Interest in genetic testing for modest changes in breast cancer risk: implications for SNP testing.

BACKGROUND: Advances in genomics may eventually lead to 'personalized genetic medicine,' yet the clinical utility of predictive testing for modest changes in risk is unclear. We explored interest in genetic testing for genes related to modest changes in breast cancer risk in women at moderate to high risk for breast cancer. METHODS: Women (n = 105) with a negative breast biopsy and ≥1 relative with breast or ovarian cancer completed telephone surveys. We measured demographic and psychosocial variables and, following presentation of hypothetical scenarios of genetic tests for lower-penetrance breast cancer gene mutations, assessed interest in willingness to pay for and comprehension of test results. We used logistic regression models with generalized estimating equations to evaluate combinations of risk level, cost and behavioral modifiers. RESULTS: Many women (77%) reported 'definite' interest in genetic testing, with greater interest in tests that conveyed more risk and cost less. Behavioral modifiers of risk (taking a vitamin; diet/exercise), having a regular physician, greater perceived benefits of genetic testing, and greater cancer worry also influenced interest. Most participants (63%) did not understand relative vs. absolute risk. Women with less understanding reported more cancer worry and greater willingness to pay for testing. CONCLUSION: Interest in genetic testing for mutations related to modest changes in risk was high, modified by both test and psychosocial factors. Findings highlight the need for education about benefits and risks of testing for mutations that convey modest changes in risk, particularly given the current lack of clinical validity/utility and availability of direct-to-consumer genetic testing.

One in four people may develop symptomatic hip osteoarthritis in his or her lifetime.

OBJECTIVE: To estimate the lifetime risk of symptomatic hip osteoarthritis (OA). DESIGN: We analyzed data from the Johnston County Osteoarthritis Project [a longitudinal population-based study of OA in North Carolina, United States (n=3068)]. The weighted baseline sample comprised 18% blacks and 54% women, and the mean age was 63 years (range=45-93). Symptomatic hip OA was defined as a Kellgren-Lawrence (K-L) radiographic score of ≥ 2 (anterior-posterior pelvis X-rays) and pain, aching or stiffness on most days, or groin pain, in the same hip. Lifetime risk, defined as the proportion who developed symptomatic hip OA in at least one hip by age 85, among people who live to age 85, was modeled using logistic regression with repeated measures (through generalized estimating equations). RESULTS: Lifetime risk of symptomatic hip OA was 25.3% [95% confidence interval (CI)=21.3-29.3]. Lifetime risk was similar by sex, race, highest educational attainment, and hip injury history. We studied lifetime risk by body mass index (BMI) in three forms: at age 18; at baseline and follow-up; and at age 18, baseline and follow-up and found no differences in estimates. CONCLUSION: The burden of symptomatic hip OA is substantial with one in four people developing this condition by age 85. The similar race-specific estimates suggest that racial disparities in total hip replacements are not attributable to differences in disease occurrence. Despite increasing evidence that obesity predicts an increased risk of both hip OA and joint replacement, we found no association between BMI and lifetime risk.

In vitro modulation of the human gastrointestinal microbial community by plant-derived polysaccharide-rich dietary supplements.

The use of prebiotics is a possible strategy to manage and steer the complex gut microbial community towards a health-promoting composition (Gastrointestinal Resource Management). In this study, the Simulator of the Human Intestinal Microbial Ecosystem was used to investigate the effects of two commercially-available plant polysaccharide supplements on the structure, composition and metabolism of an in vitro cultured colon microbial community. Microbial analyses showed both a bifidogenic (up to +1.3 log cfu/mL) and a lactobacillogenic (up to +0.9 log cfu/mL) effect during treatment with the dietary supplements. Quantitative PCR confirmed that the increase of Bifidobacteria spp. was statistically significant (P<0.05) in all of the colon compartments and showed a significant increase of the bacteroides-prevotella group concentration (+0.6 log cells/ml) in the compartment simulating the proximal colon. Denaturant gradient gel electrophoresis analyses and a relative ecological interpretation, in combination with sugar and short-chain fatty acids quantification, provided evidence of a positive effect of both the tested products. Overall, the treatment period was associated with (i) good and selective fermentability of the polysaccharide supplements along the entire colon; (ii) positive and selective bifidogenic effect; (iii) the possibility of enhancing species belonging to Bacteroidetes, a phylum recently associated with body weight management.

Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial.

OBJECTIVE: A randomised double-blind placebo controlled withdrawal clinical trial of prednisone versus placebo in patients with rheumatoid arthritis (RA), treated in usual clinical care with 1-4 mg/day prednisone, withdrawn to the same dose of 1 mg prednisone or identical placebo tablets. METHODS: All patients were from one academic setting and all trial visits were conducted in usual clinical care. Patients were taking stable doses of 1-4 mg prednisone with stable clinical status, documented quantitatively by patient questionnaire scores. The protocol included three phases: (1) equivalence: 1-4 study prednisone 1 mg tablets taken for 12 weeks to ascertain their efficacy compared with the patient's usual tablets before randomisation; (2) transfer: substitution of a 1 mg prednisone or identical placebo tablet every 4 weeks (over 0-12 weeks) to the same number as baseline prednisone; (3) comparison: observation over 24 subsequent weeks taking the same number of either placebo or prednisone tablets as at baseline. The primary outcome was withdrawal due to patient-reported lack of efficacy versus continuation in the trial for 24 weeks. RESULTS: Thirty-one patients were randomised, 15 to prednisone and 16 to placebo, with three administrative discontinuations. In "intent-to-treat" analyses, 3/15 prednisone and 11/16 placebo participants withdrew (p = 0.03). Among participants eligible for the primary outcome, 3/13 prednisone and 11/15 placebo participants withdrew for lack of efficacy (p = 0.02). No meaningful adverse events were reported, as anticipated. CONCLUSION: Efficacy of 1-4 mg prednisone was documented. Evidence of statistically significant differences with only 31 patients may suggest a robust treatment effect.

Interpretation of serum C-reactive protein (CRP) levels for cardiovascular disease risk is complicated by race, pulmonary disease, body mass index, gender, and osteoarthritis.

OBJECTIVE: High-sensitivity C-reactive protein (hsCRP) in serum is used as a marker of risk for cardiovascular disease (CVD); however CRP is a non-specific acute phase reactant. We evaluated the association between hsCRP concentrations and the most common form of arthritis, osteoarthritis (OA), and assessed the applicability of hsCRP for CVD risk prediction. METHODS: Participants (n=662) were selected from the population-based Johnston County Osteoarthritis Project, using stratified simple random sampling to achieve balance according to radiographic knee OA status, ethnic group, gender, and age group. The presence and severity of knee and hip OA were determined radiographically. CVD risk was estimated by hsCRP concentration and independently with the Framingham risk algorithm. RESULTS: Serum natural log-transformed hsCRP (ln hsCRP) was higher in African-Americans (P<0.0001) and women (P<0.0001), was higher in participants who had chronic pulmonary disease (P=0.01), hypertension (P<0.0001), or used pain medications (P=0.004), and correlated with body mass index (BMI) (r=0.40, P<0.0001) and waist circumference (r=0.33, P<0.0001), but not with age, CVD, or current smoking. Ln hsCRP was strongly positively associated with all definitions of radiographic OA (rOA; P<0.0001), but this association was not independent of BMI. Although 183 participants reported no CVD and were classified as low risk by the Framingham CVD score, 61% of them were classified as moderate or high risk for CVD using hsCRP; this proportion designated high risk for CVD on the basis of hsCRP consisted primarily of women (P<0.05) and individuals with OA (P<0.01). CONCLUSIONS: The pathogenic significance of hsCRP elevations in this subgroup is unclear. Serum hsCRP for predicting risk of CVD is confounded by obesity, ethnicity, gender and comorbidities.

Identification of an urinary metabolite profile associated with osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is one of the most common diseases among the elderly. The main characteristic is the progressive destruction of articular cartilage. We lack quantitative and sensitive biomarkers for OA to detect changes in the joints in an early stage of the disease. In this study, we investigated whether a urinary metabolite profile could be found that could serve as a diagnostic biomarker for OA in humans. We also compared the profile we obtained previously in the guinea pig spontaneous OA model. METHODS: Urine samples of 92 participants (47 non-OA controls and 45 individuals with radiographic OA of the knees or hips) were selected from the Johnston County Osteoarthritis Project (North Carolina, USA). Participants ranged in age from 60 to 84 years. Samples were measured by 1H nuclear magnetic resonance spectroscopy (NMR) with subsequent principal component discriminant analysis and partial least squares regression analysis. RESULTS: Differences were observed between urine NMR spectra of OA cases and controls (P<0.001 for both male and female subjects). A metabolite profile could be determined which was strongly associated with OA. This profile largely resembled the profile previously identified for guinea pigs with OA (approximately 40 out of the approximately 125 signals of the human profile were present in the guinea pig profile as well). A correlation was found between the metabolite profile and radiographic OA severity (R2 = 0.82 (male); R2 = 0.93 (female)). CONCLUSION: This study showed that a urine metabolite profile may serve as a novel discriminating biomarker of OA.

Serum cartilage oligomeric matrix protein and clinical signs and symptoms of potential pre-radiographic hip and knee pathology.

OBJECTIVE: To examine the cross-sectional relationship between serum cartilage oligomeric matrix protein (COMP) and hip and knee clinical signs and symptoms in a sample of adults without radiographic hip or knee osteoarthritis (OA). DESIGN: A total of 145 persons with available sera and no evidence of radiographic hip or knee OA (Kellgren-Lawrence grade 0) were randomly selected from the Caucasian participants of the Johnston County Osteoarthritis Project. COMP was quantified by a competitive ELISA assay with a monoclonal antibody 17-C10. Hip and knee clinical signs and symptoms were assessed by physical examination and interview, and their associations with Ln COMP analysed with general linear models. RESULTS: After adjustment for age, gender, body mass index (BMI), and other symptomatic joints, mean Ln COMP was statistically significantly higher among persons with hip-related clinical signs (P=0.018), among those with hip-related symptoms (P=0.046), and among individuals meeting American College of Rheumatology clinical criteria for hip OA (P=0.021). There were no statistically significant associations between any of the knee-related clinical signs and symptoms and Ln COMP. CONCLUSION: Serum COMP may be useful as a biomarker of pre-radiographic hip joint pathology; its utility as a biomarker of pre-radiographic knee joint pathology is unclear.

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee.

OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as "better" or "much better" by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as "better" or "much better" by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.

Serum carotenoids and radiographic knee osteoarthritis: the Johnston County Osteoarthritis Project.

OBJECTIVE: Antioxidant intake has been associated with less progression of radiographic knee osteoarthritis (OA), but studies of carotenoid biomarkers and OA have not been done. We examined associations between serum concentrations of nine naturally occurring carotenoids and radiographic knee OA. DESIGN: The study design was matched case-control. Sera were analysed by high-performance liquid chromatography for nine carotenoids: lutein, zeaxanthin, alpha- and beta-cryptoxanthin, trans- and cis-lycopene, alpha-carotene, and trans- and cis-beta-carotene. Conditional logistic regression was used to estimate the association between tertiles of each carotenoid and radiographic knee OA, independent of body mass index, education, serum cholesterol, and the other carotenoids. SETTING: Johnston County, North Carolina, United States of America. SUBJECTS: Two-hundred cases with radiographic knee OA (Kellgren-Lawrence grades > or = 2) and 200 controls (Kellgren-Lawrence grade = 0) were randomly selected from the Johnston County Osteoarthritis Project, and were matched on age, gender and race. RESULTS: Participants with serum levels of lutein or beta-cryptoxanthin in the highest tertile were approximately 70% less likely to have knee OA than controls (odds ratio (OR) [95% confidence interval (CI)] = 0.28 [0.11, 0.73] and 0.36 [0.14, 0.95], respectively). Those in the highest tertile of trans-beta-carotene (OR = 6.40 [1.86, 22.1]) and zeaxanthin (OR = 3.06 [1.19, 7.85]) were more likely to have knee OA. CONCLUSIONS: While certain carotenoids may protect against knee OA, others may increase the odds of knee OA. Further study of carotenoids and knee OA are warranted before clinical recommendations about these substances and knee OA can be made.

Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project.

OBJECTIVE: To characterize serum cartilage oligomeric matrix protein (COMP) levels by age and gender for a radiographically defined population free of hip and knee osteoarthritis (OA), and to examine the potential utility of COMP as a diagnostic biomarker for knee OA. METHODS: Serum samples and knee and hip radiographs were obtained at a baseline evaluation as part of the Johnston County Osteoarthritis Project, a population-based study of OA in rural North Carolina. A total of 291 Caucasian participants were randomly selected for COMP analysis, 143 patients with radiographic knee OA (Kellgren/Lawrence [K/L] grade > or = 2) and 148 controls with neither hip nor knee OA (K/L grade 0), evenly distributed by age and gender. COMP was quantified by competitive enzyme-linked immunosorbent assay with monoclonal antibody 17-C10. The natural log-transformed COMP data were analyzed using general linear models. RESULTS: Serum COMP levels were significantly elevated (P = 0.0001) in the age > or = 65 group (mean +/- SD 1,302.1 +/- 496.7 ng/ml) versus the age 45-54 and age 55-64 groups (1,058.1 +/- 432.4 and 1,038.6 +/- 313.3, respectively). Serum COMP levels of the OA group were significantly higher than those of the control group (1,208.57 +/- 487.47 ng/ml versus 1,061.83 +/- 370.58 ng/ml; P = 0.0093). Serum COMP levels also increased significantly with knee OA K/L grade (P = 0.0047), knee OA laterality (P = 0.0043), and number of knee and hip joints involved (P = 0.0001). There was no significant difference in serum COMP levels by gender or obesity. CONCLUSION: We demonstrate that in a population-based sample, serum COMP levels can distinguish an OA-affected subgroup from an unaffected subgroup and can reflect disease severity and multiple joint involvement in OA.

An application of methods for clustered binary responses to a cardiovascular study with small sample size.

This paper discusses statistical methods for a cardiovascular study in which each of eight animals had a dichotomous outcome observed for each of several treatments. There were five treatments in all: shunt, control, two doses of a test drug for potentially causing an unfavorable cardiovascular event, and a combination of the test drug and a counteracting agent. Exact conditional methods were used through LogXact, a statistical software for exact logistic regression and an alternative framework for performing a large class of nonparametric tests performed by StatXact. The results agreed reasonably with asymptotic methods even though the sample size was small.

Knee pain and knee osteoarthritis severity in self-reported task specific disability: the Johnston County Osteoarthritis Project.

OBJECTIVE: To evaluate the contributions of radiographic knee osteoarthritis (OA) and knee pain severity to self-reported disability performing upper and lower extremity tasks in a rural, population based sample. METHODS: Data from 1192 African-American and Caucasian participants in the Johnston County Osteoarthritis Project were analyzed with multiple logistic regression to examine the roles of Kellgren-Lawrence radiographic knee OA grade and knee pain severity in self-reported difficulty performing 20 activities of the Health Assessment Questionnaire. Potential confounders included age, sex, race, marital status, education, and body mass index. RESULTS: Forty-three percent reported difficulty performing at least one task. Mild knee pain was independently associated with difficulty performing 16 upper and lower extremity tasks, and moderate/severe knee pain with all 20 tasks, with little change after adjustment (p < 0.0001). In contrast, mild radiographic knee OA was associated with difficulty in only 4 mobility and transfer tasks: climbing 5 steps, taking a tub bath, getting in/out of a car, and performing chores. Moderate/severe radiographic knee OA was associated with difficulty in 17 of 20 tasks (in 10 of 17, p < 0.0001), except lifting a cup, opening car doors, and turning faucets. However, no associations between radiographic knee OA and difficulty were statistically significant after adjustment for knee pain and the above factors. CONCLUSION: Knee pain severity was the strongest risk factor for self-reported difficulty performing tasks of upper and lower extremity function. Future studies of disability should include data on knee pain severity.

Ethnic differences in self-reported functional status in the rural south: the Johnston County Osteoarthritis Project.

OBJECTIVE: We examined ethnic differences in self-reported functional status in a rural, population-based sample in North Carolina. METHODS: Data from 1,197 African-American and Caucasian participants, aged 45 and older, in the Johnston County Osteoarthritis Project were analyzed using multiple logistic regression to examine differences in difficulty performing tasks of the Health Assessment Questionnaire (HAQ) and in risk factor profiles associated with difficulty. RESULTS: Forty-three percent reported difficulty in one or more HAQ tasks. African-Americans were more likely than Caucasians to report difficulty performing 3 tasks (P < 0.04); these differences were minimal after adjustment for confounders. For some tasks, risk factor profiles included body mass index in African-Americans only, and age and female gender more often in Caucasians. Low educational attainment was part of the risk factor profile for walking in African-Americans. CONCLUSIONS: Differences in proportions of African-Americans and Caucasians reporting difficulty in performance of HAQ tasks were minimal, but risk factor profiles for difficulty appeared to vary by ethnicity.

Self-reported functional status in osteoarthritis of the knee in a rural southern community: the role of sociodemographic factors, obesity, and knee pain.

OBJECTIVE: This study examined the roles of sociodemographic factors (age, race, gender, education, marital status), obesity, and severity of radiographic knee osteoarthritis (OA) and knee pain on self-reported functional status. METHODS: The sample included 1,272 African-American and Caucasian individuals, aged 45 years or older, from the Johnston County Osteoarthritis Project. Analysis of variance was used to assess variation in mean Health Assessment Questionnaire (HAQ) scores by the above variables. RESULTS: Mean HAQ scores differed by severity of radiographic knee OA and knee pain, obesity, and all demographic factors (P < 0.0001), except race. Only age, female sex, obesity, and knee pain severity were independent effects (P < 0.0009). Disability associated with knee pain varied by both radiographic knee OA severity and obesity. CONCLUSIONS: Knee pain severity was more important than radiographic knee OA severity in determining disability. Obesity was independently associated with disability and compounded disability from knee pain. Studies of disability in knee OA should include assessment of obesity, severity of radiographic knee OA, and severity of knee pain, as well as their interactions.