 through 1995, this project was also a subproject to a cooperative research center project

(see table 5). During fiscal year 1993, the project was also supported with an R01-type Research

Project grant.

e

The first-year funding for this grant was under exploratory/developmental grants.

Table 4: NIH-Funded Intramural Research Projects Related to CFS

Fiscal year(s) Institute Grant title

Total funding in

dollars

1987-1988 NIAID Study of Sporadic Neurasthenia Associated With Epstein-Barr Virus $928,400

1989-1996 NIAID Chronic Epstein-Barr Virus Infection and CFS 6,001,482

1991-1995 NINDS Neuropsychological Investigations of Human Cognition and Mood State 30,234

1991-1993, 1995 NIMH CNS Role in the Susceptibility to Inflammatory Illness 428,000

1992-1993 NINDS Combined Clinical, Viral, and Immunological Studies of Neuromuscular

Diseases

6,125

1993-1994 NCI Epidemiology Studies and Basic Research Related to CFS Outbreaks and

Characterization of the Viruses Associated With CFS

399,000

1993-1994 NCI Support for Physicians Treating CFS Patients by the National Physicians

Advisory Group

706,000

1993, 1995-1999 NIMH Neurobiology of Unipolar Depression 1,033,808

1994, 1998 NICHD Dose-Response Relationships for Single Doses of Recombinant Human

Interleukin-6 in Normal Volunteers and in Patients With Disorders of the

Hypothalamic-Pituitary-Adrenal Axis

30,000

1995 NCI Identification of Human Genetic Loci Which Influence Susceptibility to HIV 115,000

1995 NCI Regulation of Viral and Cellular Gene Expression 30,000

1995 NCI Genetic Variation in Infected Hemophiliacs Over Time 30,000

1997-1998 NIAID Multidisciplinary Studies of CFS 1,795,181

1997-1999 NIAID Trial of Fludricortisone for Patients With CFS 524,488

Total funds $12,057,718
Appendix IV

NIH Research Efforts and Grants

Page 50 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Table 5: NIH-Funded Grants and Projects Not Including R01 (Research Project) Grants and Intramural Projects Related to CFS

Fiscal year(s) Institute Grant title

Total funding in

dollars

1987-1996 NIAID Pathogenesis of Epstein-Barr Virus Infections $2,896,620

1989 NCRR Prevalence of CFS in Ambulatory Medicine 3,949

1989 NCRR Immunologic and Virologic Studies of CFS 188

1990 NCRR Sleep and Cytokines in CFS 21,178

1990 NCRR Involvement of a Human Retrovirus in CFS 8,531

1990 NCRR Analysis of Clinical and Biological Characterization of CFS 350

1991 NCRR Psychology and Immunology of CFS and Other Disorders With Severe Fatigue 2,609

1991 NCRR Acute Experience: Stress and Immune Function in CFS Patients 3,447

1991-1992 NCRR Ampligen in Patients With CFS and Associated Encephalopathy 103,584

1992-1993 NCRR Electroencephalogram Sleep in CFS 6,170

1993-1996 NCRR Exertion Induced Cytokines in CFS 147,883

1993, 1996 NIAID Coordinating Center for Clinical and Epidemiologic Studies in Infectious

Diseases

21,567

1993-1997 NIAID Social Processes and Somatization—The Course of CFS 625,463

1993, 1995-1999 NCRR Phosphocreatine Recovery in Women With CFS 111,802

1994-1995 NIAMS Cytotoxic T Lymphocyte Mediated Cutaneous Immunity to Melanoma 185,399

1994-1995 NIAMS Molecular Basis of T-Cell Helper Function 92,610

1994-1995 NIAMS Molecular Determinants of Epstein-Barr Virus Tropism 171,203

1995-1996 NCRR Neuropsychological Disturbance in CFS 65,584

1995-1997, 1999 NCRR Exercise Intolerance in CFS 44,027

1995 NCI Viruses and Oncogenes in Hematopoietic Malignancies 102,000

1996 NCRR In Vitro Effects of Interleukin 2 on Activity of Natural Killer Cells in CFS 273

1996 NIAID Operations and Technical Support 444,673

1996 NCRR Clinical Application of Deoxymyoglobin Technique: Peripheral Vascular

Disease or CFS

28,718

1996 NIAID 1996 Scientific and Clinical Meeting, CFS 2,000

1996 NCRR Microbial Genomic Sequencing in Emerging Disease With Unknown Etiology:

Kawasaki, CFS

121,392

1997-1998 NCRR Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fibromyalgia 130,814

1997 NCRR Comparative Study of Pathophysiologic Descriptors of CFS 1,912

1997-1998 NCRR Trial of Fludrocortisone for CFS 25,119

1997-1998 NCRR Regulation of Adrenal Function in Fibromyalgia 129,609

1997 NCRR Immunoneuroendocrine Response to Tetanus Toxoid 19,690

1998 NCRR Psychiatric Diagnosis and Biological Markers in Neuresthenia, CFS, and

Depression

18,516
Appendix IV

NIH Research Efforts and Grants

Page 51 GAO/HEHS-00-98 Chronic Fatigue Syndrome

1998 NIAID CFS in Adolescents, Workshops 12,855

1999 NCRR Mitochondria in CFS Pathology 178

1999 NCRR Models for Induction of CFS 18,933

1999 NCRR Psychoimmunological and Neuroendocrinological Response 315

1999 NCRR Mechanisms of Rhinitis in CFS 47,865

1999 NCRR Skeletal Muscle in Persian Gulf Veterans With CFS 21,009

1999 NIAID Diagnosis and Treatment of CFS 250,000

1999 NIAID Venous Dysfunction in CFS 73,247

1999 NIAID Siberian Ginseng for the Treatment of CFS 67,827

Total funds $6,029,109

(Continued From Previous Page)

Fiscal year(s) Institute Grant title

Total funding in

dollars
Appendix IV

NIH Research Efforts and Grants

Page 52 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Table 6: NIAID Cooperative Research Center Projects Related to CFS

Fiscal year(s) Grant title

Total funding in

dollars

Brigham and Women’s Hospital (1991-1995)

1991-94 CFS, Fybromyalgia, and Depression $949,384

1991-94 Cytokines and CFS 543,244

1995 Core A 100,001

National Jewish Center for Immunology/Resp. Med. (1992-1995)

1992-94 Clinical Research on CFS and Quantification of Fatigue 411,666

1992-94 Developmental Research on CFS and Quantification of Fatigue 56,248

1992-95 Quantification of Fatigue in CFS 307,404

1992-95 Allergic Inflammatory Reactions in CFS 414,161

1992-95 Neurophysiologic Disturbance in CFS 486,392

1992-95 Neuropsychiatric Features of CFS 374,651

University of Medicine and Dentistry of New Jersey (1991-1995, 1995-1998, 1999-present)

1991-95 Classification of CFS Patients 1,533,813

1991-95 Virology Assessment of CFS Patients 568,659

1991-94 Immunological Assessment of CFS Patients 586,658

1995-98 Administrative and Data Analysis Core 841,868

1995-98 Categorization of CFS Patients 1,675,787

1995-98 Exercise, Fatigue, and Training 1,209,745

1999 Brain and Cardiovascular Studies 302,089

1999 Physiological Challenges in CFS 203,178

1999 Statistical and Data Core 238,008

University of Washington (1995-1998, 1999-present)

1995-99 Clinical Core 321,819

1995-98 CFS: Neuropsychological, Neuroendocrine, Sleep Function 493,145

1995-98 Immunology and Virology of CFS in Monozygotic Twins 662,290

1995-98 Biological/Psychosocial Factors: Post-Infectious Fatigue 490,453

1995-98 Prognosis of CFS 525,887

1999 Monozygotic Twins With CFS—Predisposition of Perception 269,612

1999 Population Based Twin Study of CFS 202,822

1999 Biostatistical and Data Management 140,142

1999 Children of CFS Patients 140,082
Appendix IV

NIH Research Efforts and Grants

Page 53 GAO/HEHS-00-98 Chronic Fatigue Syndrome

University of Miami (1999-present)

1999 Cognitive-Behavioral Stress Management Intervention for CFS 136,299

1999 Effect of Stress and Cognitive-Behavioral Stress Management on Natural Killer Activity in CFS 61,147

1999 Laboratory Assessment 153,311

Total funds $14,399,965

(Continued From Previous Page)

Fiscal year(s) Grant title

Total funding in

dollars
Page 54 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix V

Congressionally Requested CFS Activities for

CDC and NIH ApendxiV

CDC Response to

Congressional

Committee Requests

for CFS Activities

CDC has initiated work on most CFS activities requested in congressional

committee report language. However, procedures for ensuring that the

branch chiefs responsible for the work were aware of congressional

expectations have only recently been established. Agency officials reported

that while CDC has distributed to the centers the relevant portions from

House, Senate, and conference appropriations reports, it has only been

since the arrival of an associate director for management at the Division of

Viral and Rickettsial Diseases in 1997 that this report language has been

disseminated to the division’s branch chiefs responsible for planning the

research.

Of the 33 requested CFS activities, 3 are planned for this fiscal year (see

table 7). CDC reports that it plans to initiate a national survey in 2000, but it

is unclear that this will include a surveillance component as suggested in

congressional committee reports in 1998. CDC also reports it will begin

planning for the establishment of a CFS patient registry in fiscal year 2000

as suggested by report language in 1991. This patient registry will also

allow CDC to address the third area of congressional interest, suggested in

1997: developing a CFS brain tissue repository.

Table 7: Congressionally Requested CFS Activities for CDC

Activity requested

Year(s)

requested Year(s) started

Develop and implement a surveillance network. 1988 1988

Expand surveillance system to all states. 1988 a

Increase level of research support. 1988 1988b

Work with Nevada. 1988 1990

Expand sentinel surveillance. 1989, 1990 1990

Expand study on link between CFS and human herpesvirus-6. 1989 1992

Continue attempts to detect persistent virus infections in CFS patients and to develop appropriate

controls.

1989 1992

Expand surveillance to Nevada. 1989 1990

Enroll patients in case studies. 1990 1990

Investigate suspected clusters. 1990 1985

Train and educate physicians and health workers about CFS. 1990, 1998 1990

Develop information for the general public to increase the general understanding of CFS. 1990 1990

Expand research on immunologic abnormalities. 1990 1992

Provide CFS information, outreach, conference, and training activities. 1991 1991

Refine CFS definition. 1991 1991
Appendix V

Congressionally Requested CFS Activities

for CDC and NIH

Page 55 GAO/HEHS-00-98 Chronic Fatigue Syndrome

a

National survey planned for 2000.

b

Funding levels show an increase since 1988.

c

Meeting planned.

d

Does not include pregnant women.

e

Findings presented.

f

CDC has found no evidence that CFS is transmissible.

g

Data used as pilot of Wichita study.

h

Etiology studies began in 1996; brain tissue repositories in 2000.

i

Hiring in process.

Study the establishment of a CFS patient registry. 1991 2000c

Develop recommendations to the U.S. biomedical community on standardized clinical data

collection instruments and procedures for evaluating functional health status in CFS.

1991, 1992 1994

Advise on the establishment of standardized protocols for CFS laboratory tests. 1991, 1992 1994

Store serum and leucocyte samples from CFS patients for future testing. 1991, 1992 1992

Expand immunological, virological, and toxicological studies of CFS. 1993 1992

Expand CFS research activities, including research on the relationship of CFS to pregnancy, a study

of CFS patients in remission to monitor the long-term effects of the disease, and research on the

impact of CFS on health professionals.

1993 1994d

Make available to interested parties preliminary and pending data related to the CFS surveillance

system, data from the case-control study that began in June 1992, and data related to CDC

responses to cluster outbreaks of CFS.

1993 1990e

Expand the surveillance system to 8- to 18-year-olds 1993 1992

Conduct community-based prevalence studies to collect data on endemic cases and possible

cluster outbreaks and to document the basic epidemiology of CFS.

1995 1993

Support four studies on possible transmission routes, especially among health care workers, family

members, and maternal transmission to unborn children.

1995, 1996 f

Provide education programs, as appropriate. 1995, 1996 1997

Complete and expand current CFS surveillance projects. 1996 1996

Commence a case-control phase of the community-based surveillance study recently completed in

San Francisco.

1996 1997g

Consider implementing the review panel’s recommendations, particularly in the areas of etiology

studies and brain tissue repositories.

1997 1996, 2000h

Enhance CFS laboratory studies and surveillance projects, including outreach to populations not

previously recognized as being affected by CFS, especially minorities, children, and adolescents.

1998, 1999 1997

Encourage continuation and expansion of studies of adolescents and children. 1998 1993

Add a neuroendocrinologist to research group. 1998, 1999 1999i

Initiate studies on rates of CFS among health care workers, family members of CFS patients, and

pregnant women.

1998 1994d

(Continued From Previous Page)

Activity requested

Year(s)

requested Year(s) started
Appendix V

Congressionally Requested CFS Activities

for CDC and NIH

Page 56 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Within these activities, however, CDC is not pursuing or considers

infeasible the following areas of congressional interest: investigating the

relationship of CFS to pregnancy (part of an activity requested in 1993);

supporting four studies of possible transmission routes (requested in 1995

and 1996); commencing a new phase of the community-based surveillance

study completed in San Francisco that compared CFS patients to healthy

controls (requested in 1996); and initiating studies on the rates of CFS

among pregnant women (part of an activity requested in 1998). CDC

reported justifications for a number of these unaddressed areas. For

example, the agency has not conducted and does not anticipate studying

pregnant women because the low age-specific prevalence rate suggests

that pregnant women would rarely be affected and human subjects and

ethical considerations preclude such studies. Further, while it has

conducted studies of transmission since 1985, the agency was not aware of

the four transmission studies referred to in the report language. Finally,

while the San Francisco study was used as a pilot for the Wichita

surveillance study, CDC reported that it was not possible to compare CFS

patients with healthy individuals in San Francisco due to the nature of that

study.

NIH Response to

Congressional

Committee Requests

for CFS Activities

NIH has been asked to pursue CFS work in 34 areas by congressional

appropriations committees (see table 8). Five activities have not been

pursued or are considered by NIH to be infeasible: expand research in

identification of eventual cure (requested in 1988); expand research on

genetic disposition and allergy, immune and neurological systems

(requested in 1991); designate reference laboratories for CFS (requested in

1991); compile a CFS patient registry (requested in 1992); and address care

needs, including the education of providers in assessment, diagnosis and

treatment, case management, and rehabilitative efforts (requested in 1999).

NIH reported that all CFS research efforts are designed to find an eventual

cure. However, because so little is currently known about CFS, the agency

has not reported any specific activities directly related to a cure (although

it has initiated some studies of possible treatments) or to direct linkages

between genetic disposition and allergy, immune, and neurological

systems. NIH considered establishing a CFS patient registry but

determined that it was not feasible and that it was more part of CDC’s

purview. Finally, NIH reported to the appropriations committees that the

language regarding care needs was more appropriate for HHS’ Health

Resources and Services Administration.
Appendix V

Congressionally Requested CFS Activities

for CDC and NIH

Page 57 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Table 8: Congressionally Requested CFS Activities for NIH

Activity requested

Year(s)

requested Year started

Expand research in search for a diagnostic technique. 1988 1992

Increase efforts to discover cause and treatments. 1988, 1994 1991

Expand research in identification of an eventual cure. 1988

Consider use of the small grants program for research on the chronic Epstein-Barr virus syndrome. 1988 1991

Locate additional research in Nevada. 1989 1991

Conduct research on understanding and correcting immune system damage. 1990 1991

Study the feasibility of establishing a research center for CFS studies, including collecting and

analyzing clinical and laboratory data on patients.

1990 1991

Issue a request for applications on CFS to increase the number of extramural research grants funded. 1990 1991

Solicit and fund additional research grants. 1991 1991

Initiate a consortium of research centers for CFS research, preferably at the Universities of Nevada

and Minnesota.

1991 1992

Expand research with other institutes. 1991 1991

Expand biomedical meetings. 1991 1992

Increase extramural and intramural research studies. 1991 1991

Report annually to the Congress on activities related to CFS. 1991, 1992, 1993 1991

Conduct a conference in fiscal year 1991 on NIH activities related to CFS. 1991 1991

Expand research on genetic predisposition and allergy, immune, and neurological systems. 1991

Designate reference laboratories and facilitate data exchange among institutions in the geographic

areas in which CFS concentrates.

1991

Designate a senior agency official to act as CFS coordinator. 1991 1991

Establish a multidisciplinary study section for CFS. 1992, 1993 1993

Establish a standing study section for CFS. 1993 1993

Compile a CFS patient registry. 1992

Study the feasibility of establishing a central clearinghouse for CFS data . 1992 1992

Make grants to, or enter into contracts with, public or nonprofit entities for the development and

operation of centers to conduct basic and clinical research on CFS.

1993 1993

Ensure that individuals who have expertise in CFS or neuromuscular diseases and are representative

of a variety of disciplines and fields are appointed to appropriate NIH advisory committees and

boards.

1993, 1998, 1999 1993

Establish procedures to enable the patient community to provide input to the direction of CFS

research at NIH.

1993 1993

Consider increasing opportunities for CFS patients and researchers to participate in advisory

committees.

1993 1993

Conduct studies that continue to look into retrovirus activity and other areas of infectious disease

pathogenesis.

1994 1994
Appendix V

Congressionally Requested CFS Activities

for CDC and NIH

Page 58 GAO/HEHS-00-98 Chronic Fatigue Syndrome

a

Workshop.

b

Recompeted.

Direct resources to extramural grants focused on promising areas of biomedical research and to

investigations seeking to identify etiological agents and markers for the pathophysiology of CFS.

1996, 1998 1996

Appoint a CFS coordinator with NIAID-wide authority. 1996, 1998 1996

Include other agencies, such as CDC and HHS’ Health Resources and Services Administration, in the

planning and execution of the workshop on pediatric CFS.

1998 1998

Recommend that the Office of Research on Women’s Health develop a strategy to address chronic

pain syndromes in women.

1998 1998a

Use all mechanisms, including program announcements, to study all facets of pediatric CFS. 1999 1996

Address care needs, including the education of providers in assessment, diagnosis and treatment,

case management, and rehabilitative efforts.

1999

Establish chronic fatigue assessment and treatment centers. 1999 1999b

(Continued From Previous Page)

Activity requested

Year(s)

requested Year started
Page 59 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix VI

External Review Recommendations to CDC

and NIH ApendxiVI

Recommendations to

CDC

CDC’s 1996 peer review, conducted by four scientists and two patient

advocates, noted that considerable progress had been made, specifically

outlining some strengths of the CFS program. The review team recognized

CDC’s critical leadership role in the development of a case definition, the

valuable studies the agency had conducted on the rate of recovery from

CFS, and the agency’s effort to study retroviral agents as a cause of CFS.

The report also included several recommendations: four general

recommendations, nine recommendations related to work conducted up to

that time, three recommendations related to proposed future studies, and

two recommendations related to possible additional research areas. For

the most part, CDC has undertaken activities in response to these

recommendations. (See table 9.)

Table 9: Recommendations From CDC’s 1996 Peer Review and Agency Response

Recommendation CDC response

General recommendations

CDC’s CFS team should enhance its communications and

collaboration with NIH; NIH should regularly inform CDC about

ongoing progress and the results of both its intramural and its

extramural research programs on CFS, and CDC should regularly

inform NIH about ongoing progress and the results of its ongoing

studies. It appears that HHS’ CFS Coordinating Committee

(CFSCC) concentrates primarily on discussing the intramural

research programs at NIH and CDC.

CDC and NIH regularly provide updates to members of CFSCC and

attendees at that meeting regarding their respective CFS programs.

CDC’s CFS program should be regularly reviewed by an external

review group.

Subsequent to this 1996 review, CDC’s CFS program was reviewed

in 1999—the most recent external peer review.

Provided the Viral Exanthems and Herpesvirus Branch can

develop additional expertise in the fields of neuroendocrinology

and neuropsychology, the placement of the CFS program within

that branch continues to be appropriate.

The Viral Exanthems and Herpesvirus Branch is developing

expertise in neuroendocrinology and neuropsychology through

agreements with Emory University.

CDC’s CFS program should continue its ongoing active dialogue

with patient advocacy groups.

Meeting held at CDC in October 1999.

Recommendations related to program accomplishments to date

Statistical techniques, such as cluster analysis and discriminant

function analysis, should be used to assess the robustness of

findings related to case definition, and these same statistical

techniques (including factor analysis) should be applied to other

data sets as they emerge.

Standard operating procedure.

Investigations of potential clusters of cases should begin as early

as possible after the onset of the putative outbreak to ensure the

highest likelihood of identifying an etiologic agent.

Program begins investigations of reported clusters as early as

possible. Emphasis in both cluster investigations and population

studies is to detect and study incident CFS cases.
Appendix VI

External Review Recommendations to CDC

and NIH

Page 60 GAO/HEHS-00-98 Chronic Fatigue Syndrome

CDC should write a formal assessment of the reasons for the

considerable differences in the observed prevalence rates from

different studies, besides differences in the completeness of the

case ascertainment techniques across the studies.

Done in discussion of newest prevalence manuscript to be

submitted for publication.

CDC should comment on the possible biological implications of

some of the differences in prevalence it has observed in different

age, gender, and socioeconomic groups.

Done in discussions of all appropriate manuscripts.

Future studies should focus on prevalence in children and geriatric

populations. Widely repeated anecdotal evidence indicates that

teachers, airline workers, and health care workers may be

differently affected. (To some extent, such possible occupational

associations have been evaluated already in the San Francisco

study, but it is not clear whether the sample size of this crosssectional observational study allowed confident conclusions.)

—Wichita surveillance includes all residents 2 years and older.

—The National Survey (planned for fall 2000) will give special

emphasis to children.

—The National Survey will collect detailed information on possible

occupational associations with CFS.

CDC should continue some studies of the possible role of human

herpesvirus 6 in CFS. The group strongly supports further study of

Borna disease virus. CDC should also study the relationship of

other known or newly-discovered microorganisms that could, on

the basis of their association with other similar illnesses or their

tissue tropism, be potential triggering agents or cofactors for CFS.

—CDC’s most recent study of the possible associations between

CFS and human herpesvirus 6 and 7 found no association.

—CDC supported additional studies of Borna disease virus, which

found no association with CFS.

—The Viral Exanthems and Herpesvirus Branch is developing

expertise in identification and characterization of novel infectious

agents possibly associated with CFS.

A regular formal process should be instituted for reviewing and

updating information for the public. In particular, these updates

should reflect all published research, whether conducted at CDC or

elsewhere.

Standard operating procedure for CDC programs. Program does not

have resources to maintain and disseminate data on all published

CFS research.

CDC’s Internet web site should include a written summary of all

programs and all work on CFS currently under way at CDC. Printed

copies of the information should be available to those who do not

have access to the Internet. The web site might also contain a “Hot

Topic” button that provides brief, timely statements about CFSrelated issues that have been highly visible in the media.

—The web site now includes a summary of all new CDC work on

CFS.

—Printed copies of information are available to those without

Internet access. CDC operates a CFS voice information system that

offers the option of receiving printed materials. CDC also provides

such information in response to written queries.

—The web site contains a Hot Topics button.

Each public document about CFS and each public presentation

and media interview about CFS should state clearly and

prominently that CFS is a “priority one emerging illness.”

NCID no longer uses this classification.

Recommendations related to proposed future studies

Some follow-up beyond a 1-year review in Wichita should be

planned with at least a sample of the cases (and noncases)

identified during the initial year. The study should attempt to

assess the level of debility/functional status in this population. The

study should also follow a sample of patients who report

debilitating chronic fatigue but who do not fully meet CDC’s case

definition of CFS.

—Approximately 8,000 subjects who completed detailed interviews

during the initial survey have been followed for 3 years. In addition to

monitoring the clinical courses of the disease, this measures

incidence of CFS.

—A manuscript describing functional status at baseline is in

preparation. Following the third year of follow-up, analyses will

explore functional status over time.

The representational difference analysis technique should be used

not only with peripheral mononuclear cells but also with tissue

specimens and cerebrospinal fluid, when possible.

—Program determined after review that this technique was not the

most appropriate method and is using other strategies.

—At present, only peripheral blood cells can be collected from

subjects enrolled in population-based studies.

(Continued From Previous Page)

Recommendation CDC response
Appendix VI

External Review Recommendations to CDC

and NIH

Page 61 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Source: Recommendations from “External Peer Review of the Chronic Fatigue Syndrome Research

Program,” August 1996. CDC responses reported to GAO.

Subsequent to the 1996 review, CDC underwent a 1999 peer review and a

review of the Board of Scientific Counselors. These two concurrent

reviews had a consistent message: CDC should look for more opportunities

to collaborate. Specifically, the reviews suggested that NIH researchers

work with some of the tissue samples obtained by CDC from the Wichita

study. The peer review also suggested that there be more professional

education efforts. CDC has many activities planned to address these

recommendations (see table 10).

Table 10: Recommendations From CDC’s 1999 Peer Review, Board of Scientific Counselor Review, and Meeting With Patient

Advocates, and Agency Response

Studies of stress and herpes simplex virus 1 reactivation should

not be supported.

Herpes simplex virus 1 reactivation protocol was stopped.

Recommendations related to possible additional research areas

CDC should develop some collaborations with

neuroendocrinologists to study the hypothalamic-pituitary axis.

Neuroendocrinologist should be on staff (through agreement with

Emory) by September 2000.

CDC could provide an international service by offering to create a

brain bank of specimens available for study, including other tissue

specimens from these same patients, when possible.

CDC will convene a meeting in fall 2000 to initiate this process.

(Continued From Previous Page)

Recommendation CDC response

Recommendations CDC response

General recommendations

Broaden collaborations. Collaborations vary depending on program at the time.

Broaden communication with Council of State and Territorial

Epidemiologists, advocates.

In process.

Broaden availability of patients and specimens to scientific community. Standard operating procedure, depending on program strategy

and priorities and the quality of proposals.

Recommendations related to surveillance

Continue Wichita cohort beyond 3 years. Clinical cohort time frame extended.

Study quality of life, economic burden, patient management, long-term

care, and behavioral and functional sequelae.

A manuscript is being drafted, and CDC is hiring a medical

research officer and conducting clinical studies. CDC also plans

to conduct a national survey.

Explore CFS in families and occupations. A manuscript is being drafted, and CDC plans to conduct a

national survey.

Place more emphasis on adolescents. CDC is welcoming a pediatrician to complete a sabbatical year

at CDC; adolescents will be studied in the national survey.

Use the modified case definition in future studies. Standard operating procedure.
Appendix VI

External Review Recommendations to CDC

and NIH

Page 62 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Source: Recommendations from CDC. CDC responses reported to GAO.

Recommendations to

NIH

NIAID’s National Advisory Allergy and Infectious Diseases Council meets

about three times a year and occasionally has discussed NIH’s CFS

program. In conjunction with those discussions, the council has sometimes

made recommendations to that program. In February 1993, the council

advocated that NIH support specific studies suggested by findings from

case demographics. At its February/March 1994 meeting, the council

Recommendations related to case definition

Consider revising case definition. A workshop was conducted in May 2000 to consider this topic.

Use factor analysis on other databases. In process; planned as part of the May 2000 workshop.

Measure chronic unwellness in the national survey. Survey will be designed to capture such data.

Use factor scores (chronic unwellness) to better weight symptoms and

measure severity.

In process and part of the national survey.

Recommendations related to clinical studies

Recruit a medical research officer. In process.

Convene a review group for endocrine studies. In process.

Design protocols for neuropsychological studies combined with brain

imaging.

Exploring this with Emory University.

Recommendations related to molecular epidemiology

Improve balance of gene expression analysis program. In process.

Develop a program to search for novel uncharacterized infectious

agents.

Was part of the April 2000 Banbury Conference, Strategies for

Identification and Characterization of Unknown Pathogens,

which CDC co-organized and cosponsored.

Recognize CFS as a contagious disease that occurs in clusters. Clusters are examined on request, but CFS does not appear to

be contagious.

Assess risk of transfusion transmission. A statement regarding risk has been released, and CDC

continues to monitor.

Broaden investigations to consider environmental

exposures/toxicology.

There is no evidence from CDC’s case control studies to

support this, but the agency continues to monitor.

Recommendations related to education (focus on health care providers should continue)

Maintain web page. Done.

Develop continuing medical education materials. In process with HHS’ Health Resources and Services

Administration.

Develop national CFS information campaign. CDC maintains a web page, publishes journal articles, and

provides other information.

React to CFS articles in reviewed journals and in popular press. Standard operating procedure, when appropriate.

Explore CFS education in schools and establish liaison with the

Department of Education.

Will follow up, as appropriate.

(Continued From Previous Page)

Recommendations CDC response
Appendix VI

External Review Recommendations to CDC

and NIH

Page 63 GAO/HEHS-00-98 Chronic Fatigue Syndrome

concurred with the need and desirability of continuing and expanding the

CFS Cooperative Research Centers program and reapproved the centers

then and again in September 1997. In September 1995, the Division of

Microbiology and Infectious Diseases subcommittee of the council more

formally assessed the CFS program and determined that NIAID should

retain overall leadership of NIH’s CFS efforts but that a multidisciplinary

research approach should also continue, involving other institutes where

appropriate. At the next council meeting, in May 1996, the division asked

for and obtained approval of a program announcement on CFS, supported

by eight institutes and offices. The subcommittee noted that the initiative

was responsive to its recommendation to both explore new hypotheses of

causes and disease development and to involve other NIH entities in the

CFS research effort. The subcommittee also had a number of specific

scientific suggestions. The areas of study that were recommended included

consideration of multiple disease causes, studies of patients with shorter

duration of illness, longitudinal studies of immune markers correlated with

clinical findings, information about factors predictive of recovery and

recovery rates, the use of tissue samples to test theories involving certain

cell alterations, issues related to pregnancy, and epidemiological research

into CFS in children and adolescents. NIH has conducted investigations in

all but two of these areas (studies of patients with shorter duration of

illness and issues related to pregnancy).

NIH also has an internal coordinating committee for CFS comprised of

representatives from all relevant and interested institutes within the

agency. While this might have been intended initially to serve as a forum for

intraagency communication, it has instead, according to agency officials,

more recently served as a way of providing information for use at the

meetings of HHS’ CFSCC. Further, attendance at the meetings has been

optional, and agency officials reported that representatives from those

institutes that have small programs with only one or two grants rarely

attend.
Page 64 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix VII

NIH Expenditures on CFS Research, by

Institute and Center ApendxiVI

Note: Dollars in thousands.

a

Funding for institutes’ and centers’ projects was below NIH threshold for disease reporting of

$250,000. Because of our review, institutes and centers were asked to more carefully examine their

CFS project funding. Nevertheless, there may be a slight underreporting of CFS funding.

b

NIMH reported total funding for a CFS center project, consistent with its policy to report entire

projects. Following additional review, NIH determined that only a portion of the project was related to

CFS.

c

Due to rounding, figures in total column may not be the sum of institutes’ and centers’ yearly

expenditures.

Fiscal year NCI NCRRa NHLBI NIAID NIAMSa NICHDa NIMHb NINDSa Totalc

1987 $0 $0 $0 $782 $0 $0 $0 $0 $782

1988 0 0 0 988 0 0 0 0 988

1989 0 4 0 1,472 0 0 0 0 1,476

1990 0 30 0 1,793 0 0 0 0 1,823

1991 0 25 0 2,710 0 0 112 15 2,861

1992 0 86 0 2,978 0 0 417 11 3,492

1993 550 38 0 3,841 0 0 1,311 6 5,746

1994 555 56 0 4,226 218 10 1,107 4 6,175

1995 560 103 0 5,252 231 0 1,226 1 7,372

1996 0 249 0 4,984 0 0 1,341 0 6,574

1997 0 222 0 4,966 0 0 1,491 0 6,678

1998 0 134 819 4,233 176 20 1,406 0 6,787

1999 0 138 794 4,434 209 0 1,156 161 6,892
Page 65 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix VIII

NIH Activities in Support of CFS Research ApendxiVI

NIH has issued four program announcements to stimulate research on CFS.

The first, a program announcement initiated by NIAID in 1987, targeted

studies in the epidemiology of CFS and chronic Epstein-Barr virus infection

to advance understanding of the prevalence, causes, and natural history of

these syndromes.1 In 1992, NIAID initiated a program announcement that

called for applications to explore biologically rational hypotheses

concerning exercise-induced fatigue and/or disease origin and

development in CFS patients. In 1994, NIH issued its first joint program

announcement—with NIAID, NIAMS, and NIMH—calling for studies on the

causes, natural history, and origin and development of CFS. This

announcement listed 10 different areas that merited further study,

including low levels of cortisol, sleep disturbance, demographic risk

factors, and increased frequency of psychiatric diagnoses in CFS patients.

The most recent program announcement was issued in 1996 and involved

eight different units within NIH. This program announcement was designed

to support studies of CFS’ functional effects on the body, ideally addressing

new hypotheses and research gaps, or small studies exploring new ideas.

This program announcement listed 23 areas needing additional research.2

NIH officials told us they established a CFS Special Emphasis Panel for the

review of CFS grant applications for a number of reasons, including

demonstrating the agency’s commitment to CFS research, because CFS is

little understood and because so few applications for CFS were being

received. The panels were designed to help facilitate consideration and

scoring of CFS grant applications that might otherwise not receive scores

favorable enough to be funded if reviewed by a standing study section.

Members are selected for a special emphasis panel after grant applications

are received so that those with appropriate expertise are appointed to

serve as reviewers. Like all review panels, members of the CFS Special

Emphasis Panel are external researchers, not employees of NIH. An NIH

official told us that most applications that have gone to the CFS Special

Emphasis Panel have received better scores than they would have if they

had gone to a standing study section. At the National Advisory Allergy and

Infectious Diseases Council meeting in February 1993, the chief of the

Virology Branch commented that the application review process had

1

At the time, some experts believed there might be a relationship between CFS and EpsteinBarr virus.

2

These areas included overlapping symptomatology with neurally mediated hypotension,

the role of cardiovascular regulatory centers, role of neuroendocrine and neuroimmune

functions, hormonal effects, and the role of environmental agents.
Appendix VIII

NIH Activities in Support of CFS Research

Page 66 GAO/HEHS-00-98 Chronic Fatigue Syndrome

improved significantly since the establishment of a special emphasis panel

for CFS. To date, of the applications reviewed by the CFS Special Emphasis

Panel, a total of 30 extramural grants (R01 grants, or research projects)

have been funded. (See app. IV.)

The CFS Special Emphasis Panel was designed to help improve the

chances of CFS grants getting funded. During fiscal years 1988 through

1999, the funding rate for CFS was 24.32 percent versus 28.31 percent for

all grants across the same institutes that fund CFS research. It is plausible

that the quality of CFS applications has been inferior to the quality of those

in other areas, accounting for the lower rates. It is also plausible that this

rate of funding is indeed higher than it would have been had the

applications been reviewed by standing panels.

The agency has used an additional approach for facilitating the funding of

CFS research. NIH has a process for all areas of research, called “selective

payment,” designed to provide funding to a small number of applications

that are programmatically important but not rated favorably enough to

receive funding. From 1992 through 1996, six CFS applications were

funded—all by NIAID—through this process. NIH’s description of the

selective payment process states that it is designed to support applications

that received scores just beyond the funding cut-off; however, the CFS

applications funded through this process were, in fact, ranked quite

poorly.3 NIAID appears to have made extra efforts to fund some CFS

research.

In addition to these efforts, NIH has issued three requests for applications

for CFS Cooperative Research Centers since 1991. The centers are

designed to augment the existing grant program and to provide a sustained

multidisciplinary approach to CFS research. The intent is to advance the

field by bridging the basic science and clinical research arenas and

facilitating confirmatory testing and follow-up of new hypotheses and

observations. The purpose of the initial request for applications, issued in

1991, was to stimulate the establishment of centers of CFS research

excellence in which coordinated projects in the fields of immunology,

virology, medicine, and clinical epidemiology could be pursued. These

3

The percentile rankings of all CFS applications funded under the selective payment

program ranged from 53.7 to 75—well above what would be expected with just over 28

percent of the applications being funded overall. A high percentile ranking is assigned to

applications with poor scores and a low percentile ranking is assigned to those with good

scores.
Appendix VIII

NIH Activities in Support of CFS Research

Page 67 GAO/HEHS-00-98 Chronic Fatigue Syndrome

awards were for a period of up to 4 years, with funds set aside for this

purpose. NIAID funded three centers with the fiscal year 1991 request for

applications, two with the second request in fiscal year 1995, and three with

the final request in fiscal year 1999. Under the last request for applications,

funds had been set aside for only two centers. However, few CFS grant

applications had been funded that year, and we were told that, because the

agency wanted to spend money on CFS research, the extra grant funds

were used to support a third center.

NIH Grant Process NIH’s institutes and centers award grants to nonprofit and for-profit

organizations; institutions of higher education; hospitals; research

foundations; governments and their agencies; and, occasionally,

individuals. Applications are usually initiated by the principal investigator,

signed also by an authorized official of the applicant institution, and these

are received by NIH’s Center for Scientific Review. Approximately 37,000

grant applications are processed each year. Applications are ordinarily

unsolicited, but NIH may encourage the submission of grant applications

on particular topics through the use of one of two special devices: program

announcements—which describe continuing, new, or expanded program

interests—and requests for applications, which invite applications in a

well-defined scientific area and for which specific funds have been

earmarked and a special review process has been designed.

Within the Center for Scientific Review, all applications that are competing

for funds are assigned to a specific institute or center and to an integrated

review group. The institute or center chosen is the one that may eventually

have the opportunity to fund the research. The review group chosen is the

one that would be most appropriate for assessing the scientific merit of the

research grant application.

An integrated review group is a chartered organization divided into study

sections, each of which is composed of 12 to 20 mostly nonfederal

scientists who are selected for their competence and generally serve 4-year

terms. These members are sent copies of the relevant applications about 6

weeks before the study section’s scheduled meeting; for each application,

specific members are chosen to provide written reviews or to act as

discussants. A special emphasis panel operates like a study section in that

it peer reviews applications, but it is formed on an ad hoc basis, and it

reviews applications on only a relatively specific topic.
Appendix VIII

NIH Activities in Support of CFS Research

Page 68 GAO/HEHS-00-98 Chronic Fatigue Syndrome

One week before a study section meets, the Scientific Review

Administrator from the Center for Scientific Review solicits from all

members a list of applications believed not to rank in the top half for

scientific merit. The individual lists are compared and those on all lists are

not discussed at the meeting. At a meeting of the study section, the review

administrator and a chairperson from the study section jointly conduct the

peer review, which usually lasts 2 days. Observers, such as program staff

from the relevant institutes and centers may attend but do not participate

in the discussions. Reviewers and discussants assigned to an application

provide their evaluations. Then, after a general discussion, members mark

their priority scores privately for each application. Average priority scores

and percentiles are eventually generated for each one as summary

outcomes of this peer review process. The review instructions are the same

for standing study sections and special emphasis panels.

Applicants are provided with detailed feedback from the study section

meeting in about 6 to 8 weeks, but final decisions about awards depend on

further steps centering around a second level of review by the institute’s

advisory council. For NIAID, the National Advisory Allergy and Infectious

Diseases Council conducts this second review. This council and the

equivalent councils or boards in other institutes and centers are

responsible, by law, for the final external review of all grant applications

recommended for further consideration. Its members represent health,

science, and the public. The second level of review is designed to evaluate

applications in relation to the needs of the institute or center and the

priorities of its director. The council may concur with the review group (or

special emphasis panel) recommendations or it may vote to change the

first-level review recommendations via several different mechanisms. This

can include applications selected for funding under selective payment.

Selective payment requires that an institute or center reserve a portion of

extramural research funds for applications that meet programmatic needs

but are scored at the margin of the pay cut-off. Generally, studies are

identified for selective payment by the institute or center director and are

evaluated by the unit’s advisory council.
Page 69 GAO/HEHS-00-98 Chronic Fatigue Syndrome

Appendix IX

Comments From the Department of Health

and Human Services ApendxiIX
Appendix IX

Comments From the Department of Health

and Human Services

Page 70 GAO/HEHS-00-98 Chronic Fatigue Syndrome

See comment 1, p. 73.
Appendix IX

Comments From the Department of Health

and Human Services

Page 71 GAO/HEHS-00-98 Chronic Fatigue Syndrome

See comment 2, p. 73.

See comment 3, p. 73.

See comment 4, p. 73.

See comment 5, p. 73.
Appendix IX

Comments From the Department of Health

and Human Services

Page 72 GAO/HEHS-00-98 Chronic Fatigue Syndrome
Appendix IX

Comments From the Department of Health

and Human Services

Page 73 GAO/HEHS-00-98 Chronic Fatigue Syndrome

GAO Comments 1. Our draft report acknowledged that agency officials told us that

communication between agency scientists occurs on an informal basis

and that much of the research funded by the agencies is extramural in

nature. Moreover, we did not question whether CDC or NIH officials

communicate with each other. Rather, we reported that we found no

evidence of collective research resulting from this informal

communication.

2. We noted in the draft report a number of misperceptions that patient

advocates seem to have about the work at NIH. For example, regarding

patient advocates’ concern about the lack of research on mycoplasma,

we note that the agency has not received grant applications on

mycoplasma; therefore, NIH is unable to fund such work. We also note

that the agency has not disproportionately funded research on issues

related to CFS and mental health.

3. We noted in multiple places in the draft report that only one planned

study—on CFS in adolescents—was not initiated by CDC because of

insufficient funds and that the agency later determined the study would

be infeasible. However, CDC now has activities planned in at least five

areas, using $12.9 million the agency is providing to replace funds

previously redirected. This suggests that had those funds been available

at the time they were budgeted and had adequate planning occurred,

these activities could have been initiated earlier.

4. There is no objective way for either NIH or us to know how the use of a

special emphasis panel to review grant applications has influenced the

scoring and funding of those applications. We have added to our report

that agency officials believe that review by the special emphasis panel

improves the chances that a grant application will get a fundable score.

5. The state of the science meeting was originally discussed during the

April 1999 meeting of CFSCC and was planned to run in conjunction

with the fall meeting of the committee. According to documents we

received, meetings began in August 1999 between agency officials and a

patient advocate member of CFSCC around planning the state of the

science meeting. In October 1999, members of CFSCC were informed

by the executive secretary of the committee that the state of the

science meeting would not take place at the same time as the fall

committee meeting because many of those who were invited were

unable to attend on the dates selected. The October communication
Appendix IX

Comments From the Department of Health

and Human Services

Page 74 GAO/HEHS-00-98 Chronic Fatigue Syndrome

also indicated that members of CFSCC would be informed as soon as a

new date was selected, presumably so they could plan to attend the

meeting. While the meeting was briefly discussed at CFSCC’s

November 1999 meeting, the draft minutes of that meeting do not make

clear that the meeting would no longer be public. It was not until

December 1999 that an agency official reported to a CFS professional

association that the meeting would not be open to the public. It was

some time later that CFSCC members were invited to observe the

meeting. However, they were not consulted in the agency’s decision to

shift the focus of the meeting from informing CFSCC on the current

state of the science to an NIH CFS consultation. The draft report noted

that CFSCC members raised concerns about the participants in general,

as well as a number of specific participants invited to attend.

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