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1.  Symptom Assessment in Knee Osteoarthritis Needs to Account for Physical Activity Level 
Pain is not always correlated with radiographic osteoarthritis (OA) severity possibly because people modify activities to manage symptoms. Measures of symptoms that consider pain in the context of activity level may therefore provide greater discrimination than pain alone. Our objective was to compare discrimination of a measure of pain alone with combined measures of pain relative to physical activity across radiographic OA levels.
This is a cross-sectional study of the Osteoarthritis Initiative accelerometer substudy, including those with and without knee OA. Two composite pain and activity knee symptom (PAKS) scores were calculated as Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Pain Scale plus one divided by physical activity measures (step and activity counts). Symptom score discrimination across Kellgren and Lawrence (KL) grades were evaluated using histograms and quantile regression.
1806 participants, mean age 65.1 (9.1) years, mean BMI 28.4 (4.8) kg/m2, and 55.6% female, were included. WOMAC, but not PAKS scores, exhibited a floor effect. Adjusted median WOMAC by KL grades 0 – 4 were 0, 0, 1, 1, and 3 respectively. Median PAKS1 and PAKS2 were 24.9, 26.0, 32.4, 46.1, 97.9, and 7.2, 7.2, 9.2, 12.9, 23.8, respectively. PAKS scores had more statistically significant comparisons between KL grades compared with WOMAC.
Symptom assessments incorporating pain and physical activity did not exhibit a floor effect and were better able to discriminate radiographic severity than pain alone, particularly in milder disease. Pain in the context of physical activity level should be used to assess knee OA symptoms.
PMCID: PMC4626322  PMID: 26407008
2.  Knee Pain and a Prior Injury Are Associated With Increased Risk of a New Knee Injury: Data from the Osteoarthritis Initiative 
The Journal of rheumatology  2015;42(8):1463-1469.
We explored if knee pain or a history of knee injury was associated with a knee injury in the following 12 months.
We conducted longitudinal knee-based analyses among knees in the Osteoarthritis Initiative. We included both knees of all participants who had at least one follow-up visit with complete data. Our first sets of exposures were knee pain (chronic knee symptoms and severity) at baseline, 12-month, 24-month, and 36-month visits. Another exposure was a history of injury, which we defined as a self-reported injury at any time prior to baseline, 12-month, 24-month, or 36-month visits. The outcome was self-reported knee injury during the past year at 12-month, 24-month, 36-month, and 48-month visits. We evaluated the association between ipsilateral and contralateral knee pain or history of injury and a new knee injury within 12 months of the exposure using generalized linear mixed model for repeated binary outcomes.
A knee with reported chronic knee symptoms or ipsilateral or contralateral history of an injury was more likely to experience a new knee injury in the following 12 months than a knee without chronic knee symptoms (odds ratio [OR]=1.84, 95% confidence interval [CI]=1.57, 2.16) or prior injury (prior ipsilateral knee injury OR=1.81, 95% CI=1.56, 2.09; prior contralateral knee injury OR=1.43, 95% CI=1.23, 1.66).
Knee pain and a history of injury are associated with new knee injuries. It may be beneficial for individuals with knee pain or a history of injury to participate in injury prevention programs.
PMCID: PMC4522334  PMID: 26034152
knee injuries; osteoarthritis; musculoskeletal pain
3.  Association of Objectively Measured Physical Activity and Metabolic Syndrome among U.S. Adults with Osteoarthritis 
Arthritis care & research  2015;67(10):1371-1378.
To investigate the association between objectively-measured physical activity and metabolic syndrome among adults with osteoarthritis (OA).
Using cross-sectional data from 2003–2006 NHANES, we identified 566 adults with OA with available accelerometer data assessed using Actigraph AM-7164 and measurements necessary to determine metabolic syndrome by Adult Treatment Panel III. Analysis of variance was conducted to examine the association between continuous variables in each activity level and metabolic syndrome components. Logistic models estimated the relationship of quartile of daily minutes of different physical activity levels to odds of metabolic syndrome adjusted for socioeconomic and health factors.
Among persons with OA, most were female with average age 62.1 years and average duration of disease of 12.9 years. Half of adults with OA had metabolic syndrome (51.0%; 95% Confidence Interval (CI): 44.2% to 57.8%), and only 9.6% engaged in the recommended 150 minutes per week of moderate/vigorous physical activity. Total sedentary time was associated with higher rates of metabolic syndrome and its components while light and moderate/vigorous objectively-measured physical activity were inversely associated with metabolic syndrome and its components. Higher levels of light activity was associated with lower prevalence of metabolic syndrome (quartile 4 versus quartile 1: adjusted odds ratio: 0.45; 95% CI: 0.24 to 0.84; p-value for linear trend < 0.005).
Most U.S. adults with OA are sedentary. Increased daily minutes in physical activity, especially in light intensity, is more likely to be associated with decreasing prevalence of metabolic syndrome among persons with OA.
PMCID: PMC4573382  PMID: 25777463
Environmental research  2015;142:522-528.
Living near major roadways has been associated with increased risk of cardiovascular morbidity and mortality, presumably from exposure to elevated levels of traffic-related air and/or noise pollution. This association may potentially be mediated through increased risk of incident hypertension, but results from prior studies are equivocal. Using Cox proportional hazards models we examined residential proximity to major roadways and incident hypertension among 38,360 participants of the Women's Health Initiative (WHI) Clinical Trial cohorts free of hypertension at enrollment and followed for a median of 7.9 years. Adjusting for participant demographics and lifestyle, trial participation, and markers of individual and neighborhood socioeconomic status, the hazard ratios for incident hypertension were 1.13 (95% CI: 1.00, 1.28), 1.03 (0.95, 1.11), 1.05 (0.99, 1.11), and 1.05 (1.00, 1.10) for participants living ≤50, >50-200, >200-400, and >400-1000 m versus >1000 m from the nearest major roadway, respectively (ptrend=0.013). This association varied substantially by WHI study region with hazard ratios for women living ≤50m from a major roadway of 1.61 (1.18, 2.20) in the West, 1.51 (1.22, 1.87) in the Northeast, 0.89 (0.70, 1.14) in the South, and 0.94 (0.75, 1.19) in the Midwest. In this large, national cohort of post-menopausal women, residential proximity to major roadways was associated with incident hypertension in selected regions of the U.S. If causal, these results suggest residential proximity to major roadways, as a marker for air, noise and other traffic-related pollution, may be a risk factor for hypertension.
PMCID: PMC4609282  PMID: 26282224
hypertension; women; blood pressure; traffic pollution; air pollution; noise pollution
5.  Best performing definition of accelerated knee osteoarthritis: data from the Osteoarthritis Initiative 
We evaluated agreement among several definitions of accelerated knee osteoarthritis (AKOA) and construct validity by comparing their individual associations with injury, age, obesity, and knee pain.
We selected knees from the Osteoarthritis Initiative that had no radiographic knee osteoarthritis [Kellgren–Lawrence (KL) 0 or 1] at baseline and had high-quality quantitative medial joint space width (JSW) measures on two or more consecutive visits (n = 1655 knees, 1143 participants). Quantitative medial JSW was based on a semi-automated method and was location specific (x = 0.25). We compared six definitions of AKOA: stringent JSW (averaged): average JSW loss greater than 1.05 mm/year over 4 years; stringent JSW (consistent): JSW loss greater than 1.05 mm/year for at least 2 years; lenient JSW (averaged): average JSW loss greater than 0.25 mm/year over 4 years; lenient JSW (consistent): JSW loss greater than 0.25 mm/year for at least 2 years; comprehensive KL based: progression from no radiographic osteoarthritis to advance-stage osteoarthritis (KL 3 or 4; development of definite osteophyte and joint space narrowing) within 4 years; and lenient KL based: an increase of at least two KL grades within 4 years.
Over 4 years the incidence rate of AKOA was 0.4%, 0.8%, 15.5%, 22.1%, 12.4%, and 7.2% based on the stringent JSW (averaged and consistent), lenient JSW (averaged and consistent), lenient KL-based definition, and comprehensive KL-based definition. All but one knee that met the stringent JSW definition also met the comprehensive KL-based definition. There was fair substantial agreement between the lenient JSW (averaged), lenient KL-based, and comprehensive KL-based definitions. A comprehensive KL-based definition led to larger effect sizes for injury, age, body mass index, and average pain over 4 years.
A comprehensive KL-based definition of AKOA may be ideal because it represents a broader definition of joint deterioration compared with those focused on just joint space or osteophytes alone.
PMCID: PMC5037496  PMID: 27721902
classification; phenotype; osteoarthritis; knee; radiography
6.  The Choice of Analytical Strategies in Inverse-Probability-of-Treatment–Weighted Analysis: A Simulation Study 
American Journal of Epidemiology  2015;182(6):520-527.
We sought to explore the impact of intention to treat and complex treatment use assumptions made during weight construction on the validity and precision of estimates derived from inverse-probability-of-treatment–weighted analysis. We simulated data assuming a nonexperimental design that attempted to quantify the effect of statin on lowering low-density lipoprotein cholesterol. We created 324 scenarios by varying parameter values (effect size, sample size, adherence level, probability of treatment initiation, associations between low-density lipoprotein cholesterol and treatment initiation and continuation). Four analytical approaches were used: 1) assuming intention to treat; 2) assuming complex mechanisms of treatment use; 3) assuming a simple mechanism of treatment use; and 4) assuming invariant confounders. With a continuous outcome, estimates assuming intention to treat were biased toward the null when there were nonnull treatment effect and nonadherence after treatment initiation. For each 1% decrease in the proportion of patients staying on treatment after initiation, the bias in estimated average treatment effect increased by 1%. Inverse-probability-of-treatment–weighted analyses that took into account the complex mechanisms of treatment use generated approximately unbiased estimates. Studies estimating the actual effect of a time-varying treatment need to consider the complex mechanisms of treatment use during weight construction.
PMCID: PMC4564939  PMID: 26316599
as-treated analysis; data simulation; intention to treat; marginal structural models
7.  Meniscal Extrusion or Subchondral Damage Characterize Incident Accelerated Osteoarthritis: Data from the Osteoarthritis Initiative 
Clinical anatomy (New York, N.Y.)  2015;28(6):792-799.
Knee osteoarthritis (KOA) is typically a slowly progressive disorder; however, a subset of knees progress with dramatic rapidity. We aimed to describe magnetic resonance imaging (MRI) findings that are associated with accelerated KOA.
Materials and Methods
We conducted a longitudinal descriptive study in the Osteoarthritis Initiative (OAI) cohort. We selected participants who had no radiographic KOA at baseline with one of the following in the most severe knee: 1) accelerated KOA (progressed to end-stage KOA within 48 months), 2) common KOA, and 3) no KOA at all visits. We enriched the sample by selecting knees with a self-reported or suspected knee injury. A musculoskeletal radiologist blinded to group assignments but not to time sequence performed MRI readings for the visit before and after an injury.
We assessed 38 participants (knees), 66% were female, mean age 61 (9) years, and mean body mass index 28.5 (4.9) kg/m2. Fifteen of 20 knees with no or common KOA, had no incident findings consistent with acute damage. Among the 18 knees with accelerated KOA most had incident findings: 13 (72%) had incident medial meniscal pathology with extrusion and 5 (28%) knees had subchondral damage.
Incident MRI findings that are associated with incident accelerated KOA are characterized by structural damage that compromises subchondral bone or the function of the meniscus. Recognizing meniscal extrusion and/or change in shape, lateral meniscal tear, or acute subchondral damage may be vital for identifying individuals at risk for accelerated KOA.
PMCID: PMC4679290  PMID: 26149125
osteoarthritis; meniscus; ligaments; magnetic resonance imaging
8.  Positive Associations of Dispositional Mindfulness with Cardiovascular Health: the New England Family Study 
Mindfulness (the ability to attend nonjudgmentally to one’s own physical and mental processes) is receiving substantial interest as a potential determinant of health. However, little is known whether mindfulness is associated with cardiovascular health.
The aim of this study is to evaluate whether dispositional mindfulness is associated with cardiovascular health.
Study participants (n=382) were from the New England Family Study, born in Providence, RI, USA, with mean age 47 years. Dispositional mindfulness was assessed using the Mindful Attention Awareness Scale (MAAS). Cardiovascular health was assessed based on American Heart Association criteria. Cross-sectional multivariable-adjusted log binomial regression analyses were performed.
Analyses demonstrated that those with high vs. low MAAS had prevalence ratio (PR) for good cardiovascular health of 1.83 (95 % confidence interval (CI) 1.07, 3.13), adjusted for age, gender, and race/ethnicity. There were significant associations of high vs. low mindfulness with non-smoking (PR=1.37, 95 % CI 1.06, 1.76), body mass index <25 kg/m2 (PR=2.17, 95 % CI 1.16, 4.07), fasting glucose <100 mg/dL (PR = 1.47, 95 % CI 1.06, 2.04), and high physical activity (PR = 1.56, 95 % CI 1.04, 2.35), but not blood pressure, total cholesterol, or fruit/vegetable consumption. Exploratory mediation analyses suggested that sense of control and depressive symptomatology may be mediators.
This study demonstrated preliminary cross-sectional evidence that dispositional mindfulness is positively associated with cardiovascular health, with the associations particularly driven by smoking, body mass index, fasting glucose, and physical activity. If in future research mindfulness-based practices are found to consistently improve cardio-vascular disease risk factors, such interventions may have potential to strengthen effects of cardiovascular health promotion programs.
PMCID: PMC4429005  PMID: 25339282
Mindfulness; Cardiovascular health; Epidemiology; Prevention
9.  Adiposity is associated with DNA methylation profile in adipose tissue 
Background: Adiposity is a risk factor for type 2 diabetes and cardiovascular disease, suggesting an important role for adipose tissue in the development of these conditions. The epigenetic underpinnings of adiposity are not well understood, and studies of DNA methylation in relation to adiposity have rarely focused on target adipose tissue. Objectives were to evaluate whether genome-wide DNA methylation profiles in subcutaneous adipose tissue and peripheral blood leukocytes are associated with measures of adiposity, including central fat mass, body fat distribution and body mass index.
Methods: Participants were 106 men and women (mean age 47 years) from the New England Family Study. DNA methylation was evaluated using the Infinium HumanMethylation450K BeadChip. Adiposity phenotypes included dual-energy X-ray absorptiometry-assessed android fat mass, android:gynoid fat ratio and trunk:limb fat ratio, as well as body mass index.
Results: Adipose tissue genome-wide DNA methylation profiles were associated with all four adiposity phenotypes, after adjusting for race, sex and current smoking (omnibus p-values <0.001). After further adjustment for adipose cell-mixture effects, associations with android fat mass, android:gynoid fat ratio, and trunk:limb fat ratio remained. In gene-specific analyses, adiposity phenotypes were associated with adipose tissue DNA methylation in several genes that are biologically relevant to the development of adiposity, such as AOC3, LIPE, SOD3, AQP7 and CETP. Blood DNA methylation profiles were not associated with adiposity, before or after adjustment for blood leukocyte cell mixture effects.
Conclusion: Findings show that DNA methylation patterns in adipose tissue are associated with adiposity.
PMCID: PMC4588857  PMID: 25541553
Adiposity; adipose tissue; DNA methylation; epigenetics
Psychosomatic medicine  2015;77(3):237-245.
Increasing evidence suggests that early life factors may influence coronary heart disease (CHD) risk, however little is known about contributions of prenatal cortisol. Objectives were to prospectively assess associations of maternal cortisol levels during pregnancy with offspring’s 10-year CHD risk during middle-age.
Participants were 262 mother-offspring dyads from the New England Family Study. Maternal free cortisol was assessed in third trimester maternal serum samples. Ten-year CHD risk was calculated in offspring at mean age 42 years, using the validated Framingham risk algorithm incorporating diabetes, systolic and diastolic blood pressure, total and HDL cholesterol, smoking, age and sex.
In multivariable-adjusted linear regression analyses adjusted for age and race/ethnicity, high vs. low maternal cortisol tertile was associated with 36.7% (95% CI: 8.4%, 72.5%) greater mean 10-year CHD risk score in females. There was no association in males (−2.8%, 95% CI: −23.8%, 24.0%). Further adjustment for in utero socioeconomic position showed 25.9% (95% CI: −1.0%, 60.0%) greater CHD risk in females. Adjustment for maternal age and size for gestational age had little effect on findings.
Maternal prenatal cortisol levels were positively associated with 10-year CHD risk among female, and not male, offspring. Adjusting for socioeconomic position during pregnancy reduced effect size in females, suggesting it may be a common prior factor in both maternal cortisol and CHD risk. These findings provide evidence that targeting mothers who have elevated prenatal cortisol levels, including elevated cortisol in the setting of low socioeconomic position, may potentially reduce long-term CHD risk in their offspring.
PMCID: PMC4965800  PMID: 25768844
cortisol; stress; coronary heart disease; prospective; life course; prenatal
11.  Coronal tibial slope is associated with accelerated knee osteoarthritis: data from the Osteoarthritis Initiative 
Accelerated knee osteoarthritis may be a unique subset of knee osteoarthritis, which is associated with greater knee pain and disability. Identifying risk factors for accelerated knee osteoarthritis is vital to recognizing people who will develop accelerated knee osteoarthritis and initiating early interventions. The geometry of an articular surface (e.g., coronal tibial slope), which is a determinant of altered joint biomechanics, may be an important risk factor for incident accelerated knee osteoarthritis. We aimed to determine if baseline coronal tibial slope is associated with incident accelerated knee osteoarthritis or common knee osteoarthritis.
We conducted a case–control study using data and images from baseline and the first 4 years of follow-up in the Osteoarthritis Initiative. We included three groups: 1) individuals with incident accelerated knee osteoarthritis, 2) individuals with common knee osteoarthritis progression, and 3) a control group with no knee osteoarthritis at any time. We did 1:1:1 matching for the 3 groups based on sex. Weight-bearing, fixed flexion posterior-anterior knee radiographs were obtained at each visit. One reader manually measured baseline coronal tibial slope on the radiographs. Baseline femorotibial angle was measured on the radiographs using a semi-automated program. To assess the relationship between slope (predictor) and incident accelerated knee osteoarthritis or common knee osteoarthritis (outcomes) compared with no knee osteoarthritis (reference outcome), we performed multinomial logistic regression analyses adjusted for sex.
The mean baseline slope for incident accelerated knee osteoarthritis, common knee osteoarthritis, and no knee osteoarthritis were 3.1(2.0), 2.7(2.1), and 2.6(1.9); respectively. A greater slope was associated with an increased risk of incident accelerated knee osteoarthritis (OR = 1.15 per degree, 95 % CI = 1.01 to 1.32) but not common knee osteoarthritis (OR = 1.04, 95 % CI = 0.91 to 1.19). These findings were similar when adjusted for recent injury. Among knees with varus malalignment a greater slope increases the odds of incident accelerated knee osteoarthritis; there is no significant relationship between slope and incident accelerated knee osteoarthritis among knees with normal alignment.
Coronal tibial slope, particularly among knees with malalignment, may be an important risk factor for incident accelerated knee osteoarthritis.
PMCID: PMC4950083  PMID: 27432004
Knee; Osteoarthritis; Bone; Alignment; Radiography
13.  Primary Care Providers’ Views on Using Lung Age as an Aid to Smoking Cessation Counseling for Patients with Chronic Obstructive Pulmonary Disease 
Lung  2015;193(3):321-327.
Smoking cessation is the primary goal for managing patients with chronic obstructive pulmonary disease (COPD) who smoke. However, previous studies have demonstrated poor cessation rates. The “lung age” concept (an estimate of the age at which the FEV1 would be considered normal) was developed to present spirometry data in an understandable format and to serve as a tool to encourage smokers to quit. Primary care physicians’ (PCPs) views of using lung age to help COPD patients to quit smoking were assessed.
Post-intervention interviews were conducted with PCPs in the U.S. who participated in the randomized clinical trial, “Translating the GOLD COPD Guidelines into Primary Care Practice.”
29 physicians completed the interview. Themes identified during interviews included: general usefulness of lung age for smoking cessation counseling, ease of understanding the concept, impact on patients’ thoughts of quitting smoking, and comparison to FEV1. Most providers found lung age easy to communicate. Moreover, some found the tool to be less judgmental for smoking cessation and others remarked on the merits of having a simple, tangible number to discuss with their patients. However, some expressed doubt over the long-term benefits of lung age and several others thought that there might be a potential backfire for healthy smokers if their lung age was ≤ to their chronological age.
This study suggests that lung age was well received by the majority of PCPs and appears feasible to use with COPD patients who smoke. However, further investigation in needed to explore COPD patients’ perspectives of obtaining their lung age to help motivate them to quit in randomized clinical trials.
PMCID: PMC4433592  PMID: 25791068
Chronic obstructive pulmonary disease; Smoking; Lung age
15.  Association of Baseline Depressive Symptoms with Prevalent and Incident Pre-Hypertension and Hypertension in Postmenopausal Hispanic Women: Results from the Women’s Health Initiative 
PLoS ONE  2016;11(4):e0152765.
Depression and depressive symptoms are risk factors for hypertension (HTN) and cardiovascular disease (CVD). Hispanic women have higher rates of depressive symptoms compared to other racial/ethnic groups yet few studies have investigated its association with incident prehypertension and hypertension among postmenopausal Hispanic women. This study aims to assess if an association exists between baseline depression and incident hypertension at 3 years follow-up among postmenopausal Hispanic women.
Prospective cohort study, Women’s Health Initiative (WHI), included 4,680 Hispanic women who participated in the observational and clinical trial studies at baseline and at third-year follow-up. Baseline current depressive symptoms and past depression history were measured as well as important correlates of depression—social support, optimism, life events and caregiving. Multinomial logistic regression was used to estimate prevalent and incident prehypertension and hypertension in relation to depressive symptoms.
Prevalence of current baseline depression ranged from 26% to 28% by hypertension category and education moderated these rates. In age-adjusted models, women with depression were more likely to be hypertensive (OR = 1.25; 95% CI 1.04–1.51), although results were attenuated when adjusting for covariates. Depression at baseline in normotensive Hispanic women was associated with incident hypertension at year 3 follow-up (OR = 1.74; 95% CI 1.10–2.74) after adjustment for insurance and behavioral factors. However, further adjustment for clinical covariates attenuated the association. Analyses of psychosocial variables correlated with depression but did not alter findings. Low rates of antidepressant medication usage were also reported.
In the largest longitudinal study to date of older Hispanic women which included physiologic, behavioral and psychosocial moderators of depression, there was no association between baseline depressive symptoms and prevalent nor incident pre-hypertension and hypertension. We found low rates of antidepressant medication usage among Hispanic women suggesting a possible point for clinical intervention.
Trial Registration NCT00000611
PMCID: PMC4849764  PMID: 27124184
16.  Racial and Ethnic Differences in Incident Hospitalized Heart Failure in Post Menopausal Women: The Women’s Health Initiative 
Circulation  2012;126(6):688-696.
The differences in the incidence of heart failure (HF) by race/ethnicity as well as the potential mechanisms for these differences are largely unexplored in women.
Methods and Results
155,335 post menopausal women free of self-reported HF enrolled from 1993-1998 at 40 clinical centers throughout the United States as part of the Women’s Health Initiative and were followed until 2005, for an average of 7.7 years for incident hospitalized heart failure. Incident rates, hazard’s ratios and 95% CI were determined using Cox-proportional hazard’s model comparing racial/ethnic groups and population attributable risk percentages were calculated for each racial/ethnic group. African Americans had the highest age-adjusted incidence of HF (405/100,000 person-years) followed by whites (283) Hispanics (191) and Asian/Pacific Islanders (102). The excess risk in African Americans compared to whites (age-adjusted HR= 1.47) was significantly attenuated by adjustment for household income (HR=0.99) and diabetes mellitus (HR=0.92) but the lower risk in Hispanics (age-adjusted HR=0.76) and Asian/Pacific Islanders (age-adjusted HR=0.40) remained despite adjustment for traditional risk factors, socioeconomic status, lifestyle and access to care variables. The effect of adjustment for interim CHD on non-white versus white hazard ratios for heart failure differed by race/ethnic group.
Asian/Pacific Islander and Hispanic women have a lower incidence of heart failure while African American women have higher rates of heart failure compared to white women. The excess risk of incident heart failure in African American women is largely explained by adjustment for lower household incomes and diabetes in African American women while the lower rates of heart failure in Asian/Pacific Islanders and Hispanics are largely unexplained by the risk factors measured in this study.
Clinical Trial Registration Information; Unique Identifier: NCT00000611
PMCID: PMC4618499  PMID: 22753306
heart failure; incidence; population; race/ethnicity
17.  Effects of glucosamine and chondroitin on treating knee osteoarthritis: an analysis with marginal structural models 
The purpose of this study was to estimate the effectiveness of glucosamine and chondroitin in relieving knee symptoms and slowing disease progression among patients with knee osteoarthritis (OA).
The 4-year follow-up data from Osteoarthritis Initiative were analyzed. We used a “new-user” design, for which only participants who were not using glucosamine/chondroitin at baseline were included in analyses (n=1,625). Cumulative exposure was calculated as the number of visits when participants reported use of glucosamine/chondroitin. Knee symptoms were measured with WOMAC scale and structural progression was measured with joint space width (JSW). To control for the time-varying confounders that might be influenced by prior treatments, we used marginal structural models to estimate the effects of using glucosamine/chondroitin for three years, two years and one year on treating OA.
During the study period, 18% of the participants initiated treatment with glucosamine/chondroitin. After adjustment for potential confounders with marginal structural models, we found no clinically significant differences between users at all assessments and never-users of glucosamine/chondroitin in WOMAC Pain: 0.68 (95% CI: -0.16 to 1.53); WOMAC Stiffness: 0.41 (95% CI: 0 to 0.82); WOMAC Function: 1.28 (95% CI: -1.23 to 3.79); or JSW: 0.11 (95% CI: -0.21 to 0.44).
Use of glucosamine/chondroitin did not appear to relieve symptoms or modify disease progression among patients with radiographically confirmed OA. Our findings, which are consistent with meta-analyses of clinical trials, extend the results to a more general population with knee OA.
PMCID: PMC4342281  PMID: 25369761
18.  Effects of prescription non-steroidal anti-inflammatory agents on symptoms and disease progression among patients with knee osteoarthritis 
The effect of short and long term non-steroidal anti-inflammatory agents (NSAIDs) use on structural change is equivocal. We estimate the extent to which recent and long-term use of prescription NSAIDs relieve symptoms and delay structural progression among patients with radiographically confirmed osteoarthritis (OA) of the knee.
We applied a new-user design among participants with confirmed OA not reporting NSAID use at enrollment in the Osteoarthritis Initiative. Participants were evaluated for changes in the Western Ontario and McMaster Universities Arthritis Index, WOMAC (n=1,846) and joint space width measured using serial x-rays and a customized software tool (n=1,116) over 4 years. We used marginal structural modeling to estimate the effect of NSAIDs.
Compared to participants who never reported prescription NSAID use, those reporting use at 1 or 2 assessments had no clinically important changes, but those reporting prescription NSAID use on all 3 assessments had on average 0.88 point improvement over the follow-up period (95% Confidence Interval (CI): -0.46 to 2.22) in Pain, 0.72 point improvement (95% CI: -0.12 to 1.56) in Stiffness, 4.27 points improvement (95% CI: -0.31 to 8.84) in Function, and decreased by 0.28mm in joint space width (95% CI: -0.06 to 0.62) less than no use. Recent NSAID use findings were not clinically or statistically significant.
Long term but not recent NSAID use was associated with a priori defined minimally important clinical change in stiffness, function and structural change but not in pain. While showing modest clinical importance, estimates did not reach statistical significance.
PMCID: PMC4342290  PMID: 25369996
19.  Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans 
EBioMedicine  2016;4:153-161.
Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene–environment interactions is not well understood.
We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case–control study of African-American females and males (1078 lung cancer cases and 822 controls).
Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10− 5). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = − 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.
These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.
•Genetic by environment (e.g., cigarettes/day, CPD) interactions for lung cancer are understudied in non-European ancestry populations.•We analyzed interactions between nominal smoking quantity SNPs (n = 7156 discovery sample) and CPD and risk of lung cancer (n = 1078 cases, n = 822 controls).•Six SNPs were effect modifiers of CPD for lung cancer, suggesting that the allelic dose effect is most pronounced in light smokers.
Lung cancer is the leading cause of cancer death, disproportionately affecting African-Americans. Prior studies have reported specific genetic markers linked to both smoking quantity and risk of lung cancer in multiple ethnic/racial groups. Investigators analyzed associations between 28 polymorphisms and average cigarettes smoked per day (CPD) in 7156 African-American females and examined interactions between the top polymorphisms and CPD in a cohort of African-American males and females (1078 lung cancer cases and 822 health control patients). The results suggested that six polymorphisms within one genomic region increased lung cancer risk in African-Americans, which was most pronounced in light smokers.
PMCID: PMC4776066  PMID: 26981579
African-Americans; Environment; Genetics; Lung Cancer; rs2036527; Single Nucleotide Polymorphisms; Smoking
20.  Risk of Heart Failure Among Postmenopausal Women: A Secondary Analysis of the Randomized Trial of Vitamin D Plus Calcium of the Women’s Health Initiative 
Circulation. Heart failure  2014;8(1):49-56.
Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in post-menopausal women and whether the effects differ between those at high versus low risk for HF.
Methods and Results
Analyses were restricted to 35,983 (of original 36,282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1,000 mg/day of calcium plus 400 IU/day of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared to placebo, was not associated with reduced HF risk in the overall population, hazard ratio (HR), 0.95; P=0.46. However, CaD supplementation had differential effects (P-interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high-risk=17,449) or absence (low-risk=18,534) of preexisting HF precursors including coronary heart diseases, diabetes, or hypertension: 37% (HR, 0.63 [95% CI, 0.46 to 0.87]) lower risk of HF in the low-risk versus HR, 1.06; P=0.51, in the high-risk subgroups.
CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism.
PMCID: PMC4303506  PMID: 25398967
21.  Relationship of Meeting Physical Activity Guidelines with Quality Adjusted Life Years 
The Quality Adjusted Life Year (QALY) is a standard outcome measure used in cost-effectiveness analyses. This study investigates whether attainment of federal physical activity guidelines is associated with higher QALY estimates among adults with or at increased risk for knee osteoarthritis.
This is a prospective study of 1794 Osteoarthritis Initiative participants. Physical activity was measured using accelerometers at baseline. Participants were classified as 1) Meeting Guidelines (≥150 minutes of moderate-to-vigorous [MV] activity per week acquired in sessions ≥10 minutes), 2) Insufficiently Active (≥1 MV session[s]/week but below guideline), or 3) Inactive (zero MV sessions/week). A health-related utility score was derived from participant responses to the 12 item Short-Form Health Survey at baseline and two years later. QALY was calculated as the area under utility curve over two years. Relationship of physical activity level to median QALY adjusted for socioeconomic and health factors was estimated using quantile regression.
Relative to the Inactive, median QALYs over two years were significantly higher for the Meeting Guidelines (0.112, 95% confidence interval [CI] 0.067–0.157) and Insufficiently Active (0.058, 95% CI 0.028–0.088) groups controlling for socioeconomic and health factors.
We found a significant graded relationship between greater physical activity level and higher QALYs. Using the more conservative estimate of 0.058, if an intervention could move someone out of the Inactive group and costs <$2900 over two years, it would be considered cost effective. Our analysis supports interventions to promote physical activity even if recommended levels are not fully attained.
PMCID: PMC4258164  PMID: 25074656
22.  Knee Injuries Are Associated with Accelerated Knee Osteoarthritis Progression: Data from the Osteoarthritis Initiative 
Arthritis care & research  2014;66(11):1673-1679.
We aimed to evaluate if a recent knee injury was associated with accelerated knee osteoarthritis (KOA) progression.
In the Osteoarthritis Initiative (OAI) we studied participants free of KOA on their baseline radiographs (Kellgren-Lawrence [KL]<2). We compared three groups: 1) individuals with accelerated progression of KOA: defined as having at least one knee that progressed to end-stage KOA (KL Grade 3 or 4) within 48 months, 2) common KOA progression: at least one knee increased in radiographic scoring within 48 months (excluding those defined as accelerated KOA), and 3) no KOA: no change in KL grade in either knee. At baseline, participants were asked if their knees had ever been injured and at each annual visit they were asked about injuries during the prior 12 months. We used multinomial logistic regressions to determine if a new knee injury was associated with the outcome of accelerated KOA or common KOA progression after adjusting for age, sex, body mass index, static knee malalignment, and systolic blood pressure.
A knee injury during the total observation period was associated with accelerated KOA progression (n=54, odds ratio [OR]=3.14) but not common KOA progression (n=187, OR=1.08). Furthermore, a more recent knee injury (within a year of the outcome) was associated with accelerated (OR=8.46) and common KOA progression (OR=3.12).
Recent knee injuries are associated with accelerated KOA. Most concerning is that certain injuries may be associated with a rapid cascade towards joint failure in less than one year.
PMCID: PMC4211979  PMID: 24782446
23.  Healthy Lifestyle and Risk of Heart Failure in the Women's Health Initiative Observational Study 
The impact of a healthy lifestyle on risk of heart failure (HF) is not well known.
To evaluate the effect of a combination of lifestyle factors on incident HF, and further investigate whether weighting each lifestyle factor has additional impact.
Participants were 84,537 post-menopausal women from the Women's Health Initiative Observational Study, free of self-reported HF at baseline. A healthy lifestyle score (HL-score) was created, where women received 1 point for each healthy criterion met: high-scoring Alternative Healthy Eating Index, physically active, healthy body mass index, and currently not smoking. A weighted score (wHL-score) was also created where each lifestyle factor was weighted according to its independent magnitude of effect on HF. Incident hospitalized HF was determined by trained adjudicators using standardized methodology.
There were 1,826 HF cases over a mean follow-up of 11 years. HL-score was strongly associated with risk of HF (multivariable-adjusted HR [95% CI] = 0.49 [0.38,0.62], 0.36 [0.28,0.46], 0.24 [0.19,0.31], and 0.23 [0.17,0.30] for HL-score of 1,2,3,4 vs 0, respectively]. The HL-score and wHL-score were similarly associated with HF risk (HR [95% CI] = 0.46 [0.41,0.52] for HL-score and 0.48 [0.42,0.55] for wHL-score, comparing the highest tertile to the lowest). The HL-Score was also strongly associated with HF risk among women without antecedent coronary heart disease, diabetes, or hypertension.
An increasingly healthy lifestyle was associated with decreasing HF risk among post-menopausal women, even in the absence of antecedent coronary heart disease, hypertension, and diabetes. Weighting the lifestyle factors had minimal impact.
PMCID: PMC4254927  PMID: 25443698
heart failure; lifestyle; cardiovascular diseases; risk factors; primary prevention
24.  Mediterranean and DASH Diet Scores and Mortality in Women with Heart Failure: The Women’s Health Initiative 
Circulation. Heart failure  2013;6(6):1116-1123.
Current dietary recommendations for heart failure (HF) patients are largely based on data from non-HF populations; evidence regarding associations of dietary patterns with outcomes in HF is limited. We therefore evaluated associations of Mediterranean and DASH diet scores with mortality among postmenopausal women with HF.
Methods and Results
Women’s Health Initiative participants were followed from the date of HF hospitalization through the date of death or last participant contact prior to August 2009. Mediterranean and DASH diet scores were calculated from food-frequency questionnaires. Cox proportional hazards models adjusted for demographics, health behaviors, and health status were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Over a median of 4.6 years of follow-up, 1,385 of 3,215 (43.1%) participants who experienced a HF hospitalization died. Multivariable-adjusted HRs were 1 (reference), 1.05 (95% CI 0.89–1.24), 0.97 (95% CI 0.81–1.17), and 0.85 (95% CI 0.70–1.02) across quartiles of the Mediterranean diet score (p-trend = 0.08) and 1 (reference), 1.04 (95% CI 0.89–1.21), 0.83 (95% CI 0.70–0.98), and 0.84 (95% CI 0.70–1.00) across quartiles of the DASH diet score (p-trend = 0.01). Diet score components vegetables, must, and whole grain intake were inversely associated with mortality.
Higher DASH diet scores were associated with modestly lower mortality in women with HF, and there was a non-significant trend towards an inverse association with Mediterranean diet scores. These data provide support for the concept that dietary recommendations developed for other cardiovascular conditions or general populations may also be appropriate in HF patients.
PMCID: PMC4564006  PMID: 24107587
diet; heart failure; mortality; nutrition
25.  Relationship of Meeting Physical Activity Guidelines with Health-Related Utility 
Arthritis care & research  2014;66(7):1041-1047.
Health-related utility measures overall health status and quality of life and is commonly incorporated into cost-effectiveness analyses. This study investigates whether attainment of federal physical activity guidelines translates into better health-related utility in adults with or at risk for knee osteoarthritis (OA).
Cross-sectional data from 1908 adults with or at risk for knee OA participating in the accelerometer ancillary study of the Osteoarthritis Initiative (OAI) were assessed. Physical activity was measured using 7 days of accelerometer monitoring and was classified as 1) Meeting Guidelines (≥150 bouted moderate-to-vigorous [MV] minutes per week); 2) Insufficiently Active (≥1 MV bout[s] per week but below guidelines); or 3) Inactive (zero MV bouts per week). A Short Form 6D (SF6-D) health-related utility score was derived from patient-reported health status. Relationship of physical activity levels to median health-related utility adjusted for socioeconomic and health factors was tested using quantile regression.
Only 13% of participants met physical activity guidelines; 45% were inactive. Relative to the Inactive, median health-related utility scores were significantly greater for the Meeting Guidelines (0.063; confidence interval [CI] 0.055–0.071) and Insufficiently Active (0.059; CI 0.054–0.064) groups. These differences showed a statistically significant linear trend and strong cross-sectional relationship with physical activity level even after adjusting for socioeconomic and health factors.
We found a significant positive relationship between physical activity level and health-related utility. Interventions that encourage adults, including persons with knee OA, to increase physical activity even if recommended levels are not attained may improve their quality of life.
PMCID: PMC4051873  PMID: 24339324

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