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1.  Differences in multi-joint radiographic osteoarthritis phenotypes among African Americans and Caucasians: The Johnston County Osteoarthritis Project 
Arthritis and rheumatism  2011;63(12):3843-3852.
To define and contrast multiple joint radiographic osteoarthritis (rOA) phenotypes describing hand and whole-body rOA among African Americans and Caucasians.
We conducted a cross-sectional analysis in the Johnston County Osteoarthritis Project, using radiographic data for the hands, tibiofemoral (TFJ) and patellofemoral joints, hips, and lumbosacral spine (LS). Films were read for rOA by a single radiologist using standard atlases. Sixteen mutually exclusive hand (n=2083) and 32 whole-body rOA phenotypes (n=1419) were identified. Fisher’s exact tests, corrected for multiple comparisons, were used to compare phenotype frequencies by race and gender. Logistic regression was used to provide odds ratios adjusted for gender, age, and body mass index (BMI).
Hand rOA phenotypes: African Americans compared with Caucasians had significantly less frequent rOA of the distal interphalangeal joints, in isolation and in combination with other hand joint sites, but comparable frequencies of rOA for other hand joint sites. Whole-body rOA phenotypes: African Americans compared with Caucasians had less frequent Hand rOA, in isolation and in combination with other joint sites. In contrast, African Americans compared with Caucasians had more than twice the odds of isolated TFJ rOA and 77% higher odds of TFJ and LS rOA together.
Even after adjustment for gender, age, and BMI, African Americans compared to Caucasians were less likely to have hand rOA phenotypes, but more likely to have knee rOA phenotypes involving the TFJ. African Americans may have a higher burden of multiple large joint OA involvement not captured by most definitions of “generalized OA.”
PMCID: PMC3227756  PMID: 22020742
2.  Urinary CTX‐II levels are associated with radiographic subtypes of osteoarthritis in hip, knee, hand, and facet joints in subject with familial osteoarthritis at multiple sites: the GARP study 
Annals of the Rheumatic Diseases  2005;65(3):360-365.
To assess the relation between the urinary concentrations of type II collagen C‐telopeptide (UCTX‐II) and radiographic signs of osteoarthritis (ROA) in the GARP (Genetics, Arthrosis and Progression) study.
UCTX‐II levels were measured in GARP study participants, who are sibling pairs predominantly with symptomatic osteoarthritis at multiple sites. Kellgren and Lawrence scores were used to assess ROA in the knees, hips, hands, and vertebral facet joints, and spinal disc degeneration. A proportionate score was made for each joint location, based on the number of joints with ROA. The sum total ROA score represents a measure of cartilage abnormalities within each patient. By using linear mixed models the total ROA score and the joint site specific ROA scores were correlated with the UCTX‐II level.
In 302 subjects the mean (SD) and median (range) for UCTX‐II were 265 (168) and 219 (1346) ng/mmol creatine, respectively. There was a significant association between the total ROA score and UCTX‐II levels. Subsequent multivariate analysis showed that the joint site specific ROA score at all joint sites, except for spinal disc degeneration, contributed independently to this association.
The total ROA score of GARP patients, representing cartilage abnormalities at the most prevalent ROA joint locations, showed an excellent correlation with UCTX‐II levels. The specific ROA scores at the hip, hand, facet, and knee joints additively and independently explained this association. Even in patients with osteoarthritis at multiple sites, UCTX‐II may be a sensitive quantitative marker of ROA.
PMCID: PMC1798062  PMID: 16079167
osteoarthritis; CTX‐II; GARP study; biomarker
3.  The Prevalence of Knee Osteoarthritis in Elderly Community Residents in Korea 
Journal of Korean Medical Science  2010;25(2):293-298.
The purpose of this study was to estimate the prevalence of radiographic and symptomatic knee osteoarthritis (OA) among community residents and to elucidate the relevant risk factors. This prospective, population-based study was conducted on residents over 50 yr of age in Chuncheon. Subjects completed an interview based on a standardized questionnaire and clinical evaluation including standardized weight bearing semiflexed knee A-P radiographs. We defined a subject with the Kellgren and Lawrence grade ≥2 as having radiographic knee OA (ROA). Symptomatic knee OA (SOA) was defined by the presence of both ROA and knee pain. We obtained symptom information and radiographs from 504 subjects. The prevalence of ROA and SOA was 37.3% and 24.2%, respectively. The prevalence of both ROA and SOA was significantly higher among women than among men. Multivariate analysis revealed that the presence of hypertension, and a manual occupation were significantly associated with the presence of ROA and SOA. Lower level of education was significantly associated with the presence of ROA, and female sex with the presence of SOA. In conclusion, both ROA and SOA are common in the aged adult population of Korea, with preponderance for women.
PMCID: PMC2811300  PMID: 20119586
Osteoarthritis, Knee; Risk Factors; Prevalence
4.  Insulin-like growth factor I gene promoter polymorphism, collagen type II α1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study 
Annals of the Rheumatic Diseases  2004;63(5):544-548.
Objective: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene.
Methods: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested.
Results: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years.
Conclusions: Subjects with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested.
PMCID: PMC1754973  PMID: 15082485
5.  Meeting Physical Activity Guidelines and the Risk of Incident Knee Osteoarthritis: The Johnston County Osteoarthritis Project 
Arthritis care & research  2014;66(1):139-146.
Knee osteoarthritis (OA) remains a leading cause of disability and joint pain. Though other risk factors of knee OA have been identified, how physical activity affects incident knee OA remains unclear.
Using data from the Johnston County Osteoarthritis Project study’s first (1999–2004) and second follow-up (2005–2010), we tested the association between meeting physical activity guidelines and incident knee outcomes among 1522 adults aged ≥ 45 years. The median (range) follow-up time was 6.5 (4.0–10.2) years. Physical activity at baseline (moderate-equivalent min/week) was calculated using the Minnesota Leisure Time Physical Activity questionnaire. Incident knee radiographic OA (ROA) was defined as the development of a Kellgren-Lawrence grade of ≥ 2 in a knee at follow-up. Incident knee symptomatic ROA (sROA) was defined as the development of ROA and symptoms in at least one knee at follow-up. Weibull regression modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for interval censored data.
In multivariable models, meeting the 2008 HHS physical activity guidelines (≥150 min/week) was not significantly associated with ROA (HR: 1.20; 95% CI=0.94, 1.56) or sROA (HR: 1.24; 95% CI=0.87, 1.76). Adults in the highest (≥300 min/week) level of physical activity had a higher risk of knee ROA and sROA compared with inactive (0-<10 min/week) participants; however these associations were not statistically significant (HR: 1.62; 95% CI=0.97, 2.68 and HR: 1.42; 95% CI=0.76, 2.65, respectively).
Meeting HHS physical activity guidelines was not associated with incident knee ROA or sROA in a cohort of middle-aged and older adults.
PMCID: PMC4309362  PMID: 23983187
physical activity; radiographic and symptomatic knee osteoarthritis; incidence; Weibull regression modeling; interval censoring
6.  Serum transforming growth factor-beta 1 is not a robust biomarker of incident and progressive radiographic osteoarthritis at the hip and knee: The Johnston County Osteoarthritis Project 
To test whether serum transforming growth factor-beta 1 (TGF-β1) predicts incident and progressive hip or knee radiographic OA (rOA).
Serum TGF-β1 was measured for 330 participants aged 45 years and older in the Johnston County Osteoarthritis Project, with paired longitudinal films available for 618 hips and 658 knees. Incident and progressive rOA were defined using Kellgren-Lawrence (K-L) grade as well as osteophyte (OST) and joint space narrowing scores (JSN). Natural logarithm transformation was used to produce near-normal distributions for continuous TGF-β1 (lnTGF-β1). Separate multivariable Weibull regression models were used to provide hazard ratios (HR) for a 1-unit increase lnTGF-β1 with each rOA outcome, accounting for variable follow-up times and clustering by individual, adjusted for age, race, gender, and body mass index (BMI). Interaction terms were considered statistically significant at p <0.10.
The mean (±SD) age of the sample was 61.9 ± 9.7 years, the mean BMI was 30.3 ± 6.9 kg/m2, with 60.6% women and 42.4% AA. The mean (± SD) TGF-β1 was 17.8 ± 6.1 ng/ml; follow up time was 6.1 ± 1.3 years. There were no significant interac tions by race or gender. HRs showed no significant relationship between lnTGF-β1 and incident or progressive rOA, OST, or JSN, at the knee or the hip.
Levels of TGF-β1 do not predict incident or progressive rOA, OST, or JSN at the hip or knee in this longitudinal, population-based study, making it unlikely that TGF-β1 will be a robust biomarker for rOA in future studies.
PMCID: PMC2873050  PMID: 20206313
Osteoarthritis; Biomarkers; Transforming growth factor-beta 1 (TGF-β1); Radiography
7.  Hazard of Incident and Progressive Knee and Hip Radiographic Osteoarthritis and Chronic Joint Symptoms in Individuals with and without Limb Length Inequality 
The Journal of rheumatology  2010;37(10):2133-2140.
Examine the hazard of incident and progressive radiographic OA (rOA) and chronic joint symptoms at the hip and knee by limb length inequality (LLI) in a large, community-based sample.
A longitudinal cohort completed baseline (1991–1997) clinical evaluation and identical follow-up assessment (1999–2003) (median follow-up time = 5.9 years, range=3.0–13.1 years). LLI was defined at baseline as a measured difference between limbs of ≥ 2 cm. The study groups with LLI data comprised 1,583 participants with paired (baseline and follow-up) knee radiographs and 1,453 participants with paired hip radiographs. Multivariable Cox regression models were used to examine the hazard of incident and progressive knee and hip rOA and chronic joint symptoms, while adjusting for demographic and clinical factors.
The hazard of developing incident knee or hip rOA was 20–30% higher and of developing progressive knee or hip rOA was 35–83% higher among participants with LLI, but results were only statistically significant for progressive knee rOA (adjusted hazard ratio = 1.83, 95% confidence interval = 1.10–3.05). The hazards of progressive chronic knee symptoms and incident and progressive chronic hip symptoms were 13–59% higher among participants with LLI, but were not statistically significant.
LLI was associated with progressive knee rOA and was non-significantly associated with incident knee or hip rOA and progressive hip rOA, progressive chronic knee symptoms, and incident and progressive chronic hip symptoms. Longer studies may strengthen these associations and help determine whether LLI is a risk factor or marker of these outcomes.
PMCID: PMC4077024  PMID: 20634243
8.  Failure of serum transforming growth factor-beta (TGF-β1) as a biomarker of radiographic osteoarthritis at the knee and hip: A cross-sectional analysis in the Johnston County Osteoarthritis Project 
To assess associations between serum TGF-β1 and radiographic knee and hip osteoarthritis (rOA) in African American (AA) and White men and women.
Baseline data from 330 participants in the Johnston County Osteoarthritis Project were used in the analysis. Radiographs were scored with the Kellgren-Lawrence scale and rOA defined as grade ≥ 2. Individual radiographic features (IRFs) were rated 0–3. TGF-β1 was measured using a sandwich ELISA. General linear models were used to estimate associations between lnTGF-β1 and rOA presence, laterality or severity, and IRF presence and severity, adjusting for age, gender, race, and body mass index. Interactions by race and gender were considered significant at p < 0.1.
Mean lnTGF-β1 levels were higher among AAs compared to Whites, and among women compared to men (p<0.009). Mean lnTGF-β1 levels were higher in those with knee OST, but this association was not significant after adjustment. There were no other significant differences in mean lnTGF-β1 levels by presence, laterality, or severity of knee or hip rOA or IRFs. No race or gender interactions were identified, although a borderline significant association between lnTGF-β1 and knee OST was seen among AAs (p < 0.06).
Although serum TGF-β1 varied by race and gender and several rOA variables, there were no independent significant associations with presence, laterality, or severity of knee or hip rOA by K-L grade or IRFs, suggesting that serum TGF-β1 is unlikely to be useful as a stand-alone biomarker in OA studies. A possible association between TGF-β1 and OST in AAs cannot be excluded.
PMCID: PMC2746496  PMID: 19091605
Biomarkers; Transforming growth factor-beta (TGF-β1); Radiography
9.  Prevalence and pattern of radiographic hand osteoarthritis and association with pain and disability (the Rotterdam study) 
Annals of the Rheumatic Diseases  2004;64(5):682-687.
Objective: To investigate the prevalence and pattern of radiographic osteoarthritis (ROA) of the hand joints and its association with self reported hand pain and disability.
Methods: Baseline data on a population based study (age ⩾55 years) were used (n = 3906). Hand ROA was defined as the presence of Kellgren–Lawrence grade ⩾2 radiological changes in two of three groups of hand joints in each hand. The presence of hand pain during the previous month was defined as hand pain. The health assessment questionnaire was used to measure hand disability.
Results: 67% of the women and 54.8% of the men had ROA in at least one hand joint. DIP joints were affected in 47.3% of participants, thumb base in 35.8%, PIP joints in 18.2%, and MCP joints in 8.2% (right or left hand). ROA of other joint groups (right hand) co-occurred in 56% of DIP involvement, 88% of PIP involvement, 86% of MCP involvement, and 65% of thumb base involvement. Hand pain showed an odds ratio of 1.9 (1.5 to 2.4) with the ROA of the hand (right). Hand disability showed an odds ratio of 1.5 (1.1 to 2.1) with ROA of the hand (right or left).
Conclusions: Hand ROA is common in the elderly, especially in women. Co-occurrence of ROA in different joint groups of the hand is more common than single joint disease. There is a modest to weak association between ROA of the hand and hand pain/disability, varying with the site of involvement.
PMCID: PMC1755481  PMID: 15374852
10.  Whole blood lead levels are associated with radiographic and symptomatic knee osteoarthritis: a cross-sectional analysis in the Johnston County Osteoarthritis Project 
Lead (Pb) is known to affect bone, and recent evidence suggests that it has effects on cartilage as well. As osteoarthritis (OA) is a highly prevalent disease affecting bone and cartilage, we undertook the present analysis to determine whether whole blood Pb levels are associated with radiographic and symptomatic OA (rOA and sxOA, respectively) of the knee.
The analysis was conducted using cross-sectional data from the Johnston County Osteoarthritis Project, a rural, population-based study, including whole blood Pb levels, bilateral posteroanterior weight-bearing knee radiography and knee symptom data. rOA assessment included joint-based presence (Kellgren-Lawrence (K-L) grade 2 or higher) and severity (none, K-L grade 0 or 1; mild, K-L grade 2; moderate or severe, K-L grade 3 or 4), as well as person-based laterality (unilateral or bilateral). SxOA was deemed present (joint-based) in a knee on the basis of K-L grade 2 or higher with symptoms, with symptoms rated based on severity (0, rOA without symptoms; 1, rOA with mild symptoms; 2, rOA with moderate or severe symptoms) and in person-based analyses was either unilateral or bilateral. Generalized logit or proportional odds regression models were used to examine associations between the knee OA status variables and natural log-transformed blood Pb (ln Pb), continuously and in quartiles, controlling for age, race, sex, body mass index (BMI), smoking and alcohol drinking.
Those individuals with whole blood Pb data (N = 1,669) had a mean (±SD) age of 65.4 (±11.0) years and a mean BMI of 31.2 (±7.1) kg/m2, including 66.6% women and 35.4% African-Americans, with a median blood Pb level of 1.8 μg/dl (range, 0.3 to 42.0 μg/dl). In joint-based analyses, for every 1-U increase in ln Pb, the odds of prevalent knee rOA were 20% higher (aOR, 1.20; 95% CI, 1.01 to 1.44), while the odds of more severe rOA were 26% higher (aOR, 1.26; 95% CI, 1.05 to 1.50, under proportional odds). In person-based analyses, the odds of bilateral rOA were 32% higher for each 1-U increase in ln Pb (aOR, 1.32; 95% CI, 1.03 to 1.70). Similarly for knee sxOA, for each 1-U increase in ln Pb, the odds of having sxOA were 16% higher, the odds of having more severe symptoms were 17% higher and the odds of having bilateral knee symptoms were 25% higher. Similar findings were obtained with regard to ln Pb in quartiles.
Increases in the prevalence and severity measures for both radiographically and symptomatically confirmed knee OA (although statistically significant only for rOA) were observed with increasing levels of blood Pb, suggesting that Pb may be a potentially modifiable environmental risk factor for OA.
PMCID: PMC3132016  PMID: 21362189
11.  Gender difference in symptomatic radiographic knee osteoarthritis in the Knee Clinical Assessment – CAS(K): A prospective study in the general population 
A recent study of adults aged ≥50 years reporting knee pain found an excess of radiographic knee osteoarthritis (knee ROA) in symptomatic males compared to females. This was independent of age, BMI and other clinical signs and symptoms. Since this finding contradicts many previous studies, our objective was to explore four possible explanations for this gender difference: X-ray views, selection, occupation and non-articular conditions.
A community-based prospective study. 819 adults aged ≥50 years reporting knee pain in the previous 12 months were recruited by postal questionnaires to a research clinic involving plain radiography (weight-bearing posteroanterior semiflexed, supine skyline and lateral views), clinical interview and physical examination. Any knee ROA, ROA severity, tibiofemoral joint osteoarthritis (TJOA) and patellofemoral joint osteoarthritis (PJOA) were defined using all three radiographic views. Occupational class was derived from current or last job title. Proportions of each gender with symptomatic knee ROA were expressed as percentages, stratified by age; differences between genders were expressed as percentage differences with 95% confidence intervals.
745 symptomatic participants were eligible and had complete X-ray data. Males had a higher occurrence (77%) of any knee ROA than females (61%). In 50–64 year olds, the excess in men was mild knee OA (particularly PJOA); in ≥65 year olds, the excess was both mild and moderate/severe knee OA (particularly combined TJOA/PJOA). This male excess persisted when using the posteroanterior view only (64% vs. 52%). The lowest level of participation in the clinic was symptomatic females aged 65+. Within each occupational class there were more males with symptomatic knee ROA than females. In those aged 50–64 years, non-articular conditions were equally common in both genders although, in those aged 65+, they occurred more frequently in symptomatic females (41%) than males (31%).
The excess of knee ROA among symptomatic males in this study seems unlikely to be attributable to the use of comprehensive X-ray views. Although prior occupational exposures and the presence of non-articular conditions cannot be fully excluded, selective non-participation bias seems the most likely explanation. This has implications for future study design.
PMCID: PMC2443794  PMID: 18547403
12.  Independent associations of socioeconomic factors with disability and pain in adults with knee osteoarthritis 
The purpose of this study is to explore the relationship between function, pain and stiffness outcomes with individual and community socioeconomic status (SES) measures among individuals with radiographic knee osteoarthritis (rOA).
Cross-sectional data from the Johnston County Osteoarthritis Project were analyzed for adults age 45 and older with knee rOA (n = 782) and a subset with both radiographic and symptomatic knee OA (n = 471). Function, pain and stiffness were measured using the Western Ontario and McMasters Universities Index of Osteoarthritis (WOMAC). Individual SES measures included educational attainment (<12 years, ≥12 years) and occupation type (managerial, non-managerial), while community SES was measured using Census block group poverty rate (<12%, 12-25%, ≥25%). SES measures were individually and simultaneously examined in linear regression models adjusting for age, gender, race, body mass index (BMI), occupational physical activity score (PAS), comorbidity count, and presence of hip symptoms.
In analyses among all individuals with rOA, models which included individual SES measures were observed to show that occupation was significantly associated with WOMAC Function (β =2.91, 95% Confidence Interval (CI) = 0.68-5.14), WOMAC Pain (β =0.93, 95% CI = 0.26-1.59) and WOMAC Total scores (β =4.05, 95% CI = 1.04-7.05), and education was significantly associated with WOMAC Function (β =3.57, 95% CI = 1.25-5.90) and WOMAC Total (β =4.56, 95% CI = 1.41-7.70) scores. In multivariable models including all SES measures simultaneously, most associations were attenuated. However, statistically significant results for education remained between WOMAC Function (β =2.83, 95% CI = 0.38-5.28) and WOMAC Total (β =3.48, 95% CI = 0.18-6.78), as well as for the association between occupation and WOMAC Pain (β =0.78, 95% CI = 0.08-1.48). In rOA subgroup analyses restricted to those with symptoms, we observed a significant increase in WOMAC Pain (β =1.36, 95% CI = 0.07-2.66) among individuals living in a block group with poverty rates greater than 25%, an association that remained when all SES measures were considered simultaneously (β =1.35, 95% CI = 0.06-2.64).
Lower individual and community SES are both associated with worse function and pain among adults with knee rOA.
PMCID: PMC3906978  PMID: 24134116
Osteoarthritis; Knee; Pain evaluation; Education; Occupation; Poverty; Social class; Socioeconomic
13.  Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis 
Bone  2015;71:171-179.
We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip.
HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12.
609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%.
Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.
•We examined associations between high bone mass and radiographic knee osteoarthritis (OA).•High bone mass cases had an increased prevalence of knee OA compared with controls.•The OA phenotype in high bone mass is characterised by osteophytosis.•Body mass index is a partial mediator of the high bone mass–OA association.
PMCID: PMC4289915  PMID: 25445455
Osteoarthritis; DXA; Bone mineral density; High bone mass
14.  Is symptomatic knee osteoarthritis a risk factor for a fast decline in gait speed? Results from the Osteoarthritis Initiative 
Arthritis care & research  2013;65(2):187-194.
Gait speed is an important marker of health in adults and slows with aging. While knee osteoarthritis (OA) can result in difficulty walking, it is not known if radiographic knee OA (ROA) and/or knee pain are associated with a fast decline trajectory of gait speed over time.
Gait speed trajectories were constructed using a multinomial modeling strategy from repeated 20-meter walk tests measured annually over four years among participants from the Osteoarthritis Initiative (OAI), a prospective cohort study of adults with or at high risk of knee OA aged 45 to 79 at baseline. We grouped participants into four knee OA categories (having neither ROA nor knee pain, ROA only, knee pain only, or symptomatic knee OA (ROA and pain)) and examined their association with trajectories of gait speed using a multivariable polytomous regression model adjusting for age and other potential confounders.
Of the 4179 participants (mean age (sd) = 61.1 (9.1), women =57.6%, mean BMI =28.5 (4.8) kg/m2), 5% (n=205) were in a fast decline trajectory slowing 2.75%/year. People with symptomatic knee OA had almost a 9-fold risk (OR = 8.9, 95% CI [3.1, 25.5]) of being in a fast decline trajectory compared with those with neither pain nor ROA. Participants with knee pain had 4.5 times the odds of fast decline (95% CI [1.4, 14.6]) and those with ROA only had a slight but non-statistically significant increased risk.
People with symptomatic knee OA have the highest risk of fast decline trajectory of gait speed compared with people with ROA or pain alone.
PMCID: PMC3529801  PMID: 22899342
Gait speed; Knee Osteoarthritis; Trajectory
15.  Radiographic assessment of the femorotibial joint of the CCLT rabbit experimental model of osteoarthritis 
BMC Medical Imaging  2010;10:3.
The purposes of the study were to determine the relevance and validity of in vivo non-invasive radiographic assessment of the CCLT (Cranial Cruciate Ligament Transection) rabbit model of osteoarthritis (OA) and to estimate the pertinence, reliability and reproducibility of a radiographic OA (ROA) grading scale and associated radiographic atlas.
In vivo non-invasive extended non weight-bearing radiography of the rabbit femorotibial joint was standardized. Two hundred and fifty radiographs from control and CCLT rabbits up to five months after surgery were reviewed by three readers. They subsequently constructed an original semi-quantitative grading scale as well as an illustrative atlas of individual ROA feature for the medial compartment. To measure agreements, five readers independently scored the same radiographic sample using this atlas and three of them performed a second reading. To evaluate the pertinence of the ROA grading scale, ROA results were compared with gross examination in forty operated and ten control rabbits.
Radiographic osteophytes of medial femoral condyles and medial tibial condyles were scored on a four point scale and dichotomously for osteophytes of medial fabella. Medial joint space width was scored as normal, reduced or absent. Each ROA features was well correlated with gross examination (p < 0.001). ICCs of each ROA features demonstrated excellent agreement between readers and within reading. Global ROA score gave the highest ICCs value for between (ICC 0.93; CI 0.90-0.96) and within (ICC ranged from 0.94 to 0.96) observer agreements. Among all individual ROA features, medial joint space width scoring gave the highest overall reliability and reproducibility and was correlated with both meniscal and cartilage macroscopic lesions (rs = 0.68 and rs = 0.58, p < 0.001 respectively). Radiographic osteophytes of the medial femoral condyle gave the lowest agreements while being well correlated with the macroscopic osteophytes (rs = 0.64, p < 0.001).
Non-invasive in vivo radiography of the rabbit femorotibial joint is feasible, relevant and allows a reproducible grading of experimentally induced OA lesion. The radiographic grading scale and atlas presented could be used as a template for in vivo non invasive grading of ROA in preclinical studies and could allow future comparisons between studies.
PMCID: PMC2828401  PMID: 20089151
16.  Rates of change and Sensitivity to Change in Cartilage Morphology in Healthy Knees and in Knees with Mild, Moderate, and End Stage Radiographic Osteoarthritis 
Arthritis care & research  2011;63(3):311-319.
To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (ROA), specifically healthy knees and knees with end-stage ROA.
One knee of 831 Osteoarthritis Initiative (OAI) participants was examined: 112 healthy, without ROA or risk factors for knee OA, and 719 ROA knees: 310 calculated Kellgren Lawrence [cKLG] grade 2, 300 cKLG3, and 109 cKLG4. Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and at one year from coronal MRI. Regional and ordered values (OV) of change were compared by baseline ROA status.
Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed around zero. In cKLG2 knees, changes in cartilage thickness were small (≤1%; minimal SRM -0.22) and not significantly different from healthy knees. Knees with cKLG3 showed substantial loss of cartilage thickness (up to -2.5%; minimal SRM -0.35), with OV changes being significantly (p<0.05) greater than those in healthy knees. cKLG4 knees displayed the largest rate of loss across ROA grades (up to -3.9%; minimal SRM -0.51), with OV changes also significantly (p<0.05) greater than in healthy knees.
MRI-based cartilage thickness showed high rates of loss in knees with moderate and end-stage ROA, and small rates (indistinguishable from healthy knees) in mild ROA. From the perspective of sensitivity to change, end-stage ROA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an endpoint.
PMCID: PMC3106126  PMID: 20957657
End-stage; Radiographic osteoarthritis; sensitivity to change; cartilage thickness; magnetic resonance imaging
17.  Quantification of the whole-body burden of radiographic osteoarthritis using factor analysis 
Arthritis Research & Therapy  2011;13(5):R176.
Although osteoarthritis (OA) commonly involves multiple joints, no widely accepted method for quantifying whole-body OA burden exists. Therefore, our aim was to apply factor analytic methods to radiographic OA (rOA) grades across multiple joint sites, representing both presence and severity, to quantify the burden of rOA.
We used cross-sectional data from the Johnston County Osteoarthritis Project. The sample (n = 2092) had a mean age of 65 ± 11 years, body mass index (BMI) 31 ± 7 kg/m2, with 33% men and 34% African Americans. A single expert reader (intra-rater κ = 0.89) provided radiographic grades based on standard atlases for the hands (30 joints, including bilateral distal and proximal interphalangeal [IP], thumb IP, metacarpophalangeal [MCP] and carpometacarpal [CMC] joints), knees (patellofemoral and tibiofemoral, 4 joints), hips (2 joints), and spine (5 levels [L1/2 to L5/S1]). All grades were entered into an exploratory common factor analysis as continuous variables. Stratified factor analyses were used to look for differences by gender, race, age, and cohort subgroups.
Four factors were identified as follows: IP/CMC factor (20 joints), MCP factor (8 joints), Knee factor (4 joints), Spine factor (5 levels). These factors had high internal consistency reliability (Cronbach's α range 0.80 to 0.95), were not collapsible into a single factor, and had moderate between-factor correlations (Pearson correlation coefficient r = 0.24 to 0.44). There were no major differences in factor structure when stratified by subgroup.
The 4 factors obtained in this analysis indicate that the variables contained within each factor share an underlying cause, but the 4 factors are distinct, suggesting that combining these joint sites into one overall measure is not appropriate. Using such factors to reflect multi-joint rOA in statistical models can reduce the number of variables needed and increase precision.
PMCID: PMC3308111  PMID: 22027269
Radiography; osteoarthritis; factor analysis
18.  The Association of Disability and Pain with Individual and Community Socioeconomic Status in People with Hip Osteoarthritis 
To examine associations between disability and socioeconomic status (SES) in persons with hip radiographic OA (rOA) or symptomatic OA (sxOA) in the Johnston County Osteoarthritis Project.
Cross-sectional analyses were conducted on individuals with hip rOA (708) or sxOA (251). rOA was defined as Kellgren-Lawrence ≥ 2. Educational attainment (<12 years or ≥12 years) and occupation (managerial or non-managerial) were individual SES measures. Census block group poverty rate (<12%, 12-25%, ≥25%) was the community SES measure. Disability was measured by the HAQ-DI and the WOMAC (function, pain, total). Covariates included age, gender, race, BMI, and presence of knee symptoms. Analyses examined associations of disability with each SES effect separately, followed by multivariable analyses using all SES variables, adjusting for covariates.
In models with single SES variables adjusted for covariates, WOMAC scores were associated significantly (p<0.05) with low educational attainment and non-managerial occupation in rOA and sxOA. HAQ was significantly associated with low educational attainment in rOA and sxOA and with high community poverty in rOA. In models including all SES variables, the patterns of association were similar although with diminished significance. There was indication that education was more strongly associated with HAQ and WOMAC function, while occupation was more strongly associated with WOMAC pain.
Our data provide evidence that individual SES is an important factor to consider when examining disability and pain outcomes in older adults with hip OA.
PMCID: PMC3204417  PMID: 22046207
Disability; hip osteoarthritis; socioeconomic status; educational attainment; occupation; community poverty; pain.
19.  The association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study 
The associations between leptin, interleukin (IL)-6, and hip radiographic osteoarthritis (OA) have not been reported, and their roles in obesity-related hip OA are unclear. The aim of this study was to describe the associations between leptin, IL-6, and hip radiographic osteoarthritis (ROA) in older adults.
A cross-sectional sample of 193 randomly selected subjects (mean age, 63 years; range, 52 to 78 years; 48% female subjects) were studied. Hip ROA, including joint-space narrowing (JSN) and osteophytes, was determined by anteroposterior radiograph. Serum levels of leptin and interleukin (IL)-6 were measured with radioimmunoassay. Fat mass was measured with dual-energy x-ray absorptiometry (DXA). Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated.
In multivariable analysis, hip JSN was associated with serum levels of leptin in the whole sample (β = 0.046 per μg/L, P = 0.024 for superior; β = 0.068 per μg/L, P = 0.004 for axial compartment) and IL-6 only in females (β = 0.241 per pg/ml, P = 0.002 for superior; β = 0.239 per pg/ml, P = 0.001 for axial compartment). The positive associations between body-composition measures (BMI, WHR, percentage total fat mass, and percentage trunk fat mass) and hip JSN in women became nonsignificant after adjustment for leptin but not for IL-6. No significant associations were found between leptin, IL-6, and the presence or severity of osteophytes.
This study suggests that metabolic and inflammatory mechanisms may play a role in the etiology of hip OA and that the associations between body composition and hip JSN are mediated by leptin, particularly in women.
PMCID: PMC2911879  PMID: 20482813
20.  Associations of educational attainment, occupation and community poverty with knee osteoarthritis in the Johnston County (North Carolina) osteoarthritis project 
Arthritis Research & Therapy  2011;13(5):R169.
The purpose of this study was to examine data from the Johnston County Osteoarthritis (OA) Project for independent associations of educational attainment, occupation and community poverty with tibiofemoral knee OA.
A cross-sectional analysis was conducted on 3,591 individuals (66% Caucasian and 34% African American). Educational attainment (< 12 years or ≥12 years), occupation (non-managerial or not), and Census block group household poverty rate (< 12%, 12 to 25%, > 25%) were examined separately and together in logistic models adjusting for covariates of age, gender, race, body mass index (BMI), smoking, knee injury and occupational activity score. Outcomes were presence of radiographic knee OA (rOA), symptomatic knee OA (sxOA), bilateral rOA and bilateral sxOA.
When all three socioeconomic status (SES) variables were analyzed simultaneously, low educational attainment was significantly associated with rOA (odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.20, 1.73), bilateral rOA (OR = 1.43, 95% CI 1.13, 1.81), and sxOA (OR = 1.66, 95% CI 1.34, 2.06), after adjusting for covariates. Independently, living in a community of high household poverty rate was associated with rOA (OR = 1.83, 95% CI 1.43, 2.36), bilateral rOA (OR = 1.56, 95% CI 1.12, 2.16), and sxOA (OR = 1.36, 95% CI 1.00, 1.83). Occupation had no significant independent association beyond educational attainment and community poverty.
Both educational attainment and community SES were independently associated with knee OA after adjusting for primary risk factors for knee OA.
PMCID: PMC3308104  PMID: 22011570
knee osteoarthritis; educational attainment; occupation; community poverty; socioeconomic status
21.  Do worsening knee radiographs mean greater chance of severe functional limitation? The Multicenter Osteoarthritis Study 
Arthritis care & research  2010;62(10):1433-1439.
Development of functional limitation is thought to be unrelated to changes in severity of radiographic knee osteoarthritis (ROA). We evaluated the relation of change in ROA to the incidence of severe functional limitation.
Participants of the Multicenter Osteoarthritis (MOST) Study, a cohort study of persons with or at high risk of knee OA were evaluated at 0 and 30 months. Subjects were classified as having no, incident, stable, or worsening ROA. Incidence of severe functional limitation was defined as 1) WOMAC physical function scores (≥ 36/68) and 2) walking speed (≤ 1.0 m/s) at 30 months. The relation of change in ROA to the incidence of severe functional limitation was evaluated by calculating risk ratios adjusted for potential confounders.
Of the 2110 subjects included (mean age 62, mean BMI 30 kg/m2, female 60%), 53% had no, 6% incident, 14% stable, and 27% worsening ROA. Persons with incident ROA had 1.9 and 1.8 times the risk by WOMAC physical function and walking speed, respectively, to have incident severe functional limitation compared with those with no ROA over 30 months. Compared with those with stable ROA, persons with worsening ROA had 2.2 and 2.5 times the risk of incident severe functional limitation, respectively.
Changes in structural disease are associated with the development of severe functional limitations in persons with or even those at high risk of knee OA.
PMCID: PMC2939286  PMID: 20506398
22.  Differences in Multi-joint Symptomatic Osteoarthritis Phenotypes by Race and Gender: The Johnston County Osteoarthritis Project 
Arthritis and rheumatism  2013;65(2):373-377.
To determine race and gender differences in phenotypes (patterns) of multiple joint symptomatic osteoarthritis (sOA) involvement.
We performed a cross-sectional analysis of sOA phenotypes in a community-based cohort, for those with sOA data for the hands, knees, hips, and lumbosacral spine (LS) collected at a single visit (2003–10). Mutually exclusive phenotypes describing all combinations of these 4 sites were compared using Fisher exact tests. For phenotypes occurring in more than 40 persons, logistic regression adjusted for race, gender, age, and body mass index (BMI) was performed and interactions by race and gender were assessed.
The sample included 1650 participants, 36% men, 32% African American, with a mean age of 66 years and BMI 31 kg/m2. Overall, 13% had hand, 25% knee, 11% hip, and 28% had LS sOA. African Americans compared with Caucasians were less likely to have Hand Only or in some combination, but more likely to have Knee Only. Men compared to women were less likely to have Hand Only, but more likely to have LS Only.
There are differences in phenotypes of multiple joint sOA involvement by race and gender that may influence definitions of multiple joint, or “generalized” OA.
PMCID: PMC3558926  PMID: 23359309
23.  A genetic association study of the IGF-1 gene and radiological osteoarthritis in a population-based cohort study (the Rotterdam study) 
Annals of the Rheumatic Diseases  1998;57(6):371-374.
OBJECTIVE—A genetic association study was performed to investigate whether radiographical osteoarthritis (ROA) was associated with specific genotypes of the insulin-like growth factor I (IGF-1) gene.
METHODS—Subjects aged 55-65 years were selected from a population-based study of which ROA at the knee, hip, spine, and hand was assessed. Genotypes were determined of a polymorphism in the promoter region of the IGF-1 gene.
RESULTS—The IGF-1 locus was significantly associated with the presence of ROA (overall adjusted OR for heterozygous subjects = 1.9, 95% CI 1.2, 3.1 and for homozygous subjects 3.6, 95% CI 0.8, 16.2).
CONCLUSION—These results suggest that variation at the IGF-1 locus is associated with ROA development and may play a part in ROA pathogenesis. To confirm these findings replication in another population-based sample is needed.

 Keywords: osteoarthritis; genetics; IGF-1
PMCID: PMC1752614  PMID: 9771213
24.  Association of Bone Scintigraphic Abnormalities with Knee Malalignment and Pain 
Annals of the rheumatic diseases  2008;68(11):1673-1679.
We evaluated the information content of knee bone scintigraphy, including pattern, localization and intensity of retention relative to radiographic features of knee osteoarthritis (rOA), knee alignment, and knee symptoms.
A total of 308 knees (159 subjects) with symptomatic and radiographic knee OA (rOA) of at least one knee were assessed by late phase technetium-99m-methylene disphosphonate bone scintigraph, fixed-flexion knee radiograph, full limb radiograph for knee alignment, and for self-reported knee symptom severity. Generalized linear models were used to control for within subject correlation of knee data.
The compartmental localization (medial versus lateral) and intensity of knee bone scan retention were associated with the pattern (varus versus valgus) (p<0.001) and severity (p=0.0008) of knee malalignment, and localization and severity of rOA (p<0.0001). Bone scan agent retention in the tibiofemoral, but not patellofemoral compartment, was associated with severity of knee symptoms (p=0.0009), and persisted after adjusting for rOA (p=0.0012).
To our knowledge, this is the first study describing a relationship between knee malalignment, joint symptom severity, and compartment specific abnormalities by bone scintigraphy. This work demonstrates that bone scintigraphy as a sensitive and quantitative indicator of symptomatic knee OA. Used selectively, bone scintigraphy is a dynamic imaging modality that holds great promise as a clinical trial screening tool and outcome measure.
PMCID: PMC3684623  PMID: 18981032
osteoarthritis; bone scintigraphy; malalignment; knee
25.  Association between synovial fluid levels of aggrecan ARGS fragments and radiographic progression in knee osteoarthritis 
Arthritis Research & Therapy  2010;12(6):R230.
Aggrecanase cleavage at the 392Glu-393Ala bond in the interglobular domain (IGD) of aggrecan, releasing N-terminal 393ARGS fragments, is an early key event in arthritis and joint injuries. We determined whether synovial fluid (SF) levels of ARGS-aggrecan distinguish subjects with progressive radiographic knee osteoarthritis (ROA) from those with stable or no ROA.
We studied 141 subjects who, at examination A, had been given meniscectomies an average of 18 years earlier (range, 15 to 22 years). Seventeen individuals without surgery, and without known injury to the menisci or cruciate ligaments, were used as references. At examinations A and B, with a mean follow-up time of 7.5 years, we obtained SF and standing tibiofemoral and skyline patellofemoral radiographs. SF ARGS-aggrecan was measured with an electrochemiluminescence immunoassay, and we graded radiographs according to the OARSI atlas. The association between SF ARGS levels at examination A and progression of radiographic features of knee OA between examinations A and B was assessed by using logistic regression adjusted for age, gender, body mass index, and time between examinations, and stratified by ROA status at examination A.
We found a weak negative association between SF ARGS concentrations and loss of joint space: the likelihood of progression of radiographic joint space narrowing decreased 0.9 times per picomole per milliliter increase in ARGS (odds ratio (OR) 0.89; 95% confidence interval (CI), 0.79 to 0.996). In subjects with and without preexisting ROA at examination A, the association was OR, 0.96; 0.81 to 1.13; and 0.77; 0.62 to 0.95, respectively. Average levels of SF ARGS 18 years after meniscectomy were no different from those of reference subjects and were not correlated to radiographic status at examination A.
In subjects with previous knee meniscectomy but without ROA, levels of SF ARGS-aggrecan were weakly and inversely associated with increased loss of joint space over a period of 7.5 years.
PMCID: PMC3046543  PMID: 21194461

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