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 ROBERT B. BRIGHAM ARTHRITIS AND MUSCULOSKELETAL DISEASES
                 CLINICAL RESEARCH CENTER
A.      OVERVIEW

        The Robert. B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center (ARC) is a
focus for interdisciplinary clinical research in arthritis and musculoskeletal diseases at Harvard. The Center
complements vigorous programs in basic research and innovative therapies in RA with studies emphasizing
theory-driven, quantitative, interdisciplinary, patient- and action-oriented research to improve patient outcomes.
These include the development and critical evaluation of innovative health care programs and development of
basic methodologies in human research and improved understanding of basic theory.

        Our early work identified the needs of patients with rheumatic diseases, developed the conceptual
framework and the metrics of outcomes research, and evaluated health care innovations. These themes are
continued in this current application with three proposals which we believe help to solve patients‟ problems and
break new methodological and theoretical ground as they seek to develop new knowledge to improve patient
outcomes.

        HISTORY OF INSTITUTION AND MAMDC

         The Division of Rheumatology, Immunology and Allergy and the Department of Orthopedic Surgery of
the Brigham and Women‟s Hospital are devoted to patient care, teaching, and research in rheumatic and
musculoskeletal diseases. The hospital that housed these original units, the Robert B. Brigham Hospital, shared
the family name and architectural style with its sister institution, the Peter Bent Brigham. Robert B. Brigham
followed his uncle Peter to Boston, made his mark in the restaurant business, and bequeathed his estate to
establish a hospital, the Robert Breck Brigham for Incurables (1914), a name it maintained until it was mercifully
shortened to Robert B. Brigham Hospital in 1956. Originally founded as an institution for indigents which
„chronic or incurable diseases or permanent disability,” it became the first teaching hospital in the country
devoted to arthritis and related diseases.

        A free-standing Department of Rheumatology, Immunology and Allergy was established in 1966 under
the leadership of Dr. K. Frank Austen, Theodore B. Bayles Professor of Medicine at Harvard Medical School, and
Dr. John R. David, Professor of Medicine at Harvard Medical School. Shortly thereafter, the faculty was joined
by Dr. Peter H. Schur. When first formed, the Division had five postdoctoral fellows, three full-time faculty
member, eight part-time faculty members, including Dr. Theodore B. Bayles, J. Sydney Stillman, and Arthur Hall.
Since that time, the Department has experienced steady growth. Dr. Michael Brenner succeeded Dr. Austen and
holds the chair endowed in his honor. Dr. Brenner is a success story of the original Multipurpose Arthritis Center
(MAC) program which evolved into this Center. His MAC Developmental and Feasibility grant led to his first
successful R01 application.




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CURRENT FACULTY
Those bolded represent past and current ARC investigators.

Assistant Professors, Associate Professors, Professors
K. Frank Austen, MD                            Theodore B. Bayles Professor
Paul J. Anderson, MD, PhD                      Assoc. Prof.
Ronald J. Anderson, MD                         Assoc. Prof.
Jonathan Arm, MD                               Asst. Prof.
Hamid Band, MD PhD                             Assoc. Prof.
Joshua Boyce, MD                               Asst. Prof.
Michael Brenner, MD                            K. F. Austen Professor
Maria Castells, MD                             Asst. Prof.
Jonathan Coblyn, MD                            Assoc. Clin
Lawren Daltroy, DrPH                           Assoc. Prof.
John David, MD                                 Professor
Patricia Fraser, MD                            Asst. Prof.
Laurie Glimcher, MD                            Irene Heinz Given Professor
Michael Grusby, PhD                            Assoc. Prof./HSPH
Michael Gurish, PhD                            Asst. Prof.
Arthur Hall, MD                                Assoc. Clin Prof.
Donald Harn, PhD                               Assoc. Prof.
Smon Helfgott, MD                              Asst. Prof.
I-Ching Ho, MD, PhD                            Asst. Prof.
Victor Hsu, MD                                 Asst. Prof.
Richard Horan, MD, PhD                         Asst. Clin Prof. Dermatology
Elizabeth Karlson, MD                          Asst. Prof.
Howard Katz, PhD                               Assoc. Prof.
Jeffrey Katz, MD, MS                           Assoc. Prof.
Lloyd Klickstein, MD, PhD                      Asst. Prof.
Bing Lam, PhD                                  Asst. Prof.
Matthew Liang, MD, MPH                         Professor
Christina Parker, MD                           Asst. Prof.
John Penrose, MD                               Asst. Prof.
Heinz Remold, MD, PhD                          Professor
Gary Russell, MD                               Asst. Prof.
Peter Schur, MD                                Prof. Med
Nancy Shadick, MD, MPH                         Asst. Prof.
Albert Sheffer, MD                             Clin Prof.
Jeremiah Silbert, MD                           Prof. Med/Bedford VA
Richard Sperling, MD                           Asst. Clin Prof.
Richard Stevens, PhD                           Assoc. Prof.
Masahiko Sugita, MD                            Asst. Prof.
Michael Weinblatt, MD                          Professor

Lecturers
Daniel Friend, MD
Donald Humphries, PhD
Jocelyn Spragg, PhD




Instructors
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Anu Arya, PhD                          Chifu Huang, PhD
Peter Barry, MD                        Maura Iversen, ScD
Evan Beckman, MD                       Jean Jackson, MD
Samual Behar, MD                       Yoshihide-Kanaoka, MD, PhD
Bonnie Bermas, MD                      Michael Kane, MD
Jack Bukowski, MD, PhD                 Jennifer Lu-kuo, PhD
Michelle Carr, PhD                     David Leslie, MD
Christopher Dascher, PhD               Lisa Mandl, MD, MPH
William Docken, MD                     Branch Moody, MD
Lawrence DuBuske, MD                   Theresa Podrebarac, MD, PhD
Candida Fratazzi, M                    Robert Sands, MD
Huixian Gan, MD                        Daniel Solomon, MD, MPH
Jerry Greene, MD                       Michael Vincent, MD
Jenny Gumperz, PhD                     Ji-Liang Zhao, PhD
Jonathan Higgins, PhD



Research Fellows
Gillian Barclay, DrPH, DDS             Clinical Research Fellows
Elizabeth Benito-Garcia, MD            Cassandra Adams, MD
Frank Beurskens, PhD                   J. Pablo Bonia, MD
Heike Bischoff, MD                     Karen Costenbader, MD
Lynn Bry, MD, PhD                      Anna Feldwweg, MD
Xiaochun Cao, PhD                      Fred Hsieh, MD
Manuela Cernadas, MD                   Elaine Husni, MD, MPH
Lisa Cherry, PhD                       David Lee, MD, PhD
Massoud Dahesia, PhD                   Anne Maitland, MD, PhD
Hiranmoy Das, PhD                      Stanford Peng, MD, PhD
Paola dePablo, MD                      Kristine Phillips, MD
Bruno Diaz, PhD                        Monica Piecyk, MD
Stephen Donoghue, PhD                  Kursteen Price, MD
Patrice Douillard, PhD                 Pascale Schwab, MD
Lei Duan, MD                           Davie Slone, MD
Norvin Fernandes, PhD                  Stephen Wax, MD
Minggeng Gao, PhD
Amiya Ghosh, PhD                       Predoctoral Fellows
Arati Kamath, PhD                      Alissa Chackerian
Hans Kiener, MD                        Ingrid Dodge
Mario Lacouture, MD                    Wei Peng
Lixin Li, MD                           Navin Rao
Wei Li, PhD                            Guang Wong
Karen Mullane-Robinson, PhD
Alagarsamy Lakku Reddi, PhD
Bhanu Sadasivan, PhD
Keiko Saito, MD, PhD
Yoshiyuki Satake, MD, PhD
Ulrike Strauch, MD
Jianlan Sun, PhD
Hong Tao, MD
Nicodemus Tedla, MD, PhD
Lisheng Wang, MD
Jia-Shu Yang, PhD

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        In 1970, the Orthopedic Surgical Service joined the Department of Orthopedics at Harvard Medical
School with the appointment of Dr. Clement B. Sledge as Professor of Orthopedic Surgery at Harvard Medical
School and Chairman of the Department of Orthopedics at the Robert B. Brigham and Peter Bent Brigham
Hospitals. Dr. Thomas Thornhill succeeded Dr. Sledge. The Department faculty includes:

Professors
Gergory Brick, MD                        Asst. Clin Prof.
Julie Glowacki, PhD                      Assoc. Prof.
Jonathan Schaffer, MD                    Asst. Prof.
Barry Simmons                            Assoc. Clin Prof.
Richard Scott, MD                        Assoc. Clin Prof.
Clement B. Sledge, MD                    John B. Buckminster Brown Prof.
Myron Spector, PhD                       Professor
William Thomas, MD                       Assoc. Clin Prof.
Thomas Thornhill, MD                     Professor

Instructors                                                    Clinical Instructors
Daniel Estok, II, MD                                           Charles Brown, Jr., MD
Hu-Ping Hsu, MD                                                Robert S. Chernack, MD
Scott Martin, MD                                               John Kent Davies, MD
Tamara Lynn Martin, MD                                         Jerry LynnKnirk, MD
Schuichi Mizuno, PhD                                           Mark Joseph Koris, MD
Richard Ozuna, MD                                              Robert Miegel, MD
John Ready, MD                                                 Mark Steiner, MD
R. John Wright, MD                                             Craig Stirrat, MD
                                                               Michael Wilson, MD
                                                               Sonya Shortkroff, MS
                                                               Anuj Bellare, PhD

        In 1980, the Department of Rheumatology at BWH merged teaching programs with those of the Beth
Israel Hospital (BIH), another Harvard teaching hospital. In 1977, the BIH merged with the Deaconess Hospital
(BIDMC). Dr. Steve Goldring currently leads the BIDMC unit which sees about 1500 ambulatory patients an
d500 inpatients. In 1982, the clinical fellowship programs at the two hospitals were merged as well, thus
providing training experience in a hospital with strong community ties.

        In 1080, three Harvard teaching hospitals, the Robert B. Brigham Hospital, the Peter Bent Brigham
Hospital, and the Boston Hospital for Women merged to form the Brigham and Women‟s Hospital.

        In 1984, the Brigham joined in a state-wide effort to improve and disseminate rheumatic disease care for
children under the leadership of Dr. Jane Schaller at Tufts.

        In 1986, the Brigham and Women‟s Hospital became the principal hospital for the Harvard Community
Health Plan (HCHP), the largest health maintenance organization in Massachusetts. The HCHP has since merged
with Pilgrim HMO to form Harvard Pilgrim.

         In 1991, Dr. Michael Brenner was named to the K. Frank Austen Professor of Medicine Chair and Dr.
Laurie Glimcher to the Irene Heinz Given Professorship in Medicine. Dr. Peter Schur was named as Editor of
Arthritis and Rheumatism with Drs. Liang, Michael Weinblatt, K. Frank Austen, and Robert Lew as Associate
Editors.

         In 1994, the Brigham and Women‟s Hospital and Massachusetts General Hospital merged, a move which
anticipated similar activity all over the country. To protect the hospitals‟ basic missions of research, education
and patient care, profound restructuring, new economies and partnerships were viewed as essential. In 1996, the

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Dana Farber Cancer Institute, the Faulkner Hospital, the Newton Wellesley Hospital and North Shore Hospital
were added to the system. The entity is now known as the Partners HealthCare System.

       In October 1995, after a distinguished career of over 30 years at Harvard, Dr. K. Frank Austen stepped
down as Chairman of the Department of Rheumatology. The Department became, under the leadership of Dr.
Michael Brenner, a Division of Rheumatology, Immunology and Allergy with the Department of Medicine.

        1. HISTORY OF THE ARC

         In 1977, the RBBH and the Massachusetts General Hospital were named one of the first Multipurpose
Arthritis Centers and Dr. Matthew H. Liang was recruited back to Boston to head the new program. In the first
three years of the MAC‟s existence, the RBBH had $45,000 a year and $13,000 a year grant from the Arthritis
Foundation. A staff of two full time and one half time person were housed in the sub-basement of the old hospital
and a small office upstairs. Ms. Mary Scamman was one of the full time individuals, beginning as a secretary,
and now the Administrative and Financial Manager of the MAMDC.

        Since its founding, the MAC and now the ARC has grown in number of investigators, diversity of
research, the amount of extramural, peer-reviewed funding from NIH, industry, and foundations and the Division
in which it is housed has a parallel growth. The Division has a total of $12M of extramural support
(approximately $11M in rheumatology and immunology and $1M in orthopedic research). The Division‟s basic
research laboratory is a state-of-the-art facility in one site, the Smith Building.

         The MAC played a critical role in the growth and success of the Division of Rheumatology, Immunology
and Allergy, and the Department of Orthopedic Surgery. It has become the focus for epidemiologic, health
services, behavioral research in arthritis and musculoskeletal diseases and a magnet for clinical research training
in these fields at Harvard.

        Of the total direct support from the MAC program, roughly three-fourths went to support the clinical
sciences and its critical infrastructure. By all measures, this has been a successful investment and has leveraged
other support and been responsible for economies of scale never fully envisioned at the onset by ourselves or
others. These include:

        a.      Clinical sciences training program that attracts US and International fellows.

        b.      The ability to “carry” opportunistic, high-risk projects which are either formative, too small, or
                too elusive to be supported by traditional grants mechanisms. These scholarly works outnumber
                MAC-funded projects by a ratio of almost 50 to 1.

        c.      The ability to execute a continuum of investigations from small to large studies (witness in our
                last grant cycle the completion of a large clinical trial with a final sample size of 30,000) within
                the confines of a relatively small total budget.

B.      THE CENTER LEADERSHIP

      Dr. Matthew Liang. Dr. Liang is Professor of Medicine, HMS and Professor of Health Policy and
Management, HSPH. He is the Medical Director of Rehabilitation Services at Brigham and Women‟s Hospital.

        Dr. Liang is trained in internal medicine, rheumatology, tropical public health epidemiology and health
services research, and has extensive experience in the organization, delivery and evaluation of care for both acute
and chronic diseases, having implemented and evaluated the Army‟s algorithm-based physician‟s extender
(Amosist‟s) and Chronic Disease Nurse Practitioner programs; the first hospital-based health care system for
nursing home patients in Massachusetts; and the first neighborhood health center at Boston City Hospital. At
Walter Reed Hospital, he developed the first training program in General Internal Medicine and Primary Care, re-
organized the medical clinic, and developed the specifications of the computerized medical information system
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for the new hospital. He was recruited by the late H.R. Nesson, M.D., and Eugene Braunwald and K. Frank
Austen to the then new division of General Medicine and to the Department of Rheumatology to start the
Multipurpose Arthritis Center.

         He is one of founding, principal faculty of the Clinical Effectiveness Program at the HSPH, which teaches
clinical research methods to clinician scientists from all over the world. Since its inception, it has trained over
450 clinician-scientists. Dr. Liang runs the clinical research training program in the Division of Rheumatology,
Immunology, and Allergy and has trained over 40 individuals ranging from Instructor to Professor.

        At the Brigham and Women‟s Hospital he is a member of the Clinical Research Committee, which
oversee clinical research for the entire hospital community.

        At Harvard Medical School, he is one of the principals of the Clinical Research Curriculum group funded
in 1999 and developed the Harvard-wide Longitudinal Seminar for all clinician scientists in training.

        In 1998, he was the co-awardee of the L. Howley Jr. Prize for research in arthritis, which is given
annually for outstanding contributions and advances in “the understanding, treatment or prevention of arthritis and
rheumatic diseases”. This was the first time in the history of the award that a scientist was so honored for primary
contributions to clinical research. Of note 4 Brigham investigators in our Division (Drs. Frank Austen, Mike
Brenner, Laurie Glimscher) have won the Howley since 1994.

        His major research interests include the epidemiology of rheumatic disease and disability, clinimetrics,
health services research, technology assessment, and clinical decision making.

          Dr. Lawren Daltroy. Dr. Daltroy directs the education research of the Center. Dr. Daltroy has an MPH
and DrPH in health education, with 21 years' experience in patient education programs in chronic disease. He is a
primary investigator in health education, and participates in all projects with behavioral sciences components. His
work in psychometrics has advanced outcomes measurement in rheumatology and orthopedics.

          Dr. Daltroy is a major faculty member in Health and Behavior at the Harvard School of Public Health,
and has received recognition from students for teaching excellence. He is the only health educator on the Harvard
Medical School faculty of Medicine. He has consulted on patient education to the Arthritis Foundation, the
National Arthritis Advisory Board, and the National Institutes of Health. He was organizer of the 1989
conference on Financing Arthritis Patient Education, and wrote the background paper on national standards for
arthritis patient education for the Committee, chaired by the National Arthritis Foundation, that is charged with
developing them, and has been recognized nationally for his work in patient education an doctor-patient
communication.

         Dr. Jeffrey Katz. Dr. Katz is the Director of Health Services Research and has been since 1995. He is an
Associate Professor of Medicine at HMS and Associate Professor of Environmental Health at HSPH. He received
his methods training in the Clinical Effectiveness Program at HSPH from 1988-90 and his rheumatology training
at BWH. He joined the faculty in Rheumatology at BWH with support from the Development and Feasibility
program of the MAC. He has firmly established a research program on outcomes of orthopedic/musculoskeletal
disorders. He holds an appointment at HSPH in occupational health and is an adjunct faculty member of the
Institute for Work and Health in Toronto. In addition, Dr. Katz directs the Spine Center at BWH, a clinical
service devoted to evaluation and management of spinal disorders.

         Dr. Katz has served on the Editorial Board of Arthritis and Rheumatism and as Associate Editor of
Arthritis Care and Research. He is Deputy Editor of Spine, the major international journal devoted to spinal
disorders.

         This fall, Dr. Katz will receive the Henry Kunkel Young Investigator Award from the American College
of Rheumatology, given to the investigator under 45 years of age who has contributed most to arthritis research.
He is just the third clinical investigator to ever receive this annual award.
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       In recognition of his work on musculoskeletal disorders and their impact on work, he was selected to the
National Academy of Science Panel on Work and Musculoskeletal Disorders. Dr. Katz also serves on the
External Scientific Advisory Boards of the Canadian Arthritis Network and the Center for VDT and Health
Research at Johns Hopkins University.

C.      THE CLINICAL RESEARCH BASE FOR THE ARC

         In this section we highlight the major research programs housed in the Division. Investigators interact
with each other and through the Arthritis Research Center by a series of committees with overlapping
membership and clinical conferences throughout the week. Collaborations within the faculty are extensive; these
include grant making, scholarly work, clinical descriptive work, consultation over statistical or study design
issues. Some of this is unfunded work on scholarly interests, opportunistic observations, and natural experiments
but are frequently grist for formal research applications that ARC principals facilitate. The medical/surgical
community is invited to present and/or participate in our Clinical Sciences Research seminar and to use the
consultative services of Biometry.

     Clinical Sciences Research Program

Experimental Therapeutics in RA
M. Weinblatt (PI), Maier A, Clinical Faculty
Sources of Support: Industry
Objectives: To test new agents in the management of RA refractory to conventional therapy.

         Many patients with RA do not respond at all or do not respond adequately to the host of drugs available.
This research group is comprised of several full-time and part-time clinical faculty members and interfaces
directly with the basic science laboratory. The group was involved with the development of methotrexate and
establishing its long-term efficacy and safety. It has become established as standard therapy. Dr. Weinblatt and
his research group has played a key role in testing the current new generation of agents include methotrexate and
leflunomide and etanercept. Other drugs that have been studied include: cyclosporin A, interferon gamma,
several novel immunosuppressive drugs, unique antiinflammatory compounds including a 5-lipoxygenase
inhibitor, fish oil, tenidap, a T cell directed monoclonal antibody, Campath 1H and a retinoid, fenretinide, in
refractory RA.

Immunogenetics of SLE
P. Fraser (PI), E. Karlson, PH Schur, MH Liang, G. Cooper (NIOSH)

Objectives: 1. To establish immunogenetics of SLE in African Americans
            2. To test the Prevalence-Gradient hypothesis in SLE
            3. To establish gene-environment interactions in SLE
Sources of Support: HL-29583 (NHLBI), MH-47029 (NIMH), AI42374 (NIAID), AI42374 (NIAID), HL29883
(NHLBI), AR43523 (NIAMS), AR42459 (NIAMS)

        Our studies found evidence that HLA-Cw*17 polymorphism is conserved in different ethnic populations,
that HLA-B42 alleles seem to separate at least different African-derived haplotypes, and HLA-DRB3 genes with
increased risk of CDR3 oligoclonality is associated with SLE. The latter is compatible with the hypothesis that
molecules encoded by HLA-DRB3 may facilitate autoantigen recognition by CD4 T cells.

         With the Department of Public Health and NIOSH, the group is investigating a cluster of SLE in Afro-
Americans living the Dorchester-Roxbury area in the hopes that it may shed light on possible gene-environmental
interactions.

         The group is also identifying possible sites and populations along the Atlantic slave trade route to perform
definitive studies of the prevalent gradient hypothesis. Ghana, Jamaica, the Gullah people in the Sea Islands off

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the coast of South Carolina or first and second Ghanians in London appear to have the strongest possibility, thus
far.

Immunologic Effects of Silicone Organ Implants
PH Schur (PI), E. Karlson, M. Liang, G. Colditz (Channing Laboratories), M. Stampfer (Channing Laboratories,
Harvard School of Public Health), W. Willett (Channing Laboratories), F. Speizer (Channing Laboratories)

Objectives: 1. To examine frequency of autoantibodies in women with silicone breast implants
            2. To examine frequency of monoclonal gammopathy in women with silicone breast implants
            3. To monitor safety of penile implants
Sources of Support: AR42630 (NAIMS), CA40356 (NCI), CA49449 (NCI, AMS

        To study the possible association of silicone breast implant exposure and immunologic abnormalities, we
have randomly selected 2100 women from the Nurses Health Study Cohort who had been exposed to silicone
breast implants and who had never reported connective tissue diseases, and 500 age-matched, nonexposed
women, including 100 with definite connective tissue diseases validated by medical record review, 100 with at
least one symptom of a connective tissue disease, 100 with diabetes, and 200 healthy controls. Assays for
antinuclear antibodies (ANA), including anti-dsDNA, anti-ssDNA, anti-Sm/RNP/Ro/La and anti-Scl-70,
rheumatoid factor, immunoglobulins, serum complement, and C-reactive protein level, and anticardiolipin,
antithyroglobulin, antithyroid microsomal, and antisilicone antibodies are performed.

        Penile implants contain a silicone elastomer and there is a concern that they may cause connective tissue
disease. The FDA has required the manufacturer to evaluate this. Recipients are being screened for potential
signs and symptoms of connective tissue disease using a validated questionnaire we have developed for
epidemiologic studies. Subjects with any possible disease are sent to a local rheumatic disease specialist for
detailed evaluation.

Behavioral Determinants of Patient Outcome in Rheumatic Disease
L. Daltroy (PI), H. Eaton, M. Liang, N. Shadick, J. Katz, G. Barclay, C. Phillips, L. Wright, M. Iversen,
(Simmons) D. Solomon, C. Schwartz (UMass), R. Rudd (HSPH)

Objectives: 1. To develop and test novel behavioral interventions in the rheumatic diseases
            2. To improve doctor-patient communications
Sources of Support: Arthritis Foundation, AR36308 (NIAMS), Pfizer

     In this program behavioral sciences are applied to studies to improve patient management and prevention of
chronic disease; and psychometric theory is applied to develop and improve outcome instruments in
rheumatology and orthopaedics. This program seeks ways to improve communication and decision making
between patients and doctors and between patients and family members. The approach is to design and test
practical, theory-based behavioral-change interventions. These have included interventions for heart attack
survivors and spouses, arthritis patients undergoing total joint replacement, workers at risk of low back injury,
rheumatologists and patients decision making in major therapeutic changes, lupus patients and their partners,
visitors to areas in which Lyme disease is endemic, and adults with asthma.

         The research also contributed to psychosocial theory by (1) establishing important differences between
perceived and actual social support in three settings – post myocardial infarction patients in supervised exercise
programs, workers at risk for low back injuries, and lupus patients and partners (pending) (2) establishing that
effectiveness of preoperative education in total joint arthroplasty depends on patient coping style, (3) developing
an integrated theoretical basis for effective doctor-patient communication and decision making regarding
management of chronic disease, and (4) showing that discrepancies between self-reported function and actual
function in the elderly are largely due to specific psychological mechanisms, including response shift and
satisfaction with function.


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          The patient educational materials developed in many of these programs have been adopted by Brigham &
Women‟s Hospital. Dr. Daltroy‟s industrial low back injury prevention study was the first large-scale controlled
trial in this important area, and provided definitive evidence that a common approach to primary prevention of
low back injuries was ineffective.

Epidemiology of Rheumatic Disease
M. Liang, E. Karlson, F. Speizer (CL), L. Mandl, G. Cooper (NIOSH). O.Sangha (Munich), J. Jordan (University
of North Carolina)

Objectives:    1. To identify modifiable risk factors for incidence and outcomes of systemic rheumatic diseases
Sources of support: Arthritis Foundation, NIAID, NIOSH

        The Nurses Health Study and the Women‟s Health Study are the two largest prospectively followed
cohorts for the study of etiology of RA and of SLE; and environmental risk factors such as oral contraceptives,
smoking, female hormone replacement, hair dyes, silicone breast implants. OA as an endpoint is being explored.
The group has collaborated with Dr. Joanne Jordan to develop a self-report screening questionnaire for OA knee
and OA hip which should open research opportunities in the Cohorts. The Nurses Health Study Cohorts I and II
operate out of the Channing Labs under the leadership of Drs. Frank Speizer, Walt Willett, Graham Colditz, Meir
Stampfer. The Women‟s Health Study operates out of the Division of Preventive Medicine under the leadership
of Dr. Jo Ann Manson and Julie Buring. ARC investigators have participated in every other week investigators
meetings since the 1980‟s to plan investigations and to define exposures and outcomes of interest. A critical
methodologic innovation which has allowed us to utilize these rich data sets was the development of a way to
define rheumatic disease cases in a large population.

Clinical Trials Methodology
M. Liang (PI), J. Katz, R. Lew, L. Daltroy, C. Phillips, P. Fortin (UToronto), M.Abrahamowicz (McGill)

Objectives:    1. To develop and test patient-oriented outcome measures.
               2. To develop and test standardized clinical taxonomy and nomenclature systems for clinical
                    research and trials.
Sources of support: SLE Foundation, American College of Rheumatology, Arthritis Foundation

        The evaluation of medical and surgical interventions requires the measurement of important clinical states
and patient-centered outcomes. We have developed the conceptual framework and practical, valid, reliable and
responsive methods for regional musculoskeletal disorders (back, shoulder, arm, hand, lower limb), pediatric
musculoskeletal disorders, burn care, SLE disease activity, patient satisfaction with musculoskeletal disease
among others. With the advent of new biological agents for SLE, we have developed a conceptual framework for
how such clinical trials will be done. With a charge from the ACR we have developed standard nomenclature for
CNS lupus and are working on response criteria for SLE clinical trials.

Carpal Tunnel Syndrome (CTS) and Upper Extremity Disorders
JN Katz, (PI), B Amick, AH Fossel, RB Keller

Objectives: 1. To assess diagnostic tests for CTS and other upper extremity disorders to enhance epidemiologic
            studies and clinical practice
            2. To develop outcome measures in CTS
            3. To evaluate the outcome of operative and nonoperative therapy for CTS
            4. To examine factors associated with work disability from CTS
            5. To establish the epidemiology of upper extremity disorders associated with computer use in college
            students.
Sources of support: AR36308 (NIAMS), NIOSH, Arthritis Foundation Investigator Award and Clinical Science
Award, American Society for Surgery of the Hand, Harvard University Provost Fund for Interfaculty
Collaboration

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         Dr. Katz has had an active research program on upper extremity disorders for over ten years. He
examined the diagnostic value of clinical signs and symptoms of CTS and assessed the accuracy of the case
definition of work associated CTS proposed by the NIOSH. The group developed measures of symptom severity
and functional status in patients with CTS and showed that these self-administered measures are more valid
reflections of disease severity, more important to patients, and more responsive to change than traditional physical
examination parameters. The Maine Carpal Tunnel Study, the largest prospective study of CTS in a community
setting, has shown that surgery for CTS leads to significantly greater pain relief and functional improvement than
nonoperative therapy, even among Workers‟ Compensation recipients. Further, work absence is frequent in
workers with CTS and is best predicted by functional limitations and the presence of litigation. The team used an
administrative database to confirm established risk factors and identify new risk factors for carpal tunnel
syndrome including corticosteroid use. Collaborating with investigators and administrators at Harvard College,
the group has demonstrated the high risk of upper extremity symptoms associated with computer use in college
students.

Lumbar Spinal Stenosis (LSS)
JN Katz, (PI), SJ Lipson, M Iversen, AH Fossel

Objectives:
               1. To develop measures of outcome in LSS
               2. To evaluate the outcomes of operative and nonoperative therapy for LSS
               3. To examine outcomes of CTS
Sources of support: AR36308 (NIAMS), Arthritis Foundation, North American Spine Society, American Physical
Therapy Association

         The group evaluated the diagnostic value of physical examination and history findings among patients
with spinal stenosis. It developed measures of symptom severity, functional status and satisfaction and showed
that these disease specific measures are more responsive to change than generic measures of patient status. We
studied a retrospective cohort of patients who had surgery for stenosis, and demonstrated that 7-10 years
following surgery 25% of patients had repeat operations, and 30% of patients continued to experience severe back
or leg pain. In the largest prospective cohort of patients with spinal stenosis ever studied the team showed that
lumbar fusion without instrumentation improves the outcome of decompressive surgery for stenosis with
spondylolisthesis and the addition of instrumentation adds cost without further improving outcomes.

Total Joint Replacement
JN Katz, (PI), C Phillips, N Mahomed, AH Fossel, E Losina, EA Lingard, R Poss, W Harris (MGH), J.Baron
(Dartmouth)

Objectives: 1. To evaluate the outcome of TJR in the Medicare population; specifically to ascertain the
               associations between hospital and surgeon procedure volume and outcome
            2. To examine utilization of TJR by women

Sources of support: AR36308 (NIAMS), Arthritis Foundation, R01 HS09775-02 (Agency for Health Care
Research and Quality; AHRQ)

         The group collaborated with the AAOS to propose and evaluate a set of outcome parameters for total hip
replacement. The team demonstrated that women are more functionally disabled than men at the time of total
joint replacement for osteoarthritis, suggesting they are operated upon later in the progression of functional
decline. In qualitative research it observed that these utilization patterns reflect women‟s risk aversion and men‟s
preferences for greater physical function. The group showed that patient with worse preoperative functional status
have worse outcomes, independent of comorbidity, age and other covariates, suggesting that the practice of
delaying TJR until more advanced stages of functional decline may compromise outcomes. The epidemiology and




                                                      Page 10
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selected outcomes of total hip replacement was examined in the US Medicare population.

Quality of Care in Arthritis and Management
JN Katz (PI), DH Solomon, C Phillips, E Losina, M. Liang, O. Sangha (Munich)

Objectives: 1. Evaluate the quality of care provided by various specialty groups caring for patents with
                musculoskeletal problems
             2. Identify hospital-based indicators of the quality of total hip replacement.
Sources of Support: American Academy of Orthopedic Surgeons, AR36308 (NIAMS), AHRQ

        The team proposed methodologic standards for evaluating differences in quality of care provided by
different physician specialty groups. In a study that controlled carefully for case mix, we showed that patients
with shoulder and knee problems are more satisfied with care provided by orthopedists and rheumatologists than
by general internists, but that the specialists utilize more resources. Work on hospital quality of total hip
replacement and total knee replacement are in progress.

        The group validated a standardized hospital appropriate of care tool for use in Germany, documented
important variation in rates of surgery in Germany and former East Germany; developed 2 different self-
administered questionnaires for evaluating co-morbidity; develop a patient satisfaction tool in arthritis
management.

        Dr. Liang guided the production of the first 3 clinical guidelines for the ACR, the first annotated
bibliography of the cost and outcomes of rheumatologic care, and participated in the AHCPR guidelines for the
management of low back pain and the Quebec Taskforce on Whiplash injuries.

Lyme Disease
M. Liang (PI), N. Shadick (PI), C. Phillips, H. Fossel, L. Wright, R. Platt (Harvard Pilgrim)
Objectives:     1. To identify risk factors for chronic Lyme disease
                2. To design and evaluate a primary and secondary prevention program
                3. To evaluate safety of Lyme vaccine

         We have assembled a population cohort on Nantucket Island, MA, an area with the highest Lyme Disease
(LD) rates in the US and have followed the permanent residents for 8 years in an effort to understand the
trajectory of LD, its determinants, and its outcomes. Enrolling 39,000 subjects traveling to Nantucket by ferry
over 3 summers we have designed and tested in a randomized controlled trial a novel primary and secondary
prevention trial. The Lyme vaccine has been approved for use but its risk profile is not established. With
epidemiologists based at Harvard Pilgrim, we are carrying out a post-marketing surveillance study in a large
health maintenance organization.

Evaluation of Rehabilitation Interventions in Rheumatic Disease
M. Iversen (Simmons College), J. McGinnes, JN Katz, MH Liang, L. Lingard
Objectives: 1. To evaluate rehabilitation interventions in rheumatic disease
            2. To improve compliance with rehabilitation in rheumatic disease
Sources of Support: Arthritis Foundation, Foundation for Physical Therapy, Northeastern University

      Studies are in progress to determine the efficacy of an endurance bicycle program on elders with LSS and to
describe the elements important to elders‟ compliance with exercise. While the intervention is being tested on a
well-defined population, the results of this study can be generalized to the broader population of patients with
chronic low back pain from degenerative lumbar disease. If successful, this intervention will represent a n
inexpensive, easily accessible method of enhancing the quality of life and function of millions of elders.

       Examples of other interventions studied include continuous passive motion in the post-operative
management of patients after total knee replacement and the variation in postoperative management of patients
after total joint arthroplasty.
                                                      Page 11
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Technology Assessment
J. Katz, D. Solomon, M. Liang, N. Mahomed (UToronto), N. Shadick,
Objectives: 1. To evaluate the cost effectiveness of emerging technology used in the diagnosis and management
                of arthritis and musculoskeletal conditions
Sources of support: Arthritis Foundation, NIH, CDC, American Lyme Disease Foundation, Smith Kline
Beecham, Engelhard Foundation

        Emerging technologies in medicine and surgery present potential advantages for increased diagnostic
accuracy or sensitivity and improving patient outcomes but incur cost which may limit their dissemination. We
were the first group to use decision analysis and cost-effectiveness analysis in rheumatic diseases. We have
analyzed the cost-effectiveness of eye screening in monitoring hydroxychloroquine, the cost-effectiveness of
endoscopic vs. open release in CTS. The cost-effectiveness of decompression with non-instrumented lumbar
fusion vs. decompression without fusion for LSS.

         Other examples include our work on cost-effectiveness analysis of the ACR Guidelines on the
management of steroid-induced osteoporosis, the optimal use of knee magnetic resonance imaging, the cost
effectiveness of using low dose steroids in RA and the cost effectiveness of the new Lyme vaccine.

General Clinical Research Center
G. Williams (PI)
Objectives: 1. To provide statistical, nursing, diagnostic laboratory services for projects which require subject
               evaluation and/or monitoring.
Sources of support: A fee is charged for each subject visit according to the services required, NIH

         The GCRC provides a facility and the administrative, nursing, diagnostic testing and biometry support for
in- and outpatient conduct of human research protocols. The GCRC outpatient facility has allowed us to conduct
several studies without having to interfere with normal clinic operations and also without incurring the BWH‟s
standard exam room charge.

BWH Clinical Trials Program
P. Stone (PI)

         This program is designed to work within the current context of the National Institutes of Health and
industry-sponsored research to provide a variety of support services. It provides a convenient, centralized area to
conduct clinical trials including conference rooms, rooms to interview, and examination rooms. In addition, there
are personnel available to perform phlebotomy, ECGs, Holter Monitoring, exercise testing, and specimen
processing, packaging and storage. The Center also serves as a base of operations for investigators to participate
as a single clinical unit in a multicenter clinical trial.

      Over 40 active studies utilize the Clinical Trials Center, and involve more than 2,500 patient visits per year.
BWH departments and divisions using the Center include Medicine, Cardiovascular Disease, Infectious Disease,
Geriatrics, Renal, Pulmonary, GI, Rheumatology, Neurology, Ob/Gyn, and Anesthesia.

       The CGRC Core Laboratory (directed by Vincent Ricchuiti, PhD) provides laboratory tests for diagnostic,
therapeutic and research purposes. These tests include general chemistries, thyroid function tests, steroid
hormones (including salivary cortisol), peptide and protein hormones, markers of bone metabolism, ionized
calcium, Vitamin D assays, catecholamines, melatonin (plasma, saliva, urine) and other esoteric Endocrine related
tests. The Core Laboratory also provides specimen processing services and/or support for research protocols
conducted through the GCRC inpatient and outpatient facilities. The Core laboratory is a CLIA registered
laboratory, and is accredited through the JCAHO.


      Requests for tests nor normally done in the Core lab are considered on a case-by-case basis and depends on
                                                      Page 12
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sample volume, availability of instrumentation, the need for developmental work, interest to other investigators
and test complexity. The laboratory will also perform tests on a charge per specimen basis or on a one-time
assessment basis.

D.      CLINICAL TRAINING PROGRAM at the Brigham and Women’s Hospital

         Clinician-scientists must first achieve mastery of their basic clinical discipline before they can create new
knowledge. For many in our program, this comes from the clinical fellowship. The development of clinical skills
seems to follow two distinct "learning curves". The first curve has a steep slope and involves the acquisition of
the technical skills and factual knowledge. The second "learning
curve" has a gradual slope and is primarily a function of understanding the course of rheumatic disorders and their
response to intervention over an extended period of time. We believe that a meaningful ambulatory experience
with continuity of care is the cornerstone of training. The Robert B. Brigham Arthritis Center has over 20,000
patient visits per year and is the focus of ambulatory care. An introductory 32 hour lecture series is given for all
incoming fellows in the summer. All fellows initially see only new patients and continue to follow them
throughout their fellowship. Faculty working in the clinic review patients at the time of the visit.

        The other activities of the fellowship include:

            Harvard Pilgrim Community Health Plan (HCHP) Clinic, directed by Dr. Robert Sands, meets
            weekly. The HCHP is the largest and oldest HMO in the state. 2.5 FTE rheumatologists provide
            consultative rheumatology care to a vast network of primary care physicians.

            West Roxbury VA Hospital Arthritis Clinic, directed by Jerry Greene, MD, meets weekly. Patients
            are primarily referrals from the General Medicine Division at the hospital, which is a teaching
            hospital of the Harvard Medical School.

            Braintree Hospital Arthritis Clinic, directed by Simon Helfgott, MD, meets weekly and fellows attend
            each session. The patients seen are primarily referred for management of rheumatoid arthritis and
            orthopaedic problems.

            Beth Israel Consult Service, directed by Steve Goldring, MD, is held through the Rheumatology
            Division.

        Weekly formal teaching rounds include the Division of Rheumatology and Immunology Grand Rounds,
Consult Rounds, Radiology Rounds, Dr. Hall's Seminar and a series of seminars on special subjects. Spine
Rounds are conducted by Drs. Helfgott and Katz five times a year. Dr. Hall's seminar, named in honor of a senior
member of the part-time faculty, is given by the fellows and provides a detailed review of a selected topic in
rheumatology. Journal Club meets monthly for critical appraisal of important papers in the clinical literature and
a review of major clinical study designs. Dr. Elizabeth Karlson runs this conference. Consult Rounds and
Ambulatory Center Rounds are held weekly and discuss interesting patients seen in those settings. JRA
conferences held in conjunction with the Children's Hospital Medical Center. Ambulatory Center Rounds and X-
ray Rounds review cases or topics of interest monthly.

        The Division Research Seminar meets bi-monthly and offers a forum for formal presentation of work in
progress to the entire basic science group. The format of the conference is to have a one-hour long presentation in
which the audience is educated about the subject and discussion revolves around work planned or in progress.

         The companion to this in the Clinical Sciences is the ARC‟s Clinical Research Seminar which meets
weekly and is completely interdisciplinary. Planned studies and work in progress are the major focus. Over a
year, didactic lectures on advanced methodology, bioethics, and health services research are covered.

      A quarterly Training Committee, chaired by Dr. R.J. Anderson, reviews the progress of all trainees in
Biomedical and Clinical Sciences. Drs. Liang, Brenner, Glimcher, Weinblatt, Helfgott and Docken are the other
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members of this committee.

E.       CLINICAL RESEARCH TRACK- both domestic and international fellows
           Physicians, both domestic or international, accepted into the program are required to obtain training in
the disciplines (statistics, epidemiology, decision analysis, etc.) which are the foundation for a clinical scholar
who wishes to do quantitative research. This can be done by taking courses at the HSPH, the Masters of Public
Health, Masters of Science, or the Clinical Effectiveness summer program. All are given at the HSPH, 50 yards
away from the Center, and for now, funded by the student with some support as is available. Drs. Liang, Katz,
Daltroy teach at HSPH. Such formal classroom work prepares the student but guided experience in critical and
creative synthesis of the literature, hypothesis generation, study design, management of primary data collection,
analysis, etc. are needed to round out the training.

         Fellows are directed to individuals to help them identify projects but they should identify mentors, a
variety of them, among the faculty to utilize the full range of the clinical resources. The major mentor from the
Center should be identified before acceptance to the program and it should be a mutual decision.

         The formulation of research ideas and study designs is an essential experience of this fellowship. Fellows
are expected to define research areas for themselves in consultation with the faculty but the initiative is firmly in
the hands of the Fellow. To have a career in research, ones needs to know what has been done, to develop a sense
of what constitutes an important researchable question, to execute studies which “solve important” problems and
balance rigor, relevance, and resources, and to develop interests which can be sustained despite setbacks. We
have found no short cuts to this. Most fellows spend the first year developing questions and refining them and
start studies in earnest the second year.

        As a goal, a fellow should be involved in studies employing the following designs: analytical synthesis
(meta analysis or quantitative, critical synthesis), case-control, cohort. At least, two studies should involve
primary data collection; one the use of patient records. A controlled clinical trial should be planned and/or
executed. Fellows should perform at least one analysis for publication using an available data set or one brought
from their sponsoring institution.

        During their stay they should review critically one to two articles submitted for publication and write at
least two competitive grants. We encourage fellows to join one of the ongoing projects to experience, contribute,
and take advantage of a funded study and to acquire team leadership skills.

         Fellows are encouraged to consult freely with the Centers faculty as well as others on research ideas.
However, before committing themselves or others to the project and before Human Studies Committee approval
is sought, the proposal should be presented formally at the Clinical Research Seminar. Fellows are expected to
attend this weekly Seminar, and present their work in as many different phases of it as possible. This allows
focused multidisciplinary discussion of the project and always enhances the relevance and quality of work.

         The weekly Clinical Research Seminar is our forum for change and our center of gravity. Each
Wednesday from 9:30 to 11:00 all members of the ARC, from research assistants to principal investigators, meet
to discuss aspects of new and ongoing projects. The Meeting focuses and energizes the research. It advances
didactic education, scientific and career mentoring, and interdisciplinary collaboration. These activities lap into
informal lunchtime conversations and impromptu meetings to continue the momentum. This weekly activity
began in 1988 when the number of projects, staff, investigators, and fellows reached a critical mass. It has
elevated all aspects of research, enhanced collaboration, integrated research with educational and administrative
needs, and fostered better human relations.

        The schedule is set for each trimester (fall, spring, summer). Typically, the 15 or 16 week trimester
schedule includes sessions where research fellows describe their ongoing work, principal investigators give
progress reports on major funded projects, and all members make proposals for new projects and lead didactic
sessions. The speaker prepares a 30-minute formal presentation which allows an hour for free-flowing scientific
interchange.
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         The Seminar is a gateway through which each research fellow must pass to establish a plausible,
worthwhile, and practical research project. The fellows learn from critical review. The group establishes
expectations for regular progress and reassesses the scale and types of resources needed to complete the work.
The fellows then refine their proposed projects, ready them for IRB submission, and often pick up key
collaborators within the ARC. Thereafter, each successive presentation formally marks their professional
development, validates the soundness of their ideas, and opens up possible avenues to find better methodologies,
new collaborators, and grant opportunities. The Seminar and the one-to-one mentoring relationship with senior
faculty are essential to our training process.

         The Seminar helps an investigator build an idea with the collective wisdom of the broad group. Not all
ideas survive this exposure, but the group tries to balance criticism with constructive suggestions. These sessions
often trigger novel ideas about design, measures, analytic strategies, and logistical issues, leaving the investigator
to pursue a long list of suggestions. We call this process “barnraising” after the Harvard Business School
terminology, evoking the image of the rural culture where neighbors pitch in to help build a neighbor's barn from
the ground up.

         The Seminar is flexible and open. Over the years topics have included regulatory issues, industry-
academic relations facing specific investigators, the impact of evolving IRB regulations, dissection of
unsuccessful projects, documentation of research decisions and findings in project notebooks, guidelines for
authorship, consulting arrangements, the role of women in the ARC leadership, and means of resolving conflicts
that arise in collaborations and in mentoring relationships.

        The Seminar also covers issues of scientific conduct and by design, one seminar a trimester is devoted to
this. The format is a case study, usually a real situation faced by one of the investigators as a springboard for
open discussion. Over the last grant cycle we discussed: getting and receiving meaningful input from the entire
research team; whether or not an investigator should join a scientific Advisory Board of a pharmaceutical firm;
what was learned about industry and experts witness work in the silicone breast implants controversy; how to
handle libelous comments about scientific reputation over the internet, etc.

          Study logs of all projects need to be maintained including minutes of research meetings, documentation of
critical decisions, changes in protocol, etc. For publications, the data and analytical process supporting the
conclusions must be formally documented and checked by another individual. By Harvard rules, these and all
primary data needs to be retained at the Center. Designing a study, summarizing one‟s rationale, and behavior are
critical skills developed by these activities.

        Fellows should not expect routine secretarial support. We have office space for 5 fellows but it may have
to be shared during the period that the candidate is most actively involved with course work at the Harvard School
of Public Health.

F.      APPLICATION PROCESS

         Two positions are available each year in the Clinical Research Training track on a competitive basis.
Since each program is tailored to the individuals background, needs, and future career plans, we ask that letters of
intent or interest be sent as far in advance as possible. The letter should include a current curriculum vitae. For
U.S. physicians, applications for both clinical training and research training should be directed to the
rheumatology fellowship program under the direction of Dr. Ronald J. Anderson (Brigham and Women‟s
Hospital, 75 Francis Street, Boston, MA 02115). For those pursuing clinical research training, letters should be
sent directly to Dr. Elizabeth Karlson. Fellows who wish to concentrate in the application of social sciences to
clinical research should write directly to Dr. Lawren Daltroy at the Center. We cannot provide clinical training
for non-US citizens, nor stipends for the Clinical Research training program and for the Harvard School of Public
Health; thus, applicants must arrange their own funding. In situations where the individual will make a minimum
3-year commitment, we will work with the candidate to apply for other sources. For individuals who are

                                                       Page 15
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supporting their training by grants for which we provide documentation, it is critical that we have the grant in
hand to process at least two months in advance of its due date.

        For Non-US applicants the financial requirements of sponsored Visas must be documented at least 6
months prior to entry of the program. Ms. Mary Scamman at mscamman@partners.org is the contact person for
these individuals.

        Acceptance into the Clinical Research Training Program is conditional on acceptance to the Master‟s of
Public Health or Master‟s of Science Program at the Harvard School of Public Health. For non-English speaking
individuals a test of language proficiency is required; details should be obtained directly from the Harvard School
of Public Health (phone 617-432-1031; Fax: 617-432-2009).

        We strongly advise that a minimum of two and preferably three years should be spent in residence at the
Center to fully take advantage of the resources and to complete projects. We believe that systematic
methodologic training coupled with supervised applied work provides the most optimal experience.

         Except in unusual circumstances, all candidates should interview with Dr. Liang, Mrs. Mary Scamman,
the Center‟s administrator, Dr. Lawren Daltroy, Associate Director and select colleagues in the Center. This
interview is essential to construct the most appropriate program for the individual and sponsoring institution sand
to identify the resources that will be needed to support the individual.

G.      COMPUTER, PROGRAMMING AND STATISTICAL SUPPORT

       Computational work is an integral part of quantitative work. The Center uses the Computing Facility at
the HSPH which has state-of-the-art statistical software provided by the Department of Biostatistics at the HSPH.
Our SAS operates in the DOS environment.

       Most HSPH courses require a basic proficiency with the SAS statistical package and offers courses in its
use. To augment the basic programming and statistics taught at the HSPH, the Center offers periodic tutorials on
computation and statistics.

         A typical research project requires the construction of questionnaires, the abstraction of data from medical
charts, data entry, and transformation of the data into a form suitable for statistical analysis and fellows will have
ample experience in efficient ways to accomplish these tasks.

       Most fellows purchase computers and software during their stay. We have the following software.
Reference Manager, WP-DOS, PSI-plot, Harvard Graphics, Paradox, SAS, SPLUS, BMDP, Fortran and C.

H.          Trainees of ARC

        The ARC has been successful with training clinician scientists and with a few exceptions, most have
continued their research in academic centers

         Our graduate have won acclaim including the 1998 Canadian Rheumatology Association Young
Investigator Award, the 2001 American Society of Bone and Mineral Research Outstanding Young Investigator
Award, the 2000 ACR Henry Kunkel Young Investigator Award; the 2001 Ethan Sims Young Investigator
Finalist Award, the 1988 and the 2001 Edmund L. Dubois Award for Research in SLE, the 2002 Vontobel prize.




                                                      Page 16
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                                     DATES OF
NAME                                 TRAINING          CURRENT TITLE/AFFILIATION

Rowland Chang, MD, MPH               (7/81-6/82)       Professor of Preventive Medicine
                                                       Medicine & Physical Medicine and Rehabilitation
                                                       Northwestern University, Chicago

Celeste Robb-Nicholson, MD, MPH      (7/82-6/84)       Assistant Professor of Medicine
                                                       Harvard Medical School
                                                       Massachusetts General Hospital

William Neal Roberts, MD             (7/82-6/84)       Charles W. Thomas Professor of Medicine
                                                       Medical College of Virginia

John Paul Wade, MD                   (9/86-6/88)       Vancouver General Hospital
                                                       University of British Columbia
                                                       Vancouver, Canada

Steven Stern, MD                     (7/86-6/87)       Associate Professor of Medicine
                                                       University of Louisville, Kentucky

Jeffrey Katz, MD, MSc                (7/87-6/90)       Associate Professor of Medicine
                                                       Harvard Medical School
                                                       Brigham & Women's Hospital, Boston

Mauricio Hernandez-Avilla, MD, PhD   (7/87-7/89)       Professor
                                                       Instituto Nacional de Salud
                                                       Publica Cuernavacca Morelos, Mexico

Carolyn Schwartz, MS, SD             (1987-1993)       Associate Professor & Associate Director of
                                                       Research in Family Medicine and Community
                                                       Health
                                                       University of Massachusetts Medical School

Regine Brissot, MD                   (4/90-9/90)       Professor of Medicine
                                                       School of Medicine
                                                       Centre Hospitalier et Universitaire de Rennes,
                                                       France

Katherine Ginsburg, MD, MPH          (7/89-7/91)       Instructor in Medicine
                                                       Harvard Medical School
                                                       Brigham & Women's Hospital, Boston
                                                       (deceased 1992)

Paul Fortin, MD, MPH                 (7/89-7/92)       Associate Professor of Medicine
                                                       University of Toronto
                                                       Director of Clinical Research
                                                       Canadian Centre of Excellence

Jodi Grosflam, MD                    (7/90-6/93)       Rheumatologist - Private Practice
                                                       Fort Myers, FL

Nancy Shadick, MD, MPH               (7/90-6/92)       Assistant Professor of Medicine
                                             Page 17
                                                                               N:/ARC Description

                                                    Division of Rheum/Immun and Allergy,
                                                    Department of Medicine, HMS
                                                    Brigham & Women's Hospital

Jorge Sanchez-Guerrero, MD, MPH   (9/91-8/94)       Chairman
                                                    Department of Immunology and Rheumatology
                                                    Universidad Nacional Autónoma de
                                                    Mexico, Mexico City, Mexico

Elizabeth Karlson, MD             (2/91-1/93)       Assistant Professor of Medicine
                                                    Division of Rheum/Immun and Allergy,
                                                    Department of Medicine, HMS
                                                    Brigham & Women's Hospital

Oliver Sangha, MD, SD, MPH, MSc   (7/92-6/94)       Director of Research
                                  (deseased 5/01)   Bavarian Public Health Research Center
                                                    Munich, Germany
                                                    Associate Prof. of Health Services Research
                                                    Associate Professor of Medicine
                                                    Ludwig-Maximilians University
                                                    School of Medicine
                                                    Munich, Germany

Gerold Stucki, MD,MS              (7/92-6/94)       Professor of Physical Medicine and Rehabilitation
                                                    Medicine
                                                    Chairman, Department of Physical Medicine &
                                                    Rehabilitation
                                                    Ludwig-Maximilians University
                                                    Munich, Germany

Marianne Dalgas, MD               (11/92-11/93)     Associate Chief
                                                    Department of Physical Medicine
                                                    Holbæk Hospital, Denmark

Charles Rivest, MD, MPH           (1/94-12/96)     Research Fellow
                                  (deceased 12/96) Harvard Medical School
                                                   Brigham & Women's Hospital, Boston
                                                   (from Rheumatic Disease Unit of Hospital
                                                   Notre-Dame, Univ Montreal Med School

Louis Bessette, MD, MPH           (1/94-12/96)      Centre Hospitalier Regional de Rimouski
                                                    Rimouski, Quebec, Canada

Maura Iversen, PT, MPH, ScD       (1994-1997)       Associate Professor
                                                    Graduate School for Health Studies
                                                    Simmons College
                                                    Instructor in Medicine
                                                    Harvard Medical School
                                                    Brigham & Women‟s Hospital

Hideki Hashimoto, MD, MPH, ScD    (1995-1999)       Assistant Professor of Medicine
                                                    Dept. of Hygiene and Public Health
                                                    Toikyo University School of Medicine
                                                    Tokyo, Japan
                                          Page 18
                                                                                  N:/ARC Description


Gillian Barclay, DDS, MPH, DrPH     (1995-1999)       Postdoctoral Research Fellow
                                                      Department of Medicine
                                                      Harvard Medical School

Nizar Mahomed, MD, MPH, ScD, FRCSC (7/95-6/97)        * Assistant Professor, Dept. of Surgery
                                                      University of Toronto, Canada
                                                      * Assistant Professor, Dept. of Health
                                                      Administration, University of Toronto
                                                      * Director of Musculoskeletal Health & Arthritis
                                                      Program, University Health Network
                                                      * Director, Lower Extremity Arthritis Arthritis
                                                      Program
                                                      *Adjunct Scientist, Institute of Clinical &
                                                      Evaluative Sciences

Daniel Solomon, MD, MPH             (7/95-7/98)       Instructor in Medicine
                                                      Harvard Medical School
                                                      Division of Pharmacoepidemiology &
                                                      Pharmacoeconomics
                                                      Brigham & Women's Hospital

Elizabeth Brooks, MD, PhD           (1/96-1/99)       Assistant Professor of Medicine & Pediatrics
                                                      Division of Rheumatology & Clin. Immun
                                                      University of Pittsburg, PA

Liz Lingard, BPhty, MPhil, MPH      (9/96-6/97)       Research Fellow (Dept. Orthopedics)
                                                      Harvard Medical School
                                                      Brigham & Women‟s Hospital

Richard Bell, MS, ScD               (1996-1999)       Research Psychologist
                                                      US Army Natick Research, Development,
                                                      And Engineering Center

Sang Cheol Bae, PhD, MD, MPH        (7/96-6/98)       * Associate Professor
                                                      Department of Internal Medicine
                                                      Division of Rheumatology
                                                      Hospital for Rheumatic Disease
                                                      Hanyang University College of Medicine
                                                      Seoul, Korea
                                                      * Director, Lupus Clinic, Hospital for
                                                      Rheumatic Diseases
                                                      * Director, Section for Clinical Epidemiology and
                                                      Economics

Michael Corzillius, MD, MPH         (7/96-11/98)      Research Fellow
                                                      Department of Medicine
                                                      Christian-Albrechts-University
                                                      Kiel, Germany

Lisa Mandl, MD, MPH                 (7/98-6/01)       Instructor in Medicine
                                                      Harvard Medical School
                                                      Brigham & Women‟s Hospital

                                            Page 19
                                                                                N:/ARC Description

Larissa Roux, MD, MPH             (7/98-6/01)       Dept. of Community Health Services
                                                    Faculty of Medicine
                                                    Health Sciences Center
                                                    University of Calgary, Canada

Paco Wesling                      (4/98-7/98)       Student Externship
                                                    (from University of Nymegen,
                                                    The Netherlands)

Nelson Greidanus,MD, MPH, FRCSC   (9/99-9/00)       Assistant Professor
                                                    Dept. Orthopedic Surgery
                                                    University of British Columbia

Min Kocher, MD                                      Instructor in Surgery
                                                    Dept. of Orthopedic Surgery
                                                    Children‟s Hospital
                                                    Harvard Medical School

Karen Costenbader, MD             (7/00-7/03)       Research Fellow
                                                    Harvard Medical School
                                                    Massachusetts General Hospital

Hyon Choi, MD, MPH                (9/00-9/02)       Instructor in Medicine
                                                    Harvard Medical School
                                                    Massachusetts General Hospital

Elaine Husni, MD, MPH             (4/00-4/02)       Research Fellow, ARC
                                                    Brigham & Women‟s Hospital

Heiki Bischoff, MD                (6/00-9/02)       Research Fellow, ARC
                                                    Brigham & Women‟s Hospital
                                                    (from: Univ. Hospital, Zurich, Switzerland)

Ewa Roos, RPT, PhD                (9/00-12/00)      Visiting Postdoctoral Fellow
                                                    Department of Medicine
                                                    Harvard Medical School
                                                    (from: Dept. Orthopedics
                                                    Lund Univ. Hospital Sweden)

Schattner, Ami                    (5/01-9/01)       Visiting Fellow.
                                                    Associate Professor of Medicine
                                                    Hebrew University
                                                    Hadassah Medical School
                                                    Jerusalem

Pinto, Elizabeth                  (7/01-7/03)       Research Fellow
                                                    Brigham and Women‟s Hospital
                                                    Harvard Medical School
                                                    (From Hospital Garcia De Orta, Almada, Portugal)

DePablo, Paola                    (7/01-7/03)       Research Fellow
                                                    Brigham and Women‟s Hospital
                                                    (From National Institute of Cardiology Ignacio
                                                    Chavez, National Autonomous University of
                                          Page 20
                                                                                              N:/ARC Description

                                           Mexico, Mexico)
I.      INSTITUTIONAL ENVIRONMENT AND RESOURCES

        1. Clinical Facilities

         The Robert B. Brigham Arthritis and Musculoskeletal Clinical Research Center (ARC) is housed at the
BWH, one of the Harvard teaching hospitals and is a typical academic health center struggling to maintain its
traditional values of teaching, patient care and research in the current health care climate. Since 1994, it has been
one of 12 affiliated hospitals in the Partners HealthCare System. In 1999 the network had 3,188 licensed beds and
admitted 126,620 patients for an average length of stay of 5.3 days in its acute beds, and saw 1,582,833
ambulatory patients. There are nearly 6,000 physicians in the system and 717 fellows training in medicine and
surgery. Ninety-seven million dollars was spent annually on uncompensated care. Its investigators received a
total of 463 million dollars annually and 1,667 research fellows learned their craft at our institution.

        2. Patient Population/Registries

        The Robert B. Brigham Arthritis Center sees more than 21,000 patients annually – more than half of
whom are self-referred. In addition, the Juvenile Adolescent Rheumatology Program, staffed by three
rheumatologists, currently follows 500 young people with arthritis, evaluating 45 new patients each year; the
Lupus Clinic follows over 300 patients and evaluates 180 new patients each year; the Brigham Spine Center sees
over 1,000 patients. The Lyme Disease Clinic sees over 1,000 patients and 100 new patients each year. In the
same building or contiguous to the Arthritis Center, there is Dermatology, Ophthalmology, Neurology,
Hand Surgery, Orthopedic Surgery, Podiatry, Rehabilitation Services, and Bone Radiology to complete the
components of comprehensive care.

        Special registries maintained at the ARC or institution include patients with:
               Exercise induced analphylaxis
               Spinal stenosis
               TKR
               THR
               SLE
               RA receiving embrel
               RA
               Stiffman Syndrome

        All patients seen in the ambulatory center are also accessible through a registry that is maintained at a
very low cost through downloading information from encounter billing forms by the ARC staff.

        3.    ARC ENVIRONMENT AND RESOURCES

       The ARC has two sites, one in the former Peter Bent Brigham Hospital on the main campus of the
Brigham and Women‟s Hospital and the other in the old Boston Lying In hospital, about 300 yards from the main
campus, but conveniently located to Channing Laboratories, the Harvard School of Public Health, Harvard
Medical School, and Countway Medical Library. Our activities are snugly housed in 1500 square feet of space.

J.            RELATED UNITS/PROGRAMS

         ARC is just one of many clinical research activities in the Longwood Medical Area. We describe the
units with which we have had the most interactions over the years.

        Division of Preventive Medicine (BWH) is chaired by Dr. Joanne Manson, collaborator in one of the
        projects to be described. This division is an epidemiologic research unit, which has conducted many
        major studies of cardiac risk factors and is also involved in a women‟s health initiative. Drs. Beth

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Karlson, Matthew Liang, Lisa Mandl, Dan Solomon have collaborated on a number of projects.

The Channing Laboratories , directed by Drs. Frank Speizer and Walter Willett, have conducted many
of the major nutritional and lifestyle risk factor studies of cardiovascular disease, cancer and rheumatic
disease. The Nurses Health Study I Cohort and the Nurses Health Study II Cohort are the largest ongoing
cohorts studying systemic rheumatic diseases. In the early eighties, Dr. Liang worked out techniques to
use the observational cohorts for the study of systemic rheumatic illnesses and the identification of
systemic rheumatic diseases and osteoarthritis, and these techniques have been continuously updated
since.

The Clinical Research Center, directed by Drs. George Thiebault and Gordon Williams, has inpatient
and outpatient facilities to study patients. Experienced research nurses and technicians conduct study
protocols. Other individuals assist in study design, data analyses and database management. Drs.
Iversen, Katz, Liang, Karlson and Daltroy have all taken advantage of these resources for studies.

The Harvard School of Public Health is within view of ARC and provides the classroom setting for our
research trainees. Drs. Daltroy, Katz, and Liang have secondary appointments in the Departments of
Health and Social Behavior, Environmental Health, and Health Policy and Management, respectively.
Each has supervised doctoral candidates. One of the most successful tracks is the Clinical Effectiveness
Program, a formal masters level training program tailored to clinician scientists. Dr. Liang was a
founding faculty member and continues to teach along with Dr. Katz. Our clinical research fellows are
required to complete this program. Dr. Katz, Karlson, Shadick, and Mandl have all participated.

Harvard Medical School Clinical Research Curriculum is directed by Dr. Gordon Williams. Dr.
Liang was a principle architect of a longitudinal seminar. The program provides a degree to clinical
scientists and integrates elements of clinical research activities at all the major teaching hospitals and the
HSPH.

At the Brigham and Women‟s Hospital, our research is under the umbrella of the Research Council,
directed by Drs. Victor J. Dzau, Michael Gimbrone, and Dennis Casper. One of the standing committees
is the Clinical Investigation Committee of which Dr. Liang is a founding member. This body addresses
infrastructure issues that cut across all clinical research done at the institution.




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