Enhanced pain facilitation is reportedly an important contributor to the clinical pain experiences of individuals with knee osteoarthritis (OA). Ethnic differences in the prevalence and severity of knee OA in addition to associated pain are also well documented. Temporal summation (TS) of pain is a widely applicable quantitative sensory testing method that invokes neural mechanisms related to pain facilitatory processes. This study tested whether TS of pain, an index of pain facilitation, differentially predicts the clinical pain experiences of African Americans and non-Hispanic Whites with symptomatic knee OA.
A total of 225 study participants underwent assessment of TS of mechanical and heat pain stimuli applied to their most symptomatic knee and their ipsilateral hand (mechanical) or forearm (heat). Using telephone-based surveys, participants subsequently reported their average and worst clinical pain severity across four consecutive weeks following assessment of TS.
In predicting future clinical pain, ethnicity interacted with TS of mechanical pain (but not heat pain), such that TS of mechanical pain at the knee significantly predicted greater clinical ratings of average (b = .02, p = .016) and worst (b = .02, p = .044) clinical pain for non-Hispanic Whites but not African Americans (p’s > .30).
These results reveal the importance of considering ethnicity when examining pain facilitation and the clinical pain of individuals with symptomatic knee OA. The results of this study are discussed in terms of ethnic differences in the predictors of clinical pain experiences among African Americans and non-Hispanic Whites with knee OA.
Pain; Knee Osteoarthritis (OA); Ethnicity; Pain Facilitation; Temporal Summation (TS)
B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.
The strategy of evaluating every donation opportunity warrants an investigation into the financial feasibility of this practice. The purpose of this investigation is to measure resource utilization required for procurement of transplantable organs in an organ procurement organization (OPO).
Donors were stratified into those that met OPTN-defined eligible death criteria (ED Donors, n=589) and those that did not (NED Donors, n=703). Variable direct costs and time utilization by OPO staff for organ procurement were measured and amortized per organ transplanted using permutation methods and statistical bootstrapping/resampling approaches.
More organs per donor were procured (3.66 ± 1.2 vs. 2.34 ± 0.8, p<0.0001) and transplanted (3.51 ± 1.2 vs. 2.08 ± 0.8, p<0.0001) in ED donors compared to NED donors. The variable direct costs were significantly lower in NED donors ($29,879.4 ± 11590.1 vs. $19,019.6 ± 7599.60, p<0.0001). In contrast, the amortized variable direct costs per organ transplanted were significantly higher in the NED donors ($8,414.5 ± 138.29 vs. $9,272.04 ± 344.56, p<0.0001). ED donors where thoracic organ procurement occurred were 67% more expensive than in abdominal-only organ procurement. The total time allocated per donor was significantly shorter in NED donors (91.2 ± 44.9 hours vs. 86.8 ± 78.6, p=0.01). In contrast, the amortized time per organ transplanted was significantly longer in the NED donors (23.1 ± 0.8 hours vs. 36.9 ± 3.2, p<0.001).
The variable direct costs and time allocated per organ transplanted is significantly higher in donors that do not meet the eligible death criteria.
Eligible Death Donor; Non-Eligible Death Donor; Organ Procurement; Deceased Donor Organs; Variable Direct Cost; Resource Allocation
The Disease Activity Score based on 28 joints (DAS28) has been increasingly used in clinical practice and research studies of rheumatoid arthritis (RA). Studies have reported discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in RA patients. However such comparison is lacking in African-Americans with RA.
This analysis included participants from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry which enrolls self-declared African-Americans with RA. Using tender and swollen joint counts separate ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) were calculated, as were DAS28-ESR4 and DAS28-CRP4, which included the patient’s assessment of disease activity. The scores were compared using paired t-test, simple agreement and kappa, correlation coefficient and Bland-Altman plots.
Of the 233 included participants, 85% were women, mean age at enrollment was 52.6 years, and median disease duration at enrollment was 21 months. Mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs. 3.9; p<0.001). Similarly, mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs. 3.9; p<0.001). ESR-based DAS28 remained higher than CRP-based DAS28 even when stratified by age, sex, and disease duration. Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4.
There was significant discordance between the ESR-based and CRP-based DAS28 which could impact clinical treatment decisions in African-Americans with RA.
DAS28; Rheumatoid Arthritis; African-Americans
Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking.
Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t-test, Wilcoxon’s rank sum test, chi-square test, and logistic regression analyses.
Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio >2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA.
CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care.
Gene polymorphism; methotrexate; rheumatoid arthritis
Studies have shown that perceived racial discrimination is a significant predictor of clinical pain severity among African Americans. It remains unknown whether perceived racial discrimination also alters the nociceptive processing of painful stimuli, which, in turn, could influence clinical pain severity. This study examined associations between perceived racial discrimination and responses to noxious thermal stimuli among African Americans and non-Hispanic whites. Mistrust of medical researchers was also assessed given its potential to affect responses to the noxious stimuli.
One hundred and thirty (52% African American, 48% non-Hispanic white) community-dwelling older adults with symptomatic knee osteoarthritis completed two study sessions. In session one, individuals provided demographic, socioeconomic, physical and mental health information. They completed questionnaires related to perceived lifetime frequency of racial discrimination and mistrust of medical researchers. In session two, individuals underwent a series of controlled thermal stimulation procedures to assess heat pain sensitivity, particularly heat pain tolerance.
African Americans were more sensitive to heat pain and reported greater perceived racial discrimination as well as greater mistrust of medical researchers compared to non-Hispanic whites. Greater perceived racial discrimination significantly predicted lower heat pain tolerance for African Americans but not non-Hispanic whites. Mistrust of medical researchers did not significantly predict heat pain tolerance for either racial group
These results lend support to the idea that perceived racial discrimination may influence the clinical pain severity of African Americans via the nociceptive processing of painful stimuli.
The Organ Donor Breakthrough collaborative recommended high-leverage changes including “Master Effective Requesting”.
The purpose of this investigation is to measure who approaches decedent families to request organ donation. Our hypothesis is that trained specialists will solicit authorization at equal frequency regardless of donor characteristics.
A retrospective analysis of an organ center donor database was performed for the years 2006 to 2009. Decedents were stratified into those that met OPTN eligible death criteria (ED donors) and those that did not (not eligible death--NED donors).
Of decedents whose families were approached for authorization, 46% were ED donors and 54% were NED donors. Trained specialists solicited authorization from 76% of the total population, but were more likely to solicit authorization from ED donors than NED donors (86% vs. 68%, p<0.0001). Trained specialists were more likely to solicit authorization from donors whose cause of death were over-represented in ED donors, and donors under the age of 50. Trained specialists were more likely to obtain authorization in both ED and NED donors. Multivariable modeling demonstrated that having a trained specialist approach the decedent’s family was associated with the highest odds of obtaining authorization.
Trained specialists approached the majority of families of decedents for authorization, but disproportionately approached fewer families of NED donors. Having a trained specialist approach the decedent family has the strongest impact on obtaining donor authorization. These data suggest that fewer resources are allocated to NED donors, which may adversely impact deceased donor organ supply.
Donor Authorization; Eligible Death Donor; Race; Cause of Death; Deceased Donor Organs
Dispositional optimism has been shown to beneficially influence various experimental and clinical pain experiences. One possibility that may account for decreased pain sensitivity among individuals who report greater dispositional optimism is less use of maladaptive coping strategies like pain catastrophizing, a negative cognitive/affective response to pain. An association between dispositional optimism and conditioned pain modulation (CPM), a measure of endogenous pain inhibition, has previously been reported. However, it remains to be determined whether dispositional optimism is also associated with temporal summation (TS), a measure of endogenous pain facilitation. The current study examined whether pain catastrophizing mediated the association between dispositional optimism and TS among 140 older, community-dwelling adults with symptomatic knee osteoarthritis. Individuals completed measures of dispositional optimism and pain catastrophizing. TS was then assessed using a tailored heat pain stimulus on the forearm. Greater dispositional optimism was significantly related to lower levels of pain catastrophizing and TS. Bootstrapped confidence intervals revealed that less pain catastrophizing was a significant mediator of the relation between greater dispositional optimism and diminished TS. These findings support the primary role of personality characteristics such as dispositional optimism in the modulation of pain outcomes by abatement of endogenous pain facilitation and less use of catastrophizing.
Optimism; Catastrophizing; Pain Facilitation; Temporal Summation; Osteoarthritis
Gene expression profiling may be used to stratify patients by disease severity to test the hypothesis that variable disease outcome has a genetic component. In order to define unique expression signatures in African American rheumatoid arthritis (RA) patients with severe erosive disease, we undertook a gene expression study using samples of RNA from peripheral blood mononuclear cells (PBMCs). RNA from baseline PBMC samples of 96 African American RA patients with early RA (<2 years disease duration) was hybridized to cDNA probes of the Illumina Human HT-V3 expression array. Expression analyses were performed using the ca. 25,000 cDNA probes, and then expression levels were compared to the total number of erosions in radiographs of the hands and feet at baseline and 36 months. Using a false discovery rate cutoff of Q = 0.30, 1,138 genes at baseline and 680 genes at 36 months significantly correlated with total erosions. No evidence of a signal differentiating disease progression, or change in erosion scores between baseline and 36 months, was found. Further analyses demonstrated that the differential gene expression signature was localized to the patients with the most erosive disease (>10 erosions). Ingenuity Pathway Analysis demonstrated that genes with fold change greater than 1.5 implicated immune pathways such as CTLA signaling in cytotoxic T lymphocytes. These results demonstrate that CLEAR patients with early RA having the most severe erosive disease, as compared to more mild cases (<10 erosions), may be characterized by a set of differentially expressed genes that represent biological pathways with relevance to autoimmune disease.
Genome-wide gene expression; Sharp/van der Heijde; Pathway analysis; CLEAR; ABCoN
Studies have demonstrated that African American race is a strong predictor of non-donation. However, it is often and correctly argued that African American race is a crude explanatory variable that is a surrogate marker of socioeconomic status (SES), education and access to health care. We hypothesized that when controlling for these factors, African American race would cease to be a predictor of organ donation.
A retrospective review was performed of 1292 Alabama decedents approached for organ donation between 2006 and 2009. Multivariable logistic regression models were constructed to identify the most parsimonious model that could explain the variation in the log-odds of obtaining consent.
Consent for donation was obtained from 49% of the decedent's families. Household income was a predictor of organ donor consent only in Caucasians. Surprisingly, household income was not statistically different between consented and non-consented African American decedents ($25,147 vs. $26,137; p=0.90). On multivariable analysis, education, urban residence and shorter distance between the decedent residence and donor hospital were significantly associated with obtaining consent for organ donation. On univariate analysis, the odds of donor consent in Caucasians compared to African Americans was 2.76 (95% CI 2.17 – 3.57). When controlling for SES and access to healthcare variables, the odds of donor consent increased to 4.36 (95% CI 2.88 – 6.61).
We interpret this result to indicate that there remains unknown but important factor(s) associated with both race and obtaining organ donor consent. Further studies are required to isolate and determine whether this factor(s) is modifiable.
Socioeconomic Status; Organ Donation; Education; Marital Status
Dietary glycemic load (GL), glycemic index (GI), and carbohydrate could be associated with breast cancer risk by influencing long-term blood glucose and insulin concentrations. We examined associations between GL, GI, and carbohydrate and incident breast cancer in 148,767 Women’s Heath Initiative (WHI) participants. Dietary variables were estimated from food frequency questionnaires administered at baseline. Self-reported breast cancers during follow-up were confirmed by medical records review. Cox proportional hazards regression modeled time to breast cancer within quintiles of GL, GI, and carbohydrate. There were 6,115 total breast cancers after a median follow-up of 8.0 yr. We observed no associations between GL, GI, or carbohydrate and total incident breast cancer, with hazard ratios and 95% confidence intervals for the highest vs. lowest quintiles of 1.08, 0.92–1.29 (P for trend = 0.27); 1.01, 0.91–1.12 (P = 0.74); and 0.95, 0.80–1.14 (P = 0.98), respectively. There was a trend toward significance for the positive association between GL and in situ cancers (1.40, 0.94–2.13; P = 0.07). Although there was no evidence of associations between GL, GI, or carbohydrate and total breast cancer risk in WHI participants, the suggestion of an association between GL and risk of in situ cancers requires further investigation.
To show how the variance of the measurement error (ME) associated with individual ancestry proportion estimates can be estimated, especially when the number of ancestral populations (k) is greater than 2.
We extend existing internal consistency measures to estimate the ME variance, and we compare these estimates with the ME variance estimated by use of the repeated measurement (RM) approach. Both approaches work by dividing the genotyped markers into subsets. We examine the effect of the number of subsets and of the allocation of markers to each subset on the performance of each approach. We used simulated data for all comparisons.
Independently of the value of k, the measures of internal reliability provided less biased and more precise estimates of the ME variance than did those obtained with the RM approach. Both methods tend to perform better when a large number of subsets of markers with similar sizes are considered.
Our results will facilitate the use of ME correction methods to address the ME problem in individual ancestry proportion estimates. Our method will improve the ability to control for type I error inflation and loss of power in association tests and other genomic research involving ancestry estimates.
Population stratification; admixture; type I error inflation; reliability; Cronbach’s alpha; measurement errors; measurement error variance
Quantitative polymerase chain reaction (qPCR) and pp65 antigenemia assays are used to monitor cytomegalovirus (CMV) infection in renal transplant recipients, but correlation of assays in a pediatric population has not been evaluated. Paired CMV real-time qPCR and pp65 antigenemia tests from 882 blood samples collected from 115 pediatric renal transplant recipients were analyzed in this retrospective cohort study for strength of association and clinical correlates.
The assays correlated well in detecting infection (κ = 0.61). Higher qPCR values were demonstrated with increasing levels of antigenemia (p < 0.01). Discordant test results were associated with antiviral treatment (OR 4.33, p < 0.01) and low-level viremia, with odds of concordance increasing at higher qPCR values (OR 3.67, p < 0.01), and no discordance occurring above 8500 genomic equivalents/mL. Among discordant samples, neither test preceded the other in detecting initial infection or in returning to negative while on treatment. Only 2 cases of disease occurred during the 2-year study period.
With strong agreement in the detection of CMV infection, either qPCR or pp65 antigenemia assays can be used effectively for monitoring pediatric renal transplant patients for both detection and resolution of infection.
Pediatrics; Kidney Transplantation; Cytomegalovirus Infections; Polymerase Chain Reaction; CMV pp65 Antigen
Introduction and Hypothesis
The goal of this study was to characterize associations between caffeine consumption and severity of urinary incontinence (UI) in US women. We hypothesized that moderate and high caffeine intake would be associated with UI in US women when controlling for other factors associated with UI.
US women participated in the 2005–2006 and 2007–2008 National Health and Nutrition Examination Survey (NHANES), a cross-sectional, nationally representative survey. Using the Incontinence Severity Index, UI was categorized as “any” and “moderate/severe”. Types of UI included stress, urge, mixed, and other. Food diaries were completed and average water (gm/day), total dietary moisture (gm/day), and caffeine (mg/day) intake were calculated into quartiles. Step-wise logistic regression models were constructed adjusting for: sociodemographics, chronic diseases, body mass index, self-rated health, depression, alcohol use, dietary water and moisture in take, and reproductive factors.
From the 4309 non-pregnant women (aged ≥20 years) who had complete UI and dietary data, UI prevalence for any UI was 41.0% and 16.5% for moderate/severe UI, with stress UI the most common UI type (36.6%). Women consumed a mean caffeine intake of 126.7 mg/day. After adjusting for multiple factors, caffeine in take in the highest quartile (≥204 mg/day) was associated with any UI (prevalence odds ratio (POR)1.47, 95% CI 1.07, 2.01), but not moderate/severe UI (POR 1.42, 95% CI 0.98, 2.07). Type of UI (stress, urgency, mixed) was not associated with caffeine intake.
Caffeine intake ≥204 mg/day was associated with any UI, but not moderate/severe UI, in US women.
urinary; incontinence; caffeine; intake; women
The purpose of this study was to assess the impact of body mass index (BMI) on tension-free vaginal tape (TVT) success rates, patient satisfaction, and complications one year following surgery.
Baseline and one-year post-surgery outcomes were abstracted, including Urogenital Distress Inventory (UDI-6) scores, Incontinence Impact Questionnaire (IIQ-7) scores, and patient satisfaction ratings. Multivariable logistic and linear regression analyses were performed to examine relationships between outcomes and BMI.
195 subjects with a mean age of 59.3 ±12.6 were included. There was significant improvement within each group (all p-values <0.01) in total UDI-6 and IIQ-7 scores from baseline to one year post-surgery; all groups had high patient satisfaction. No differences in improvement or complications rates were observed among the BMI cohorts (all p-values >0.05)
Differential counseling of overweight or obese women regarding outcomes of the TVT procedure is not supported by these results; longer follow-up is warranted.
obesity; outcomes; TVT sling; urinary incontinence
A distribution-free method to generate high-dimensional sequences of dependent variables with an autoregressive structure is presented. The quantile or fractile correlation (i.e., the moment correlation of the quantiles) is used as measure of dependence among a set of contiguous variables. The proposed algorithm breaks the sequence in small parts and avoids having to define one large correlation matrix for the entire high-dimensional sequence of variables. Simulations based on proteomics data are presented. Results suggest that negligible or no loss of fractile correlation occurs by splitting the generation of a sequence into small parts.
Distribution-free methods; Fractile correlations; High-dimensional data; Simulation
To determine the incidence of fecal incontinence (FI) in community-dwelling older adults and identify risk factors associated with incident FI.
Planned secondary analysis of a longitudinal, population-based cohort study.
Three rural and two urban Alabama counties (in-home assessments 2000–2005).
Stratified random sample of 1,000 Medicare beneficiaries: 25% African-American men, 25% white men, 25% African-American women, 25% white women, aged 65 and older. Eligible participants for this analysis were continent at baseline and community-dwelling 4 years later (n =557).
FI was defined as any loss of control of bowels occurring during the previous year. Independent variables were sociodemographics, Charlson comorbidity counts, self-reported bowel symptoms (chronic diarrhea and constipation), depression, and body mass index (BMI). Multivariable logistic regression models were constructed using incident FI as the dependent variable.
The incidence rate of FI at 4 years was 17% (95% confidence interval (CI) =13.7–20.1), with 6% developing FI at least monthly (95% CI =4.0–8.3). White women were more likely to have incident FI (22%) than African-American women (13%, P =.04); no racial differences were observed in men. Controlling for age, comorbidity count, and BMI, significant independent risk factors for incident FI in women were white race, depression, chronic diarrhea, and urinary incontinence (UI). UI was the only significant risk factor for incident FI in men.
The occurrence of new FI is common in men and women aged 65 and older, with a 17% incidence rate over 4 years. FI and UI may share common pathophysiologic mechanisms and need regular assessment in older adults.
fecal incontinence; incidence; urinary incontinence; African Americans; gender; functional bowel disorders; epidemiology
To characterize differences in health-related quality of life among women presenting for treatment of fecal incontinence.
Among 155 women presenting for treatment of fecal incontinence in a specialty clinic, validated questionnaires measured impact on quality of life (Modified Manchester Health Questionnaire) and severity (the Fecal Incontinence Severity Index). Bowel symptoms, including frequency, urgency, and stool consistency, were ascertained. Co-morbid diseases were self-reported. Linear regression models were constructed from significant univariate variables to examine differences seen in quality of life scores.
Average age was 58.7 ± 11.5 with no differences found in quality of life scores according to race, body mass index, or number of vaginal deliveries (p > 0.05). Younger age, increased urinary incontinence symptoms, prior cholecystectomy, prior hysterectomy, and severity of bowel symptoms correlated with a negative impact on quality of life in univariate analysis (p <0.05). Average severity scores were 30.5 ± 13.7 with moderate correlation seen with increasing severity and quality of life scores (R2= 0.60). After controlling for severity, women had increased quality of life scores with more bowel urgency (15 points, 95% CI 8.1, 21.2), harder stool consistency (10 points, 95% CI 3.8, 16.3), and prior hysterectomy (9 points, 95% CI 2.7, 15.4).
Bowel symptoms and having a prior hysterectomy had the greatest negative impact on quality of life in women seeking treatment for fecal incontinence. Targeting individualized treatments to improve bowel symptoms may improve quality of life for women with fecal incontinence.
fecal incontinence; women; quality of life; urinary incontinence; bowel symptoms
To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3-year disease duration in a longitudinal cohort of African Americans (AAs) with recent-onset RA.
Participants (n=141) included AAs with < 2 years of disease duration. All patients underwent baseline BMD measurement (femoral neck and/or lumbar spine) using DXA. T-scores were calculated using AAs normative data. Patients were categorized as having osteopenia/osteoporosis (T score ≤ −1) or healthy. Hand/wrist radiographs, obtained at baseline and at 3-year disease duration, were scored using modified Sharp/van der Heijde method. The association between baseline BMD and total radiographic score at 3-year disease duration was examined using multivariable negative binomial regression.
At baseline, the mean age and disease duration were 52.4 years and 14.8 months respectively (85.1% women). Average total radiographic scores at baseline and 3-year disease duration were 2.4 and 5.7. In the final reduced multivariable model adjusting for age, gender, anti-cyclic citrullinated peptide antibody positivity, and the presence of radiographic damage at baseline, the total radiographic score at 3-years of disease duration in patients with osteopenia/osteoporosis at the femoral neck was twice that in patients with healthy bone density and the difference was statistically significant (p=0.0084). No association between lumbar spine osteopenia/osteoporosis and radiographic score was found.
These findings suggest that reduced generalized BMD may be a predictor of future radiographic damage and support the hypothesis that radiographic damage and reduced generalized BMD in RA patients may share a common pathogenic mechanism.
As genome-wide association studies expand beyond populations of European ancestry, the role of admixture will become increasingly important in the continued discovery and fine-mapping of variation influencing complex traits. Although admixture is commonly viewed as a confounding influence in association studies, approaches such as admixture mapping have demonstrated its ability to highlight disease susceptibility regions of the genome. In this study, we illustrate a powerful two-stage testing strategy designed to uncover trait-associated single nucleotide polymorphisms in the presence of ancestral allele frequency differentiation. In the first stage, we conduct an association scan by using predicted genotypic values based on regional admixture estimates. We then select a subset of promising markers for inclusion in a second-stage analysis, where association is tested between the observed genotype and the phenotype conditional on the predicted genotype. We prove that, under the null hypothesis, the test statistics used in each stage are orthogonal and asymptotically independent. Using simulated data designed to mimic African-American populations in the case of a quantitative trait, we show that our two-stage procedure maintains appropriate control of the family wise error rate and has higher power under realistic effect sizes than the one-stage testing procedure in which all markers are tested for association simultaneously with control of admixture. We apply the proposed procedure to a study of height in 201 African-Americans genotyped at 108 ancestry informative markers. The two-stage procedure identified two statistically significant markers rs1985080 (PTHB1/BBS9) and rs952718 (ABCA12). PTHB1/BBS9 is downregulated by parathyroid hormone in osteoblastic cells and is thought to be involved in parathyroid hormone action in bones and may play a role in height. ABCA12 is a member of the superfamily of ATP-binding cassette transporters and its potential involvement in height is unclear.
two-stage; structured association testing; admixture mapping; regional admixture estimate; genome-wide association studies
Associations between dietary glycemic load (GL) and cardiovascular disease (CVD) risk factors, including plasma lipoprotein/lipid levels, blood pressure (BP), and glucose metabolism factors, in the Women's Health Initiative Observational Study were examined.
A random sample of 878 Observational Study participants (postmenopausal women age 50 to 79 years) with baseline blood measures (647 White, 104 Black, 127 Hispanic) was included. Dietary GL was estimated from baseline food frequency questionnaires, which assessed dietary intake over the previous three months. At the baseline visit, participants completed demographic and health habit questionnaires, fasting blood samples were collected, anthropometric measurements were completed, and BP was assessed.
In all participants combined, GL was inversely associated with high-density lipoprotein (HDL) cholesterol (P for trend = 0.004) and positively associated with log10-transformed triglycerides (P = 0.008). While there were no statistically significant interactions of race/ethnicity with associations between GL and CVD risk factors, stratified results were suggestive, showing that GL was positively associated with total cholesterol (P = 0.018) and low-density lipoprotein (LDL) cholesterol (P = 0.038) in Hispanics. In Whites, there was a trend of reduced HDL cholesterol with higher GL (P = 0.003), while GL was positively associated with log10-transformed triglycerides (P = 0.015). Associations between GL and HDL cholesterol and GL and triglycerides also varied by BMI, although the interactions were not statistically significant.
Among these generally healthy postmenopausal women, GL was associated with HDL cholesterol and triglycerides. Suggestive effects of race/ethnicity and BMI on these associations need to be confirmed in larger studies.
Glycemic load; Glycemic index; Carbohydrate; Cardiovascular disease; Women's Health Initiative
As genome-wide association studies expand beyond populations of European ancestry, the role of admixture will become increasingly important in the continued discovery and fine-mapping of variation influencing complex traits. Although admixture is commonly viewed as a confounding influence in association studies, approaches such as admixture mapping have demonstrated its ability to highlight disease susceptibility regions of the genome. In this study, we illustrate a powerful two-stage testing strategy designed to uncover trait-associated single nucleotide polymorphisms in the presence of ancestral allele frequency differentiation. In the first stage, we conduct an association scan by using predicted genotypic values based on regional admixture estimates. We then select a subset of promising markers for inclusion in a second-stage analysis, where association is tested between the observed genotype and the phenotype conditional on the predicted genotype. We prove that, under the null hypothesis, the test statistics used in each stage are orthogonal and asymptotically independent. Using simulated data designed to mimic African-American populations in the case of a quantitative trait, we show that our two-stage procedure maintains appropriate control of the family wise error rate and has higher power under realistic effect sizes than the one-stage testing procedure in which all markers are tested for association simultaneously with control of admixture. We apply the proposed procedure to a study of height in 201 African-Americans genotyped at 108 ancestry informative markers. The two-stage procedure identified two statistically significant markers rs1985080 (PTHB1/BBS9) and rs952718 (ABCA12). PTHB1/BBS9 is downregulated by parathyroid hormone in osteoblastic cells and is thought to be involved in parathyroid hormone action in bones and may play a role in height. ABCA12 is a member of the superfamily of ATP binding cassette transporters and its potential involvement in height is unclear.
two-stage; structured association testing; admixture mapping; regional admixture estimate; genome-wide association studies
Questions remain regarding the utility of self-reported ethnicity (SRE) in genetic and epidemiologic research. It is not clear whether conditioning on SRE provides adequate protection from inflated type I error rates due to population stratification and admixture. We address this question using data obtained from the Multi-Ethnic Study of Atherosclerosis (MESA), which enrolled individuals from 4 self-reported ethnic groups. We compare the agreement between SRE and genetic based measures of ancestry (GBMA), and conduct simulation studies based on observed MESA data to evaluate the performance of each measure under various conditions.
Four clusters are identified using 96 ancestry informative markers. Three of these clusters are well delineated, but 30% of the self-reported Hispanic-Americans are misclassified. We also found that MESA SRE provides type I error rates that are consistent with the nominal levels. More extensive simulations revealed that this finding is likely due to the multi-ethnic nature of the MESA. Finally, we describe situations where SRE may perform as well as a GBMA in controlling the effect of population stratification and admixture in association tests.
The performance of SRE as a control variable in genetic association tests is more nuanced than previously thought, and may have more value than it is currently credited with, especially when smaller replication studies are being considered in multi-ethnic samples.
To determine incidence and predictors of incident urinary incontinence over 3 years in community-dwelling older adults.
MATERIALS & METHODS
A population-based, prospective cohort study was conducted with a random sample of Medicare beneficiaries, stratified to be 50% African American, 50% men, and 50% rural. In-home baseline assessment included standardized questionnaires and short physical performance battery. Three annual follow-up interviews were conducted by telephone. Incontinence was defined as any degree of incontinence occurring at least once a month in the past 6 months.
Participants were 490 women and 496 men, age 65 to 106 years (mean=75 years). Prevalence of incontinence at baseline was 41% in women and 27% in men. Three-year incidence of incontinence was 29% (84/290) in women and 24% (86/363) in men. There were no differences by race in prevalent or incident incontinence. In multivariable logistic regression models for women, significant independent baseline predictors of new incontinence included: stroke (OR 3.4, p=.011), incontinence < monthly (OR 3.3, p=.001), past or current post-menopausal estrogen (OR 2.3, p<.006), slower time to stand from a chair 5 times (OR 1.3, p<.045), and higher Geriatric Depression Scale Score (OR 1.2, p=.016). For men, significant independent baseline predictors of new incontinence included: incontinence < monthly (OR 4.2, p<.001) and lower score on the composite Physical Performance Score (OR 1.2, p<.001).
Prevalence of incontinence among community-dwelling older adults was high with an additional 29% of women and 24% of men reporting incident incontinence over 3 years of follow-up. Infrequent incontinence is a strong risk factor for developing at least monthly incontinence in both men and women.
Urinary Incontinence; Epidemiology; Incidence; African Americans