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1.  Measurement of Erythrocyte Methotrexate Polyglutamate Levels: Ready for Clinical Use in Rheumatoid Arthritis? 
Current rheumatology reports  2010;12(5):342-347.
Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identification of biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring methotrexate polyglutamates (MTX PGs) levels in circulating red blood cells (RBC) has been proposed as an objective measure that can help to optimize MTX therapy in RA. There is conflicting data with regard to the clinical utility of measurement of MTX PGs measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy and toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in RA.
doi:10.1007/s11926-010-0120-3
PMCID: PMC3769795  PMID: 20665136
Rheumatoid Arthritis; Methotrexate; Polyglutamates
2.  An imputation method for interval censored time-to-event with auxiliary information: analysis of the timing of mother-to-child transmission of HIV 
Summary
The timing of mother-to-child transmission (MTCT) of HIV is critical in understanding the dynamics of MTCT. It has a great implication to developing any effective treatment or prevention strategies for such transmissions. In this paper, we develop an imputation method to analyze the censored MTCT timing in presence of auxiliary information. Specifically, we first propose a statistical model based on the hazard functions of the MTCT timing to reflect three MTCT modes: in utero, during delivery and via breastfeeding, with different shapes of the baseline hazard that vary between infants. This model also allows that the majority of infants may be immuned from the MTCT of HIV. Then, the model is fitted by MCMC to explore marginal inferences via multiple imputation. Moreover, we propose a simple and straightforward approach to take into account the imperfect sensitivity in imputation step, and study appropriate censoring techniques to account for weaning. Our method is assessed by simulations, and applied to a large trial designed to assess the use of antibiotics in preventing MTCT of HIV.
doi:10.2202/1948-4690.1018
PMCID: PMC3419597  PMID: 22905281
HIV/AIDS; mixture models; mother to child transmission of HIV; multiple imputation
3.  Most Common SNPs Associated with Rheumatoid Arthritis in Subjects of European Ancestry Confer Risk of Rheumatoid Arthritis in African-Americans 
Arthritis and Rheumatism  2010;62(12):3547-3553.
Objective
Large-scale genetic association studies have identified over 20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African-Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA in an African-American population.
Methods
27 candidate SNPs were genotyped in 556 autoantibody-positive African-Americans with RA and 791 healthy African-American controls. Odds ratios (OR) and 95% confidence intervals (CI) for each SNP were compared to previously published ORs of RA patients of European ancestry. We then calculated a composite Genetic Risk Score (GRS) for each individual based on the sum of all risk alleles.
Results
There was overlap in the OR and 95% CI between the European and African-American populations in 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, TNFAIP3 rs6920220) demonstrated an OR in the opposite direction from those reported in RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African-American cases were enriched for the European RA risk alleles relative to controls (p=0.00005).
Conclusion
The majority of RA risk alleles previously validated among European ancestry RA patients showed similar ORs in our population of African-Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African-American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel risk alleles for RA in African-Americans.
doi:10.1002/art.27732
PMCID: PMC3030622  PMID: 21120996
4.  Latent TB detection by interferon gamma release assay (IGRA) in pregnancy predicts active TB and mortality in HIV-1 infected women and their children 
The Journal of infectious diseases  2010;202(12):1826-1835.
Background
We evaluated the prognostic utility of interferon-gamma release assays (IGRAs) for active tuberculosis (TB) and mortality in Kenyan HIV-1 infected women and their infants.
Methods
Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1 infected women. Hazard ratios, adjusted for baseline maternal CD4 count (aHRCD4) were calculated for associations between IGRA positivity and risk of active TB and mortality over 2-year postpartum follow-up in women and their infants.
Results
Of 333 women tested, 52 (15.6%) had indeterminate IGRAs. Of the remaining 281 women, 120 (42.7%) had positive IGRAs, which were associated with a 4.5-fold increased risk of active TB [aHRCD4: 4.5; 95% confidence interval (CI): 1.1–18.0; p=0.03]. Among immunosuppresed women (CD4<250 cell/mm3), positive IGRAs were associated with increased risk of maternal mortality (aHRCD4: 3.5; 95% CI: 1.02–12.1; p=0.045), maternal active TB or mortality (aHRCD4: 5.2; 95% CI: 1.7–15.6; p=0.004) and infant active TB or mortality, overall (aHRCD4: 3.0; 95% CI: 1.0–8.9; p= 0.05) and in HIV-1 exposed uninfected infants (aHRCD4: 7.3; 95% CI: 1.6–33.5; p =0.01).
Conclusions
Positive IGRAs in HIV-1 infected pregnant women were associated with postpartum active TB and mortality in mothers and their infants.
doi:10.1086/657411
PMCID: PMC3058232  PMID: 21067370
Latent tuberculosis infection; HIV-1; women; infants; T-SPOT.TB; IGRA
5.  Latent Tuberculosis Detection by Interferon γ Release Assay during Pregnancy Predicts Active Tuberculosis and Mortality in Human Immunodeficiency Virus Type 1-Infected Women and Their Children 
The Journal of Infectious Diseases  2010;202(12):1826-1835.
Background. We evaluated the prognostic usefulness of interferon γ release assays (IGRAs) for active tuberculosis and mortality in Kenyan human immunodeficiency virus type 1 (HIV-1)-infected women and their infants.
Methods. Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1-infected women. Hazard ratios, adjusted for baseline maternal CD4 cell count (aHRCD4), were calculated for associations between IGRA positivity and risk of active tuberculosis and mortality over 2-year postpartum follow-up among women and their infants.
Results. Of 333 women tested, 52 (15.6%) had indeterminate IGRA results. Of the remaining 281 women, 120 (42.7%) had positive IGRA results, which were associated with a 4.5-fold increased risk of active tuberculosis (aHRCD4, 4.5; 95% confidence interval [CI], 1.1–18.0; P = .030). For immunosuppressed women (CD4 cell count, <250 cells/µL), positive IGRA results were associated with increased risk of maternal mortality (aHRCD4, 3.5; 95% CI, 1.02–12.1; ), maternal active tuberculosis or mortality (aHRCD4 P = .045 , 5.2; 95% CI, 1.7–15.6; P = .004), and infant active tuberculosis or mortality overall (aHRCD4, 3.0; 95% CI, 1.0–8.9; P = .05) and among HIV-1-exposed uninfected infants (aHRCD4, 7.3; 95% CI, 1.6–33.5; P = .01).
Conclusions. Positive IGRA results for HIV-1-infected pregnant women were associated with postpartum active tuberculosis and mortality among mothers and their infants.
doi:10.1086/657411
PMCID: PMC3058232  PMID: 21067370
6.  Bayesian estimation of the time-varying sensitivity of a diagnostic test with application to mother-to-child transmission of HIV 
Biometrics  2010;66(4):1266-1274.
Summary
We present a Bayesian model to estimate the time-varying sensitivity of a diagnostic assay when the assay is given repeatedly over time, disease status is changing and the gold standard is only partially observed. The model relies on parametric assumptions for the distribution of the latent time of disease onset and the time-varying sensitivity. Additionally, we illustrate the incorporation of historical data for constructing prior distributions. We apply the new methods to data collected in a study of mother-to-child transmission of HIV and include a covariate for sensitivity to assess whether two different assays have different sensitivity profiles.
doi:10.1111/j.1541-0420.2010.01398.x
PMCID: PMC2940984  PMID: 20222936
Bayesian models; mother-to-child transmission of HIV; Time-varying sensitivity
7.  Determinants of failure to access care in mothers referred to HIV treatment programs in Nairobi, Kenya 
AIDS care  2010;22(6):729-736.
Background
As prevention of mother-to-child transmission of HIV (PMTCT) programs and HIV treatment programs rapidly expand in parallel, it is important to determine factors that influence the transition of HIV-infected women from maternal to continuing care.
Design
This study aimed to determine rates and co-factors of accessing HIV care by HIV-infected women exiting maternal care. A cross-sectional survey of women who had participated in a PMTCT research study and were referred to care programs in Nairobi, Kenya was conducted.
Methods
A median of 17 months following referral, women were located by peer counselors and interviewed to determine whether they accessed HIV care and what influenced their care decisions. Fisher’s exact test was used to assess the association between client characteristics and access to care.
Results
Peer counselors traced 195 (82%) residences, where they located 116 (59%) participants who provided information on care. Since exit, 50% of participants had changed residence, and 74% reported going to the referral HIV program. Reasons for not accessing care included lack of money, confidentiality, and dislike of the facility. Women who did not access care were less likely to have informed their partner of the referral (p=0.001), and were less likely believe that highly active antiretroviral therapy (HAART) is effective (p<0.01). Among those who accessed care, 33% subsequently discontinued care, most because they did not qualify for HAART. Factors cited as barriers to access included stigma, denial, poor services, and lack of money. Factors that were cited as making care attractive included health education, counseling, free services, and compassion.
Conclusion
A substantial number of women exiting maternal care do not transit to HIV care programs. Partner involvement, a standardized referral process and more comprehensive HIV education for mothers diagnosed with HIV during pregnancy may facilitate successful transitions between PMTCT and HIV care programs.
doi:10.1080/09540120903373565
PMCID: PMC3223244  PMID: 20467938
PMTCT; access; HIV
8.  Generalized Bone Loss as a Predictor of 3-Year Radiographic Damage in African American Patients with Recent-Onset Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(8):2219-2226.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/art.27510
PMCID: PMC2922001  PMID: 20506234
9.  The Non-Muscle Myosin Heavy Chain 9 Gene (MYH9) Is Not Associated with Lupus Nephritis in African Americans 
American Journal of Nephrology  2010;32(1):66-72.
Background
African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN.
Methods
Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA.
Results
A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association.
Conclusions
These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA.
doi:10.1159/000314688
PMCID: PMC2914393  PMID: 20523037
African Americans; Genetics; Lupus nephritis; Kidney; MYH9; Systemic lupus erythematosus
10.  Population Attributable Fractions for Late Postnatal Mother-to-Child Transmission of HIV-1 in Sub-Saharan Africa 
Objectives
Assess population attributable fractions (PAFs) for late postnatal transmission (LPT) of human immunodeficiency virus-1 (HIV-1) in a cohort of HIV-1-exposed infants.
Methods
We used data established from a risk factor analysis of LPT (negative HIV-1 results through the 4-6 week visit, but positive assays thereafter through the 12-month visit) from a perinatal clinical trial conducted in three sub-Saharan countries. PAFs were calculated as the proportions of excess LPTs attributed to identified risk factors.
Results
For the cohort of 1317 infants, 206 (15.6%) had only low maternal CD4+ counts (< 200 cells/mm3), 332 (25.2%) had only high maternal plasma viral loads (VLs) (> 50 000 copies/mL), and 81 (6.2%) had both low CD4+ counts and high VLs. Their PAFs were 26.0% [95% confidence interval (CI), 12.0%-36.0%], 37.0% (95% CI, 22.0%-51.0%) and 16.0% (95% CI, 6.0%-25.0%), respectively.
Conclusions
Our PAF analysis illustrates the public health impact of the substantial proportion of LPTs accounted for by high-risk women with both low CD4+ counts and high VLs. In light of these results, access to and use of antiretroviral therapy (ART) by high-risk HIV-1-infected pregnant women is essential. Additional strategies to reduce LPT for those not meeting criteria for ART should be implemented.
doi:10.1097/QAI.0b013e3181d61c2e
PMCID: PMC3086731  PMID: 20224418
Breast feeding; late postnatal transmission; prevention of mother to child transmission/vertical transmission; risk factors; viral load
11.  Polymorphisms in oxidative stress and inflammation pathway genes, low-dose ionizing radiation, and the risk of breast cancer among US radiologic technologists 
Cancer causes & control : CCC  2010;21(11):1857-1866.
Objective
Ionizing radiation, an established breast cancer risk factor, has been shown to induce oxidative damage and chronic inflammation. Polymorphic variation in oxidative stress and inflammatory-mediated pathway genes may modify radiation-related breast cancer risk.
Methods
We estimated breast cancer risk for 28 common variants in 16 candidate genes involved in these pathways among 859 breast cancer cases and 1,083 controls nested within the US Radiologic Technologists cohort. We estimated associations between occupational and personal diagnostic radiation exposures with breast cancer by modeling the odds ratio (OR) as a linear function in logistic regression models and assessed heterogeneity of the dose–response across genotypes.
Results
There was suggestive evidence of an interaction between the rs5277 variant in PTGS2 and radiation-related breast cancer risk. The excess OR (EOR)/Gy from occupational radiation exposure = 5.5 (95%CI 1.2–12.5) for the GG genotype versus EOR/Gy < 0 (95%CI < 0–3.8) and EOR/Gy < 0 (95%CI < 0–14.8) for the GC and CC genotypes, respectively, (pinteraction = 0.04). The association between radiation and breast cancer was not modified by other SNPs examined.
Conclusions
This study suggests that variation in PTGS2 may modify the breast cancer risk from occupational radiation exposure, but replication in other populations is needed to confirm this result.
doi:10.1007/s10552-010-9613-7
PMCID: PMC3076104  PMID: 20711808
PTGS2; COX-2; Inflammation; Breast cancer; Radiation
12.  Epidemiology of Invasive Meningococcal Disease with Decreased Susceptibility to Penicillin in Ontario, Canada, 2000 to 2006▿  
Neisseria meningitidis has been relatively slow to acquire resistance to penicillin. We previously reported an increase in the incidence of invasive meningococcal disease (IMD) strains with decreased susceptibility to penicillin (DSP) in Ontario. Our objectives were to evaluate trends in IMD with DSP, to identify case-level predictors of IMD with DSP, and to evaluate the relationship among DSP, bacterial phenotype, and the likelihood of a fatal outcome. All IMD isolates received in Ontario between 2000 and 2006 were submitted to the Public Health Laboratories, Toronto, for confirmation of the species, serogroup determination, and susceptibility testing. Isolates were considered to be IMD strains with DSP if the penicillin MIC was ≥0.125 μg/ml. Temporal trends were evaluated using multivariable Poisson regression models. Correlates of diminished susceptibility and fatal outcome were evaluated with multivariable logistic regression models. The overall rate of IMD caused by strains with DSP in Ontario was approximately 1.20 cases per million population annually (95% confidence interval [95% CI], 0.99 to 1.46). Seventy-nine strains (21.7%) were IMD strains with DSP. There was no year-to-year trend in the incidence of IMD with DSP. IMD with DSP was strongly associated with strains of serogroups Y (odds ratio [OR], 6.3; 95% CI, 3.6 to 11.1) and W-135 (OR, 8.2; 95% CI, 4.0 to 16.7). Infection with serogroup B or C strains was associated with a marked increase in the risk of mortality (OR, 3.07; 95% CI, 1.39 to 6.75); however, no association between IMD with DSP and mortality was observed. In contrast to trends of the 1990s, the incidence of IMD with DSP was stable in Ontario between 2000 and 2006. In Ontario, the serogroup rather than the penicillin MIC is the microbiological parameter most predictive of mortality.
doi:10.1128/AAC.01077-09
PMCID: PMC2826021  PMID: 20086160
13.  Association of IL4R single-nucleotide polymorphisms with rheumatoid nodules in African Americans with rheumatoid arthritis 
Introduction
To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans.
Methods
Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors.
Results
Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score >0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj = 8.08 (95% confidence interval (CI): 1.60-40.89), P = 0.01 and ORadj = 2.97 (95% CI, 1.08 to 8.17), P = 0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj = 8.45 (95% CI, 1.57 to 45.44), P = 0.01, and ORadj = 3.57 (95% CI, 1.18 to 10.76), P = 0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj = 4.52 (95% CI, 1.20 to 17.03), P = 0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls.
Conclusions
We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.
doi:10.1186/ar2994
PMCID: PMC2911851  PMID: 20444266

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