Centers of Research Translation (CORT)

Translation of Quantitative Imaging in Osteoarthritis (TOQIO)

Funded by National Institute of Arthritis and Musculoskeletal and Skin Diseases

CORT ImagingThe overall objective of this proposal entitled “ Translation of Quantitative Imaging in Osteoarthritis” (TOQIO) is to integrate cutting edge quantitative imaging technologies, link the image derived metrics to joint kinematics, kinetics, patient function, and translate the linkages found to the musculoskeletal clinic, thus affecting patient management and outcome. In order to accomplish these objectives we have a combined team that includes orthopedic surgeons, rheumatologists, imaging scientists, bioengineers, physical therapists, epidemiologists, and biologists. This team is built upon the strong foundation of interdisciplinary collaborations between the investigators, with a focus on translational research, and is supported by numerous individual investigator and programmatic grants that have established these collaborative research partnerships between the investigators and the institutions. The major goals of TOQIO are to (i) provide the infra-structure and develop an inter-disciplinary team to translate promising new imaging methodologies and non-invasive biomarkers from proof of principle to studies/trials in human subjects, and ultimately into widely available clinical tools that directly impact patient care and management of osteoarthritis; (ii) to develop models and relationships between the quantitative imaging measures and biomechanics that are relevant to function, not only for monitoring and diagnosing osteoarthritis, but also for assessing pharmaceutical or surgical therapies and subject selection in clinical trials; and (iii) to develop an educational program in which imaging specialists that develop the novel techniques relevant to osteoarthritis research teach basic and clinical scientists how to use such approaches in enhancing their research and translate the imaging information to the diagnosis and clinical management of osteoarthritis, as well as develop new pilot and feasibility projects utilizing the themes central to TOQIO. TOQIO consists of an administrative core, four research projects, and two research and scientific cores: Imaging and Data Analysis and Human performance and Functional Testing. In addition, there will be participants from UC San Francisco and UC Davis and an excellent External Advisory Committee that includes lay input from a community member.

CORT Directors

Sharmila Majumdar, Ph.D.
Professor & Vice Chair of Research, Director, MQIR,
UC San Francisco
sharmila.majumdar@ucsf.edu

Nancy E. Lane, M.D.
Professor, Director, Musculoskeletal Diseases of Again Research Group,
UC Davis
nancy.lane@ucdmc.ucdavis.edu

 

Principal Investigators

John Boone, PhD, M.S.
Professor and Vice Chair of Research, UC Davis
jmboone@ucdavis.edu

Deborah Grady, M.D.
Professor in Residence, Department of Medicine, UC San Francisco
deborah.grady@ucsf.edu

Hubert Kim, M.D.
Professor in Residence, Department of Orthopaedic Surgery,
UC San Francisco
kimh@orthosurg.ucsf.edu

Roland Krug, Ph.D.
Assistant Professor-in-Residence, MQIR,
UC San Francisco
roland.krug@ucsf.edu

Xiaojuan Li, Ph.D.
Associate Professor-in-Residence, MQIR,
UC San Francisco
xiaojuan.li@ucsf.edu

Thomas Link, M.D.
Professor-in-Residence; Clinical Director, MQIR,
UC San Francisco
Thomas.link@ucsf.edu

Anthony Luke, M.D.
Professor of Clinical Orthopedic Surgery,
UC San Francisco
LukeA@orthosurg.ucsf.edu

Benjamin Ma, M.D.
Chief of Sports Medicine, Associate Professor in Residence,
UC San Francisco
MaBen@orthogurg.ucsf.edu

Charles McCulloch, Ph.D.
Professor and Head, Division of Biostatistics,
UC San Francisco
chuck@biostat.ucsf.edu

Theodore Miclau, M.D.
Professor and Vice Chairman Department of Orthopaedic Surgery,
UC San Francisco
miclaut@orthosurg.ucsf.edu

Michael Nevitt, Ph.D., M.P.H.
Adjunct Professor, Division of Clinical Trials & Multicenter Studies,
UC San Francisco
MNevitt@psg.ucsf.edu

Ann Schwartz, Ph.D., M.P.H.
Associate Professor, Department of Epidemiology and Biostatistics,
UC San Francisco
aschwartz@psg.ucsf.edu

Richard Souza, P.T., Ph.D., A.T.C., C.S.C.S.
Assistant Professor-in-Residence, MQIR,
UC San Francisco
richard.souza@ucsf.edu

Thomas P. Vail, M.D.
Professor and Chairman Department of Orthopaedic Surgery,
UC San Francisco
vailt@orthosurg.ucsf.edu

Daniel Vigneron, Ph.D.
Professor, Director, HMTRC,
UC San Francisco
dan.vigneron@ucsf.edu

Barton Wise, M.D.
Assistant Professor, Center for Aging
UC Davis
barton.wise@ucdmc.ucdavis.edu

 

Postdoctoral Scholars and Researchers

Cynthia Conti, M.S.
Lab Manager, Human Performance Center,
UC San Francisco
contiC@orthosurg.ucsf.edu

Ursula Heilmeier, M.D.
Postdoctoral Scholar, MQIR,
UC San Francisco
ursula.heilmeier@ucsf.edu

Gabby Joseph, Ph.D.
Postdoctoral Scholar, MQIR,
UC San Francisco
gabby.joseph@ucsf.edu

Subburaj Karupppasamy, Ph.D.
Postdoctoral Scholar, MQIR,
UC San Francisco
subburaj.karupppasamy@ucsf.edu

Deepak Kumar, PT, Ph.D., O.C.S.
Postdoctoral Scholar, MQIR,
UC San Francisco
deepak.kumar@ucsf.edu

Felix Liu
Programmer, Epidemiology,
UC San Francisco
fliu@psg.ucsf.edu

John Lynch, Ph.D.
Director, MRI Quality Assurance,
UC San Francisco
jlynch@psg.ucsf.edu

Megan Marsh, B.S.
Staff Research Associate, MQIR,
UC San Francisco
megan.marsh@ucsf.edu

Lorenzo Nardo, M.D.
Postdoctoral Scholar, MQIR,
UC San Francisco
Lorenzo.nardo@ucsf.edu

Julien Rivoire, Ph.D.
Postdoctoral Scholar, MQIR,
UC San Francisco
julien.rivoire@ucsf.edu

Cory Wyatt, Ph.D.
Postdoctoral Scholar, MQIR,
UC San Francisco
cory.wyatt@ucsf.edu

 

Coordinators

Melissa Guan
Research Coordinator, MQIR,
UC San Francisco
melissa.guan@ucsf.edu

Delilah Peña
UC San Francisco
delilah.pena@ucsf.edu

Project 1

Characterization of Cartilage using Magnetic Resonance Imaging and Kinematics in Hip Osteoarthritis:

CORT Project 1Hip OA and subsequent hip replacement has significant impact on the adult population, and it is essential to translate some of these methods to characterizing hip OA. The initial stages of hip OA are manifested in alterations in hip loading patterns, which can be investigated using motion analysis tools. Previous studies have reported altered loading patterns in subjects with varying levels of hip OA (16-18). Changes in kinematics, kinetics, gait characteristics and functional activities have been reported in patients with early hip OA (16). While these parameters have not been linked with radiographic markers of OA (17), their relationship with early cartilage degeneration remains to be determined. Support for this link is that femoroacetabular impingement (FAI), has also including pincer and cam types, has emerged as a probable cause of OA of the hip (3-7) associated with demonstrable kinematic changes in the hip joint.

The proposed study aims to investigate early hip OA by integrating motion analysis and MRI techniques, thereby assessing the relationship between biomechanical loading and functional kinematics to cartilage degeneration and progression of hip OA. Preliminary studies from our group and others have shown promising results demonstrating altered biomechanics (18,19) and cartilage biochemistry (20) in patients with hip OA. The goal is to test the central hypothesis that imaging-based measures of hip cartilage biochemistry and bone structure differ between patients with hip OA and controls and are related to cartilage morphology, pain, function and severity of disease. The aims include: the characterization of hip cartilage biochemistry (measured by MRI T1ρ and T2 relaxation time) in patients with hip OA compared to controls and to determine the changes in cartilage T2 and T1ρ relaxation time over 4 years; and the cross-sectional and longitudinal relationship between hip cartilage biochemistry (measured by MRI T1ρ and T2 relaxation time) and cartilage morphology, patient function (kinematics, kinetics, spatiotemporal gait characteristics, functional tests) and pain (WOMAC).

The results of the proposed study will help determine whether early biochemical degeneration in cartilage, as quantified by T2 and T1ρ mapping parameters, is associated with the progression of hip OA manifested by altered hip loading patterns, changes in bone and cartilage morphology, and to the detriment of patient function.

Translational Aspect: This study translates the previously established MR and quantitative analysis methodologies for knee osteoarthritis to address detection and quantification of early degeneration at the hip joint, the second most common site of OA. The results of this project relating the MR imaging based biomarkers to function, pain, and measures of biomechanics of the joint will assist not only in understanding the pathogenesis of hip OA, but also for future design of interventions. 

Project 2

Quantitative MRI and Gait Analysis for ACL-injured and Reconstructed Knees

CORT Project 2Anterior cruciate ligament (ACL) injuries are one of the most common and severe ligament injuries of the knee. Although ACL reconstruction enables patients to return to active lifestyles (21), previous long-term studies have demonstrated that 10 to 15 years after surgery, on average, 50% of these patients have documented radiological changes of osteoarthritis (OA) (22). With the increasing number of ACL injuries in the adolescent population, we are poised to have an epidemic of young adults with post-traumatic OA and loss of function within the next decade. To date, objective evaluations of the ACL injured and reconstructed knees include laxity measurements, muscle strength and plain radiographic images (23). These examinations are useful but cannot identify subtle changes in knee kinematics and degeneration. There is a profound need for early detection of biochemical and biomechanical abnormalities in ACL-injured and reconstructed knees. This ability to diagnose early degeneration will enable early intervention, and will provide guidance and critical evaluation for new surgical or pharmacological therapies.

In this project three quantitative measures, from tissue composition to joint and entire limb function will be integrated to evaluate ACL-injured and reconstructed knees. Patients with acute ACL-injures will be studied at baseline (within 2-4 weeks post injury and prior to ACL reconstruction), 6-month, 1-year and 3-year post-ACL reconstruction. Age, gender and BMI-matched healthy controls will be studied at baseline, 1-year and 3-year. Both knees will be studied in both groups. With our extensive experience in quantitative and kinematic MRI, and the new availability of gait analysis within the Human Performance Core, we are armed to investigate the interaction between biochemical and biomechanical abnormalities of ACL-injured and reconstructed knees. Translational Aspect: A better understanding of this interaction is critical in understanding the disease mechanism of post-traumatic OA development in injured joints. Correlation between quantitative MRI and gait analysis will facilitate translating the advanced imaging techniques into daily clinical applications and will ultimately improve patient management. 

Project 3

T2 Relaxation Time in the OAI normal, incidence and progression cohorts

CORT Project 3T2 relaxation time mapping has been established as one of these techniques and has been shown to be sensitive to water concentration, collagen architecture and biomechanical characteristics of the hyaline cartilage. This technique has shown promising results in differentiating individuals with and without OA and in characterizing the hyaline cartilage and the menisci in different stages of degeneration. However, these studies were mostly performed at single centers with relatively small patient numbers and only limited information is available on the longitudinal evolution of T2 relaxation times. Given these limitations, yet promising results T2 relaxation time measurements were included in the Osteoarthritis Initiative (OAI). The OAI is an ongoing 8-year, multi-center, longitudinal cohort study, focusing on knee OA, which currently offers the best available resource to study the role and importance of T2 relaxation time in osteoarthritis.

The overall goal of this project is to study the longitudinal evolution of T2 relaxation time measurements in the OAI in relation to clinical and morphological findings at the knee. Specifically, the goal is to study the prevalence and grade of cartilage and meniscal lesions (using the semi-quantitative whole organ magnetic resonance imaging score (WORMS) in normal individuals (n=100) as well as individuals from the incidence (n=300)* and progression (n=300) cohorts of the OAI aged 45-70 years, and analyze the relationship of these scores with T2 parameters (mean, spatial distribution and laminar organization) and assess interrelationships between the 3 groups; to determine whether baseline T2 parameters will predict after 2 and 4 years change in WORMS scores and increase in WOMAC (Western Ontario and McMasters) and KOOS (Knee Injury and Osteoarthritis Outcome Score) indices; and to assess the longitudinal change in T2 parameters, cartilage and meniscal lesion progression in relation to changes of pain and function scales (WOMAC, KOOS), physical activity (PASE) and physical performance over a period of 2 and 4 years. (*Incidence cohort data will be available for 45 to 60 year old individuals from funded U01, AR059507-01).

Translational Aspect: The overall impact of this project will be to thoroughly investigate and propose imaging biomarkers that will identify individuals at high risk for OA and progression of OA. The unique study design of the OAI will provide, for the first time, T2 measurements of the cartilage matrix in a large study population, which was obtained longitudinally with rigorous quality assurance using the same type of MR scanners. The results of this project obtained in the normal, incidence and progression cohorts of the OAI will investigate in a large study population, whether T2 measurements may be used as a biomarker to predict development of OA, with concurrent assessments of physical activity, development of pain as well as radiographic signs of OA and abnormalities on morphological MR sequences. Ultimately these findings will assist in better characterization of patients clinically using T2 measurements, and the findings will also impact the follow-up studies for Project 2 above.

Project 4

Risk Factors and Health Impact of Lateral compartment Knee Osteoarthritis: The Osteoarthritis Initiative

CORT Project 4Lateral compartment osteoarthritis (OA), while much less prevalent than medial compartment disease (ranging from 4-9% in cohort studies) is also associated with pain and disability, and has not been studied with the same intensity. A few studies (including recent work by our group) have reported independent risk factors for lateral compartment tibia-femoral osteoarthritis (TFOA) including race, pelvic anatomy and malalignment. Differences in shape of the femur and tibial plateau result in varying mechanical impact in the lateral compartment, as well as potential differences in how well plain radiographs can evaluate for lateral compartment disease. A more careful evaluation of TFOA of the lateral compartment would provide the first comprehensive picture of lateral compartment disease as a separate and unique entity. Using MRIs in the Osteoarthritis Initiative (OAI), we will characterize prevalence of the lesions (localized bone marrow lesions, meniscal tear, cartilage loss, etc) in persons with lateral compartment OA and compare those prevalences to persons without lateral radiographic disease.

Our group has worked with active shape modeling to fully characterize the spectrum of hip shape andhave reported unique shapes or modes that are significant predictors of incident hip OA. In this project, we will use a case control analysis wherein we will compare prevalence of lesions on MRI, hip, knee shape or T2 mapping measurements between subjects with lateral TF ROA and knees without TF ROA. In this project we will examine the association of lesions detected by MRI with radiographic OA at the lateral compartment using a cross-sectional baseline sample of prevalent cases and controls; examine known risk factors for medial compartment OA and novel risk factors that are likely to impact lateral compartment disease, and their relationship to both prevalent and incident lateral compartment OA disease; and lastly examine the association of lateral compartment TFOA and incident functional impairment.

Translational Aspect: This project utilizes the previously developed tools, to focus on one specific and neglected aspect of OA, i.e. lateral compartment OA. The impact of hip/knee/femoral shaft shape on the progression and characteristics of disease will have considerable impact on the analysis and understanding of project 1 and 2 and the natural history of pain and functional decline in subjects with lateral compartment TFOA.

Internal Advisory Board

John Boone, PhD, M.S.
Professor and Vice Chair of Research,
UC Davis
jmboone@ucdavis.edu

Deborah Grady, M.D.
Professor of Medicine 

Associate Dean of Clinical and Translational Research 

Co-Director, Clinical and Translational Science Institute
UC San Francisco School of Medicine
deborah.grady@ucsf.edu

Hubert Kim, M.D.
Professor in Residence, Department of Orthopaedic Surgery
Director of UC San Francisco Cartilage Repair and Regeneration Center 

UC San Francisco
kimh@orthosurg.ucsf.edu

Thomas Link, M.D.
Professor and Chief of Musculoskeletal Imaging Section 

UC San Francisco
Thomas.link@ucsf.edu

Charles McCulloch, Ph.D.
Professor and Head, Division of Biostatistics,
UC San Francisco
chuck@biostat.ucsf.edu

Theodore Miclau III, M.D.
Professor, Vice Chairman and Director of Orthopaedic Trauma of the Department of Orthopaedic Surgery 

UC San Francisco
miclaut@orthosurg.ucsf.edu

Michael Nevitt, Ph.D., M.P.H.
Adjunct Professor, Division of Clinical Trials & Multicenter Studies,
UC San Francisco
MNevitt@psg.ucsf.edu

Ann Schwartz, Ph.D., M.P.H.
Professor, Department of Epidemiology and Biostatistics
Director of the San Francisco Coordinating Center DXA Quality Assurance Group 

UC San Francisco
aschwartz@psg.ucsf.edu

Thomas P. Vail, M.D.
Professor and Chair, Department of Orthopaedic Surgery,
UC San Francisco
vailt@orthosurg.ucsf.edu

Daniel Vigneron, Ph.D.
Professor, Director, HMTRC,
UC San Francisco
dan.vigneron@ucsf.edu

 

External Advisory Board

Joseph Buckwalter, M.S., M.D.
Professor and Head of Orthopaedic Surgery
University of Iowa
joseph-buckwalter@uiowa.edu

Kelley Fitzgerald, P.T., Ph.D.
Associate Professor School of Health and Rehabilitation Sciences
University of Pittsburgh
kfitzger@pitt.edu

Garry Gold, Ph.D.
Professor of Radiology,
Stanford University
gold@stanford.edu

Patricia Handeland
Arthritis Foundation
phandeland@arthritis.org

Amir A. Jamali, M.D.
Joint Perservation Institute,
Sacramento, CA
amir.jamali@ucdmc.ucdavis.edu

Robert Sah, M.D., Sc.D.
Professor, Department of Bioengineering,
UC San Diego
rsah@ucsd.edu

The goal will be to show biological and clinical researchers the full range of capabilities that are available to them through the TOQIO and to encourage new collaborations between imaging and clinicians. Another area where education is critical is in training basic researchers and clinicians on how to analyze and interpret the data from these new technically demanding modalities. Imaging courses that form part of the Joint PhD program in Bioengineering (UC San Francisco and UC Berkeley will be publicized to TOQIO faculty. In addition, Dr. Majumdar and Saloner from the Department of Radiology have developed a new Masters in Biomedical Imaging course, which is currently under approval at the University. This program will be a tuition based program, will include new courses, in imaging and processing, and is intended for a diverse set of individuals including medical trainees. We will encourage investigators new to TOQIO to participate in these courses.

The Imaging and Data Analysis and Human Performance and Functional testing core will also provide specific hands-on-training courses focusing on image data acquisition, visualization, processing, and analysis; image interpretation and methods for measuring kinematics. These courses will provide training in how to use new and existing software available through TOQIO. This will be widely advertised through the CTSI /CTSC educational programs and specifically offered to trainees who are interested in integrating imaging and motion analysis into their research projects. In addition, linked with the Friday meetings (FOAM) we will have a monthly agenda for discussing TOQIO related projects. Table 2 lists the draft agenda for these meetings. 

We propose to hold an Annual Symposium coordinated with External Advisory Committee meeting. The annual symposium will feature research conducted by all Projects and Cores. A special session will be held specifically directed to clinicians, which will highlight clinical implications of the research. The symposium will include poster sessions that give students and post-doctoral scholars an opportunity to discuss their work with the External Advisors and a wider audience. Invited attendees will include, at a minimum, all TOQIO participants and the External and Internal Advisory Committee. Additionally, notices will be sent to appropriate academic and research institutions and made available at targeted national scientific and clinician meetings. The symposium will also be advertised to those responding to the electronic subscription service offered on the website.

Melissa Guan
415-­353-­4216
Email: melissa.guan@ucsf.edu

HEALTHY VOLUNTEERS

Are you healthy without knee and/or hip pain?

CORT MRIIf you are over 18 and do not have hip and/or knee pain, you might be eligible to participate in our study which involves:

  • Hip or Knee X-Rays
  • Hip or Knee MRI
  • Functional Analysis

What?

Session 1

  • Knee OR Hip X-Ray
  • Duration up to 15 mins

If found eligible after Session 1

Session 2

  • Knee or Hip MRI
  • Duration up to 1-2 hour

Session 3

  • Functional task (like walking) analysis
  • Duration up to 2 hours 15 min

How many times?

3 times over 4 years

Where?

UC San Francisco - Mission Bay

San Francisco, CA 94158

Compensation

  • Between $ 50-100 for baseline sessions (total for x-ray, MRI and functional testing)
  • Between $75-100 for 1st follow-up (after 1 or 2 years)
  • $100 for 2nd follow-up (after 2 or 4 years)

Why?

The information obtained from this study will contribute to the knowledge on knee and hip osteoarthritis and help clinicians develop much more effective treatment for people affected by these diseases.

Contact Information

Melissa Guan
415-353-4216
melissa.guan@ucsf.edu

Deepak Kumar
Postdoctoral Scholar

1700 4th St, Suite 203

UC San Francisco - Mission Bay, Byers Hall

Dept. of Radiology & Biomedical Imaging

San Francisco, CA 94158

Tel: 415-514-9663

deepak.kumar@ucsf.edu

Incollaboration with:

UC San Francisco