Key Dates

Related Announcements

• April 17, 2023 - Notice of Special Interest (NOSI): Supporting Exploratory/Developmental Research Focused on NIAMS Core Mission Areas. See NOSI NOT-AR-23-006. 
• October 6, 2020 - NIAMS Policy for Acceptance of Clinical Trial Applications and Participation in Parent R01 and R21(Clinical Trial Required) Announcements. See Notice NOT-AR-21-009. 
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required). See NOFO PA-20-196. 
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195. 
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required). See NOFO PA-20-194. 
• May 5, 2020 - NIH Research Project Grant (Parent R01 Research Project Grant, Clinical Trial Not Allowed). See NOFO PA-20-185.
• May 5, 2020 - Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required). See NOFO PA-20-184. 
• May 5, 2020 - Research Project Grant (Parent R01 Clinical Trial Required). See NOFO PA-20-183.  

Issued by

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

National Institute on Aging (NIA)

Purpose

Purpose

The purpose of this NOSIis to notify the research community that the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute on Aging (NIA) are interested in receiving research grant applications that are focused on the use of the Osteoarthritis Initiative (OAI) database, clinical data, and images.  This NOSI seeks to expand the use of these resources by investigators in the broader research community. The publication of this NOSI indicates to investigators and peer reviewers the importance that the NIAMS, NIA, and others have placed on the use of the OAI resources.   

Background

Osteoarthritis (OA), or degenerative joint disease, is the most common form of arthritis. It is a slowly progressing disease characterized clinically by pain, deformity, enlargement of the joints, and limitation of motion. The disease usually occurs late in life and most commonly affects the hand and large weight-bearing joints. The prevalence of OA is difficult to determine because many individuals with radiographic evidence of OA have no symptoms, and the degree of radiological change varies. Approximately 27 million adults have physician-diagnosed OA. In individuals aged 60 and older, OA is estimated to be present in 17 percent of men and 29.6 percent of women. OA is a significant contributor to disability and loss of independence among the elderly. These data reinforce the growing need for therapies that prevent or delay degenerative joint diseases.  While recent advances have yielded highly effective disease-modifying therapies for rheumatoid arthritis, no such therapies exist for osteoarthritis, and current treatment regimens are predominantly designed to relieve pain.  Because of the chronic nature of the disease and variable clinical outcomes, clinical trials for new therapies are difficult, take a long time to conduct, and are exceedingly expensive. One barrier to finding drugs, devices, or nutrients that can halt the painful joint degeneration that characterizes osteoarthritis is the lack of objective, measurable standards of disease diagnosis and progression by which new interventions can be evaluated.  To overcome this problem, and to facilitate and accelerate the development of potential therapies, the NIH partnered with private industry sponsors to develop a resource that any researcher can use to identify and evaluate markers of osteoarthritis.  The OAI, which began in July 2002, has produced a wealth of data for the research community.  Baseline and eight years of follow-up data and images have been released for public use and diagnostic readings of knee x-rays have been posted to allow characterization of incident and progression cases.  Matched biospecimens, including serum, DNA, peripheral blood RNA, and urine are also available for a number of visits.

While there are many registered users of the OAI website worldwide, the number of research grant applications using this resource submitted to and funded by NIH are relatively limited. The purpose of this NOSI is to accelerate discoveries related to the onset and progression of knee osteoarthritis with particular emphasis on the development of objective, measurable standards of osteoarthritis diagnosis and progression by which new interventions can be evaluated.

Description of OAI Resources: Participants in the OAI were recruited at five clinical facilities located in four U.S. cities. Individuals who were eligible based on the telephone evaluation were invited to a Screening Clinic Visit for assessment of additional eligibility and exclusion criteria, MRI contraindications, and to obtain the baseline tibiofemoral knee radiograph. Radiographs were read locally to determine the presence of knee OA and exclusions for bilateral end-stage disease (these and follow up x-rays have been subsequently read centrally). The cohort consists of 4796 subjects (96% of goal) with 58% women and 21% minority participants. The study sample represents three subgroups: 1) Progression cohort (29%) - those with clinically significant knee OA who are at risk for disease progression; 2) Incidence cohort (69%) - those who do not have  but are at high risk for developing, clinically significant knee OA; and "Non-exposed" cohort (2%) - those without risk factors or radiographic evidence of OA.  The first group represents individuals likely to be included in clinical trials of treatments for knee OA, while the second group represents persons for whom prevention of disease may be possible. Participants in the Progression cohort have symptomatic knee OA at the baseline exam, defined as the presence in at least one knee of frequent knee symptoms in the past 12 months (pain, aching or stiffness in or around the knee on most days for at least one month) and radiographic tibiofemoral knee OA (definite tibiofemoral osteophytes, or OARSI atlas osteophyte grades 1-3) based on a reading of the baseline posterior-anterior (PA) knee radiograph by a radiologist or rheumatologist at the clinical center at this visit. A small (122) group of "non-exposed" control subjects without risk factors or disease was also enrolled. Enrollment visits occurred within 3 to 6 weeks of screening. At this visit, baseline questionnaires, knee MRIs, physical exams, additional joint radiographs, and blood and urine specimens were obtained. Follow-up visits occurred either in a clinic or by phone interview on a yearly basis for 8 years. Dedicated 3.0 Tesla Siemens Trio MR scanners were installed at four clinical centers for exclusive use by the OAI Clinical Centers.  The OAI opted to use 3.0 T MR because of the advantage over lower field scanners in signal-to-noise ratio, which can potentially be traded off for spatial resolution and/or imaging speed, and to extend the useful life of the MRI data.  These images are archived at and available for use as a public resource at OAI Home.

Another primary goal of the OAI has been the development of archived blood, urine, and DNA specimens.  These are available to investigators, through a formal application and review process (OAI Home) for testing and validation of biochemical markers of OA.  Morning blood and second morning void urine specimens, after an overnight fast, have been collected.  Follow-up visit blood draws are scheduled within +/-1 hour of the time of the baseline blood draw. The majority of blood is processed and stored as serum. A smaller amount of blood is processed and saved as plasma to accommodate assays that may require plasma.  Buffy coat from the plasma samples is saved for DNA extraction and extracted DNA is also available.  PAXgeneTM tubes are used to collect blood for RNA extraction.  All specimens have been stored at >–70°C. In addition, genomic data from the ancillary Genetic Components of Knee Osteoarthritis (GeCKO) study, a genome-wide association study on the entire OAI cohort is available at the NCBI dbGaP website.

The core clinical measurements (examinations and questionnaires) include assessment of joints and OA outcomes, general health and functioning, and risk factors for knee OA.  Joint assessments and OA outcomes focus on the knee, with a secondary emphasis on the hip, hand, and other common sites of joint symptoms. Knee assessments cover the four core outcome domains of pain, physical function, patient global assessment, and joint imaging, as recommended for OA clinical trials.  Knee pain, stiffness, and knee-related physical function are assessed using the WOMAC Osteoarthritis Index TM (version LK 3.1) and ask about the right and left knee separately during the past 7 days. When utilized in a joint-specific fashion it has been shown to discriminate between outcomes in opposite joint in the same patients. The non-WOMAC components of the Knee Outcomes in Osteoarthritis Survey (KOOS) are administered to assess knee symptoms and function during more demanding activities (e.g. sport and recreation) that are relevant to somewhat younger subjects with knee injuries or post-injury arthritis, which are both common in OAI participants.  Global knee pain severity during the past 7 and 30 days is assessed using an 11-point numerical rating scale, which is easy to administer and score, including over the telephone, and can be used with a greater variety of subjects than can a visual analog scale.  A patient global assessment of the overall impact of knee problems on the participant's sense of well-being also uses an 11-point numerical rating scale. In addition to the eligibility risk factors assessed during screening (see above), other baseline risk factor assessments include detailed questions about prior knee surgeries and  the frequency of activities requiring knee bending.  Dietary and supplement intake of nutrients of potential importance for OA or that may affect biochemical marker levels during the study data is collected using the Brief Block Questionnaire 2000, as well as with targeted questions.  Weight and height are measured for the calculation of body mass index and abdominal circumference is assessed as a measure of central adiposity associated with abnormalities of the metabolic syndrome that may affect the risk of OA.

There are six annual follow-up clinic visits (at 12, 24, 36, 48, 72, and 96 months after baseline) for all participants. There are associated MRI scans and radiographs of the knees (BL, 12, 24, 36, 48, 72, 96 months), MRI scans of the thigh (BL, 24, and 48 months), bi-lateral full-limb x-rays (one time only at 12 or 24 or 36 months) and radiographs of the hips and hands (BL, 48, 96 months). More limited data are collected by phone interviews at 60 and 84 months after baseline.  Approximately 800 participants in the Progression sub-cohort will also have a knee MRI, biospecimen collection and outcome assessment at the midway point between two annual follow-up visits, either at 18 or at 30 months after baseline. All data and images are available at OAI Home.

Scope

This NOSI encourages the use of the OAI database, clinical data and images by the broader research community. Examples of possible topics, but not limited to, are listed below:

• Identification and validation of novel risk factors for knee and hip OA, including both modifiable and non-modifiable risk factors.
• Utilization of biospecimens in conjunction with research efforts to determine biochemical markers of early and/or progressive disease.
• Utilization of biospecimens in conjunction with imaging and clinical data for more precise phenotyping patients.
• Analyses of existing OAI data for prediction and /or modeling of possible effectiveness of bio-behavioral, pharmacological, and other interventions that subjects use in response to OA pain.
• Determination of the predictive role of MRI changes for subsequent radiographic and clinical outcome changes related to the development of knee OA.
• Development of novel and efficient tools for analysis of MR images and X-rays that can be applied to large numbers of images with high degrees of reproducibility for diagnosis and monitoring of OA-related changes.Research  focused on the trajectory of disease including effects on other joint structures such as muscles, ligaments, and bone, with regard to points where interventions could be made, especially for subsets, to reduce OA severity.
• Ancillary studies in conjunction with the existing follow-up on the OAI cohort to enhance the understanding of the long-term consequences of osteoarthritis and its relationship to other musculoskeletal disorders; and
• Investigations that combine data from the OAI with that from other compatible cohorts to address more broad questions related to the development of OA-related disability. Other cohorts to be considered include but are not limited to:
  • Multicenter Osteoarthritis Study (MOST): http://most.ucsf.edu/default.asp
  • Health, Aging, and Body Composition (Health ABC):http://www.grc.nia.nih.gov/branches/ledb/healthabc/
  • Baltimore Longitudinal Study of Aging (BLSA): http://www.blsa.nih.gov/.
• Leverage novel artificial intelligence, deep learning, and other data science tools to improve data curation, integration, and meaningful clinical interpretation of OA-related data; and
• Building a complex model using multimodal data with different scales that can predict clinical outcomes with greater accuracy than single-domain predictions alone.
• Leverage real-world  data from electronic health records and other sources to evaluate treatment response and adverse outcomes, and to reduce racial disparities in OA health outcomes.

While the Osteoarthritis Initiative resource has been used widely by OAI investigators, musculoskeletal imagers, and others, rich opportunities remain for the exploration of OAI data and images, analysis of the epidemiology and natural history of osteoarthritis, and application of emerging technologies to the biospecimens and genetic data.  Additionally, the resource can also serve as an excellent training vehicle within the area of musculoskeletal research and bring together non-OAI investigators from a variety of disciplines.

Connection to Strategic Plan: Advancing and Accelerating Joint Biology, Diseases, and Orthopaedics Research; Data science, computational science, and artificial intelligence

Application and Submission Information

This notice applies to due dates on or after October 5, 2024, and subsequent receipt dates through September 7, 2027. 

Submit applications for this initiative using one of the following notices of funding opportunity (NOFOs) or any reissues of these announcements through the expiration date of this notice.

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AR-24-019” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Xincheng Zheng, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Email: xincheng.zheng@nih.gov

Lyndon Joseph, Ph.D.
National Institute of Aging (NIA)
Email: lyndon.joseph@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 
Email: erik.edgerton@nih.gov

Laura Pone
National Institute of Aging (NIA)
Phone: 301-451-9956 
Email: laura.pone@nih.gov