Robert J Glynn

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (543)4670.63 Total impact

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    ABSTRACT: -Cardiac troponin and B-type natriuretic peptide (BNP) concentrations associate with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood. -We measured high-sensitivity cardiac troponin I (hsTnI) in 12,956 and BNP in 11,076 participants without cardiovascular disease in the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial before randomization to rosuvastatin 20 mg per day or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted Hazard Ratio (aHR) 2.19, 95% CI 1.56-3.06; P-trend<0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR 1.94, 95% CI 1.41-2.68, P-trend<0.001). The risk of all-cause mortality was elevated for the highest vs. the lowest tertiles of hsTnI (aHR 2.61, 95% CI 1.81-3.78; P-trend<0.001) and BNP (aHR 1.45, 95% CI 1.03-2.04; P-trend=0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range 0.50-0.60) and BNP (aHR range 0.42-0.67) with no statistically significant evidence of interaction (P-interaction=0.53 and 0.20, respectively). -In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations. -www.clinicaltrials.gov. Identifier: NCT 00239681.
    Circulation 03/2015; DOI:10.1161/CIRCULATIONAHA.114.014522 · 14.95 Impact Factor
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    ABSTRACT: In nonrandomized studies of comparative effectiveness of medications, the prescriber may be the most important determinant of treatment assignment, yet the majority of analyses ignore the prescriber. Via Monte Carlo simulation, we evaluated the bias of 3 approaches that utilize the prescriber in analysis compared against the default approach that ignores the prescriber. Prescriber preference instrumental variable (IV) analyses were unbiased when IV criteria were met, which required no clustering of unmeasured patient characteristics within prescriber. In all other scenarios, IV analyses were highly biased, and stratification on the prescriber reduced confounding bias at the patient or prescriber levels. Including a prescriber random intercept in the propensity score model reversed the direction of confounding from measured patient factors and resulted in unpredictable changes in bias. Therefore, we recommend caution when using the IV approach, particularly when the instrument is weak. Stratification on the prescriber may be more robust; this approach warrants additional research.
    Epidemiology (Cambridge, Mass.) 03/2015; 26(2):238-41. DOI:10.1097/EDE.0000000000000241 · 6.18 Impact Factor
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    ABSTRACT: Hyperuricemia and gout are associated with an increased risk of cardiovascular disease (CVD). It is unknown whether treating hyperuricemia with xanthine oxidase inhibitors (XOI) including allopurinol and febuxostat modifies cardiovascular risks. We used U.S. insurance claims data to conduct a cohort study among gout patients, comparing XOI initiators to non-users with hyperuricemia defined as serum uric acid level ≥6.8mg/dl. We calculated incidence rates (IR) of a composite fatal and non-fatal cardiovascular outcome that included myocardial infarction, coronary revascularization, stroke, and heart failure. Propensity score (PS)-matched Cox proportional hazards regression compared the risk of composite cardiovascular endpoint in XOI initiators vs. those with untreated hyperuricemia, controlling for baseline confounders. In a subgroup of patients with uric acid levels available, PS-matched Cox regression further adjusted for baseline uric acid levels. There were 24,108 PS-matched pairs with mean age of 51 years and 88% male. The IR per 1,000 person-years for composite CVD was 24.1 (95%CI 22.6-26.0) in XOI initiators and 21.4 (95%CI 19.8-23.2) in the untreated hyperuricemia group. The PS-matched HR for composite CVD was 1.16 (95%CI 0.99-1.34) in XOI initiators versus those with untreated hyperuricemia. In subgroup analyses, the PS-matched HR for composite CVD adjusted for serum uric acid levels was 1.10 (95%CI 0.74-1.64) among XOI initiators. Among patients with gout, initiation of XOI was not associated with an increased or decreased cardiovascular risk compared to those with untreated hyperuricemia. Subgroup analyses adjusting for baseline uric acid levels also showed no association between XOI and cardiovascular risk. Copyright © 2015 Elsevier Inc. All rights reserved.
    The American Journal of Medicine 02/2015; DOI:10.1016/j.amjmed.2015.01.013 · 5.30 Impact Factor
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    ABSTRACT: PurposeThis study aims to explore the influence of gestational age at enrollment, and enrollment before or after prenatal screening, on the estimation of drug effects in pregnancy exposure registries.Methods We assessed the associations between first trimester antiepileptic drug (AED) exposure and risk of spontaneous abortion and major congenital malformations in the North American AED Registry (1996–2013). We performed logistic regression analyses, conditional or unconditional on gestational age at enrollment, to estimate relative risk (RR) for first trimester AED users compared with non-users. We also compared first trimester users of valproic acid and lamotrigine. Analyses were repeated in women who enrolled before prenatal screening.ResultsEnrollment occurred earlier among 7029 AED users than among 581 non-users; it was similar among AEDs. Comparing AED users with non-users, RR (95% confidence interval) of spontaneous abortion (n = 359) decreased from 5.1 (2.3–14.1) to 2.0 (0.9–5.6) after conditioning on gestational week at enrollment and to 1.9 (0.8–5.4) upon further restriction to before-screening enrollees. RR of congenital malformations (n = 216) changed from 3.1 (1.4–8.5) to 3.2 (1.4–9.0) after conditioning on gestational week at enrollment and to 2.0 (0.7–10.1) upon further restriction to before-screening enrollees. When comparing valproic acid users and lamotrigine users, the RR of congenital malformations was not substantially changed by conditioning or restricting.Conclusions Spontaneous abortion rates were sensitive to gestational age at enrollment. Estimates of congenital malformation risks for AED users relative to non-users were sensitive to before/after-screening enrollment. This difference was not apparent between active drugs, likely due to similar gestational age at enrollment. Copyright © 2015 John Wiley & Sons, Ltd.
    Pharmacoepidemiology and Drug Safety 02/2015; 24(4). DOI:10.1002/pds.3731 · 3.17 Impact Factor
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    ABSTRACT: Although adult obesity is known to increase endometrial cancer risk, evidence for childhood obesity is limited. We prospectively examined the association between body fatness throughout life and endometrial cancer risk. 47,289 members of the Nurses' Health Study (NHS) and 105,386 of the Nurses' Health Study II (NHS II) recalled their body fatness at ages 5, 10, and 20 using a pictogram. Childhood and adolescent body fatness were derived as the average at ages 5 and 10, and ages 10 and 20, respectively. We obtained adult weight from concurrent questionnaires. We calculated hazard ratios (HR) of endometrial cancer using Cox proportional hazards models. During follow-up, 757 incident cases of endometrial cancer were diagnosed. Body fatness in childhood, at age 10, in adolescence, and at age 20 were positively associated with endometrial cancer risk (HR for ≥ Level 5 versus ≤ Level 2 in adolescence: 1.83 (95% CI 1.41-2.37). After adjusting for most recent BMI, none of the associations persisted. Weight change since age 18 was positively associated with endometrial cancer risk [HR for ≥ 25 kg gain versus stable: 2.54 (95% CI 1.80-3.59). Adult BMI was strongly associated with endometrial cancer risk [HR BMI ≥ 35 kg/m2 versus BMI ≤ 25 kg/m2: 4.13 (95% CI 3.29-5.16)]. In postmenopausal women, the association with BMI was significantly stronger among non-users of hormone therapy. In conclusion, obesity throughout life is positively associated with endometrial cancer risk, with adult obesity one of the strongest risk factors. Maintaining a healthy weight throughout life remains important. This article is protected by copyright. All rights reserved.
    International Journal of Cancer 01/2015; DOI:10.1002/ijc.29427 · 5.01 Impact Factor
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    ABSTRACT: Recent research suggests that rheumatoid arthritis (RA) increases the risk of venous thromboembolism (VTE). This study compared the risk of VTE in newly diagnosed RA patients initiating a biologic disease-modifying anti-rheumatic drug (DMARD) with those initiating methotrexate or nonbiologic DMARDs (nbDMARDs). We conducted a population-based cohort study using U.S. insurance claims data (2001-2012).Three mutually exclusive, hierarchical DMARD groups were used: (1) a biologic DMARD with and without nbDMARDs, (2) methotrexate without a biologic DMARD, or (3) nbDMARDs without a biologic DMARD or methotrexate. We calculated incidence rates (IR) of VTE. Cox proportional hazards models stratified by propensity score (PS) deciles after asymmetric PS trimming were used for 3 pairwise comparisons, controlling for potential confounders at baseline. We identified 29,481 RA patients with 39,647 treatment episodes. From the pairwise comparison after asymmetric PS trimming, the IR of hospitalization for VTE per 1,000 person-years was 5.5 in bDMARD versus 4.4 in nbDMARD, and 4.8 in bDMARD versus 3.5 in methotrexate initiators. The PS decile-stratified hazard ratio (HR) of VTE associated with bDMARD was 1.83 (95%CI 0.91-3.66) versus nbDMARDs and 1.39 (95%CI 0.73-2.63) versus methotrexate. The HR of VTE in bDMARD initiators was the highest in the first 180 days versus nbDMARD (2.48, 95%CI 1.14-5.39) or methotrexate (1.80, 95%CI 0.90-3.62). The absolute risk for VTE was low in patients with newly diagnosed RA. Initiation of a bDMARD appears to be associated with an increased short-term risk of hospitalization for VTE compared to those initiating nbDMARDs or methotrexate. Copyright © 2014 Elsevier Inc. All rights reserved.
    The American Journal of Medicine 12/2014; DOI:10.1016/j.amjmed.2014.11.025 · 5.30 Impact Factor
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    ABSTRACT: Osteoporosis and cardiovascular disease may share common biological pathways, with inflammation playing a role in the development of both. Although observational studies have suggested that statin use is associated with a lower risk of fractures, randomized trial data addressing this issue are scant. To determine whether statin therapy reduces the risk of fracture and, in a secondary analysis, whether baseline levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of fracture. The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was an international, randomized, double-blind, placebo-controlled study enrolling 17 802 men older than 50 years and women older than 60 years with hs-CRP level of at least 2 mg/L. Participants were screened from 2003 to 2006 and observed prospectively for up to 5 years (median follow-up, 1.9 years). Rosuvastatin calcium, 20 mg daily, or placebo. Incident fracture was a prespecified secondary end point of JUPITER. Fractures were confirmed by radiographs, computed tomography, bone scan, or other methods. Cox proportional hazards models were used to calculate hazard ratios (HRs) and associated 95% confidence intervals for the risk of fracture according to randomized treatment assignment, as well as increasing tertiles of hs-CRP, controlling for potential confounders. During the study, 431 incident fractures were reported and confirmed. Among participants allocated to rosuvastatin, 221 fractures were confirmed, compared with 210 among those allocated to placebo, such that the incidence of fracture in the rosuvastatin and placebo groups was 1.20 and 1.14 per 100 person-years, respectively (adjusted HR, 1.06 [95% CI, 0.88-1.28]; P = .53). Overall, increasing baseline hs-CRP level was not associated with an increased risk of fractures (adjusted HR for each unit increase in hs-CRP tertile, 1.06 [95% CI, 0.94-1.20]; P for trend, .34). Among men and women with elevated hs-CRP level enrolled in a large trial of rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture. Higher baseline hs-CRP level was not associated with an increased risk of incident fracture. clinicaltrials.gov Identifier: NCT00239681.
    JAMA Internal Medicine 12/2014; DOI:10.1001/jamainternmed.2014.6388 · 13.25 Impact Factor
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    ABSTRACT: Background:Data from previous studies consistently suggest that maternal smoking is positively associated with the risk of obesity later in life. Whether this association persists across generations is unknown. Methods:We investigated the association between grandparent smoking status and grandchild overweight status among 3101 grandmother-mother-child triads in the Nurses’ Health Study II (NHS II), the NHS Mothers’ Cohort Study, and the children of NHS II participants who are in the Growing up Today Study (GUTS). Grandmothers of children provided information on their and their partner’s smoking during pregnancy with the child’s mother. Information on child's weight and height at ages 12 and 17 was obtained by self-report from the GUTS questionnaires. We used logistic regression to estimate odds ratios (ORs) of being overweight or obese, relative to normal weight. Results: Seventy-five percent of grandmothers reportedly did not smoke during pregnancy, while 4% quit during pregnancy, 13% continued smoking up to 14 cigarettes/day, and 7% smoked 15+ cigarettes daily throughout pregnancy. Grand-maternal smoking was not associated with being overweight or obese at age 12 or 17 years, in boys or in girls. After adjusting for multiple covariates, the OR of being overweight or obese relative to normal weight at age 12 years in girls whose grandmothers smoked 15+ cigarettes per day during pregnancy with their mothers was 1.23 (95% CI 0.75-2.01; ptrend = 0.25) and 1.08 (0.65-1.97; ptrend = 0.34) in boys. Grand-paternal smoking was positively associated with being overweight or obese at age 12 years in girls but not boys, and not at age 17 years for either: the OR for being overweight or obese at age 12 years was 1.46 (95% CI 1.07-1.99; ptrend = 0.01) in girls, and 1.26 (95% CI 0.94-1.70; ptrend = 0.11) in boys. After restricting to children of non-smoking mothers, the comparable OR for granddaughter obesity was attenuated and no longer significant [OR 1.35 (95% CI 0.93-1.97; ptrend= 0.10)]. Conclusions: Our findings suggest that grand-maternal smoking is not associated with adolescent overweight status in the grandchild. However, grand-paternal smoking may affect overweight status of the granddaughter, likely through the association between grand-paternal smoking and maternal smoking.
    142nd APHA Annual Meeting and Exposition 2014; 11/2014
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    ABSTRACT: Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk of CVD including myocardial infarction (MI), stroke, coronary revascularization, and HF associated with DPP4i in T2DM patients with and without baseline CVD as used in the community.
    Acta Diabetologica 10/2014; DOI:10.1007/s00592-014-0663-2 · 3.68 Impact Factor
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    ABSTRACT: Observational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium.
    Jama Ophthalmology 09/2014; 133(1). DOI:10.1001/jamaophthalmol.2014.3478 · 3.83 Impact Factor
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    ABSTRACT: Recent US guidelines expand the indications for high-intensity statin therapy, yet data on the safety of attaining very low-density lipoprotein cholesterol (LDL-C) levels are scarce. Among 16,304 participants in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) with on-treatment LDL-C levels, we identified 767 who did and 7,387 who did not achieve LDL-C <30 mg/dl on rosuvastatin 20 mg daily and 718 participants who did and 7,436 who did not achieve LDL-C reductions of ≥70% on rosuvastatin, and 8,150 allocated to placebo. In participants with an LDL-C <30 mg/dl, we observed an increase in the risk of physician-reported type 2 diabetes with an adjusted hazard ratio (95% confidence interval) of 1.56 (1.09 to 2.23, p = 0.01) and physician-reported hematuria (hazard ratio 2.10 [1.39 to 3.19], p <0.001) compared with rosuvastatin-treated participants with LDL-C ≥30 mg/dl. There was also an increased risk of certain musculoskeletal, hepatobiliary, and psychiatric disorders. No difference in renal failure, cancer, memory impairment, or hemorrhagic stroke was observed, although there were few events in these categories. In rosuvastatin-treated participants, achieving LDL-C reduction ≥70% versus <70% did not appear to be associated with increased risk of hepatobiliary, renal, or urinary disorders. In conclusion, in this post hoc analysis in the JUPITER, achieving LDL-C levels <30 mg/dl with high-intensity statin therapy appeared to be generally well tolerated but associated with certain adverse events, including more physician-reported diabetes, hematuria, hepatobiliary disorders, and insomnia. These data may guide the monitoring of patients on intensive statin therapy and adverse events in trials of therapies that lead to very low LDL-C levels. Copyright © 2014 Elsevier Inc. All rights reserved.
    The American Journal of Cardiology 09/2014; 114(11). DOI:10.1016/j.amjcard.2014.08.041 · 3.43 Impact Factor
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    ABSTRACT: The prognostic score, or disease risk score (DRS), is a summary score that is used to control for confounding in non-experimental studies. While the DRS has been shown to effectively control for measured confounders, unmeasured confounding continues to be a fundamental obstacle in non-experimental research. Both theory and simulations have shown that in the presence of unmeasured confounding, controlling for variables that affect treatment (both instrumental variables and measured confounders) amplifies the bias caused by unmeasured confounders. In this paper, we use causal diagrams and path analysis to review and illustrate the process of bias amplification. We show that traditional estimation strategies for the DRS do not avoid bias amplification when controlling for predictors of treatment. We then discuss estimation strategies for the DRS that can potentially reduce bias amplification that is caused by controlling both instrumental variables and measured confounders. We show that under certain assumptions, estimating the DRS in populations outside the defined study cohort where treatment has not been introduced, or in outside populations with reduced treatment prevalence can control for the confounding effects of measured confounders while at the same time reduce bias amplification.
    09/2014; 2(2):131-146. DOI:10.1515/jci-2014-0009
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    ABSTRACT: Recent posttrial analysis of a completed randomized trial found an increased risk of prostate cancer among healthy men taking high-dose vitamin E supplements. Trials that examined the effect of vitamin C supplements on cancer risk are few.OBJECTIVE: We examined whether vitamin E or vitamin C supplementation affects the risk of cancer events during posttrial follow-up of the Physicians' Health Study II.DESIGN: Beginning in 1997, a total of 14,641 US male physicians aged ≥50 y were randomly assigned to receive 400 IU of vitamin E every other day, 500 mg of vitamin C daily, or their respective placebos. The vitamin E and vitamin C treatment ended in 2007, and observational follow-up continued through June 2011.RESULTS: This study included an additional 356 cases of incident prostate cancer and 771 total cancers that developed during a mean (maximum) of 2.8 (3.8) y of posttrial observation. During an overall mean of 10.3 (13.8) y, there were a total of 1373 incident prostate cancers and 2669 total cancers documented. In comparison with placebo, vitamin E supplementation had no effect on the incidence of prostate cancer (HR: 0.99; 95% CI: 0.89, 1.10) or total cancers (HR: 1.02; 95% CI: 0.95, 1.10). There was also no effect of vitamin C supplementation on total cancers (HR: 1.02; 95% CI: 0.94, 1.10) or incident prostate cancer (HR: 1.03; 95% CI: 0.93, 1.15). Neither vitamin E nor vitamin C supplementation had effects on other site-specific cancers overall. Stratification by known cancer risk factors, history of cancer, other randomized treatment, and follow-up time showed no significant interactions.Conclusion: In this large-scale randomized trial in men, vitamin E and C supplementation had no immediate or long-term effects on the risk of total cancers, prostate cancer, or other site-specific cancers. This trial was registered at clinicaltrials.gov as NCT00270647.
    American Journal of Clinical Nutrition 07/2014; 100(3). DOI:10.3945/ajcn.114.085480 · 6.92 Impact Factor
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    ABSTRACT: Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein that has a costimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis and inflammatory bowel disease, associated with DPP4i in patients with T2DM.
    Annals of the Rheumatic Diseases 06/2014; DOI:10.1136/annrheumdis-2014-205216 · 9.27 Impact Factor
  • Samia Mora, Robert J Glynn, Paul M Ridker
    Circulation 04/2014; 129(17):e481. DOI:10.1161/CIRCULATIONAHA.114.009345 · 14.95 Impact Factor
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    ABSTRACT: Once atrial fibrillation (AF) progresses to sustained forms, adverse outcomes increase and treatment success rates decrease. Therefore, identification of risk factors predisposing to persistence of AF may have a significant impact on AF morbidity. We prospectively examined the differential associations between traditional, lifestyle, and biomarker AF risk factors and development of paroxysmal versus nonparoxysmal AF (persistent/permanent) among 34 720 women enrolled in the Women's Health Study who were free of cardiovascular disease and AF at baseline. AF patterns were defined based on current guidelines and classified according to the most sustained form of AF within 2 years of diagnosis. During a median follow-up of 16.4 years, 690 women developed paroxysmal AF and 349 women developed nonparoxysmal AF. In multivariable time-varying competing risk models, increasing age (hazard ratio [HR] 1.11, 95% CI 1.10 to 1.13, versus HR 1.08, 1.07 to 1.09, per year), body mass index (HR 1.07, 1.05 to 1.09, versus HR 1.03, 1.02 to 1.05, per kg/m(2)), and weight (HR 1.30, 1.22 to 1.39, versus HR 1.14, 1.08 to 1.20, per 10 kg) were more strongly associated with the development of nonparoxysmal AF compared with paroxysmal AF. Hemoglobin A1c levels at baseline were directly related to the development of nonparoxysmal AF but inversely associated with paroxysmal AF in multivariable competing risk models (P for nonequal association=0.01). In women without AF or CVD at baseline, increasing age, adiposity, and higher hemoglobin A1c levels were preferentially associated with the early development of nonparoxysmal AF. These data raise the hypothesis that efforts aimed at weight reduction or glycemic control may affect the proportion of the population with sustained AF.
    Journal of the American Heart Association 04/2014; 3(3):e000916. DOI:10.1161/JAHA.114.000916 · 2.88 Impact Factor
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    ABSTRACT: Previous studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). To assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer and cervical cancer, in women with SID, including IBD, psoriasis, rheumatoid arthritis (RA) or SLE, compared with the risk in women without SID. Using US insurance data (2001-2012), we conducted a cohort study of 133 333 women with SID, based on two or more diagnoses and one or more dispensed prescription for disease-specific treatment, and 533 332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%. Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100 000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in women without SID. The multivariable HR adjusted for potential confounders was 1.07 (95% CI 0.79 to 1.45) in IBD, 0.96 (95% CI 0.73 to 1.27) in psoriasis, 1.49 (95% CI 1.11 to 2.00) in RA and 1.53 (95% CI 1.07 to 2.19) in SLE. Multivariable HRs were increased, but not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids. The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID. The risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids.
    Annals of the rheumatic diseases 03/2014; DOI:10.1136/annrheumdis-2013-204993 · 9.27 Impact Factor
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    ABSTRACT: Women are advised to be vaccinated for influenza during pregnancy and may receive vaccine at any time during their pregnancy. In observational studies evaluating vaccine safety in pregnancy, to account for such time-varying vaccine exposure, a time-dependent predictor can be used in a proportional hazards model setting for outcomes such as spontaneous abortion or preterm delivery. Also, due to the observational nature of pregnancy exposure cohort studies and relatively low event rates, propensity score (PS) methods are often used to adjust for potential confounders. Using Monte Carlo simulation experiments, we compare two different ways to model the PS for vaccine exposure: (1) logistic regression treating the exposure status as binary yes or no; (2) Cox regression treating time to exposure as time-to-event. Coverage probability of the nominal 95% confidence interval for the exposure effect is used as the main measure of performance. The performance of the logistic regression PS depends largely on how the exposure data is generated. In contrast, the Cox regression PS consistently performs well across the different data generating mechanisms that we have considered. In addition, the Cox regression PS allows adjusting for potential time-varying confounders such as season of the year or exposure to additional vaccines. The application of the Cox regression PS is illustrated using data from a recent study of the safety of pandemic H1N1 influenza vaccine during pregnancy.
    International Journal of Environmental Research and Public Health 03/2014; 11(3):3074-85. DOI:10.3390/ijerph110303074 · 1.99 Impact Factor
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    ABSTRACT: Propensity scores are useful for confounding adjustment in the commonly observed setting of many potential confounders, frequent exposure, and rare events. However, with few exposed outcomes to inform covariate selection and many candidate confounders, optimal approaches to construct and implement propensity-score-based confounding adjustment remain unclear. In a cohort study on the effect of anticonvulsant drugs on cardiovascular risk among adult patients from the HealthCore Integrated Research Database, we compared the performance for confounding control of various covariate-selection strategies for propensity-score estimation (expert knowledge only, expert knowledge informed by empirical covariate selection via high-dimensional propensity-score, and high-dimensional propensity-score empirical specification only) and propensity-score-based adjustment methods (propensity-score-matching and propensity-score-decile stratification). This article focuses on the first 90 days of follow-up because any treatment effect identified in this temporal window almost certainty originates from residual confounding rather than pharmacologic action. We identified 166,031 new users and 564 ischemic cardiovascular events. Among those, 12,580 patients initiated anticonvulsants that strongly induce cytochrome P450 enzymes and experienced 68 events. The unadjusted hazard ratio was 1.72 (95% confidence interval = 1.34-2.22). Adjustment for investigator-identified covariates led to 41% to 59% reductions in the hazard ratio; adjustment for both investigator-identified and high-dimensional propensity-score empirically identified covariates led to larger reductions (54% to 72%). A selection strategy based on high-dimensional propensity-score empirical specification alone produced less-attenuated and more-volatile hazard ratio estimates. This volatility seemed to be slightly attenuated in a trimmed propensity-score-stratified analysis. The high-dimensional propensity-score algorithm complements expert knowledge for confounding adjustment, but in settings with few exposed outcomes, its performance without investigator-specified covariates is less clear and may be associated with an increased likelihood of bias. In our example, investigator specification of variables combined with high-dimensional propensity-score empirical selection and the use of trimmed propensity-score-stratified analysis seem to improve effect estimation. Plotting the relation of effect estimates to the increasing number of empirical covariates is a useful diagnostic.
    Epidemiology (Cambridge, Mass.) 03/2014; 25(2):268-78. DOI:10.1097/EDE.0000000000000069 · 6.18 Impact Factor
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    ABSTRACT: Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co-morbidities and co-medications. Propensity scores (PSs), an alternative to multivariable outcome models to control for measured confounding, have specific advantages in the presence of heterogeneous treatment effects. Implementing PSs using matching or weighting allows us to estimate different overall treatment effects in differently defined populations. Heterogeneous treatment effects can also be due to unmeasured confounding concentrated in those treated contrary to prediction. Sensitivity analyses based on PSs can help to assess such unmeasured confounding. PSs should be considered a primary or secondary analytic strategy in nonexperimental medical research, including pharmacoepidemiology and nonexperimental comparative effectiveness research.
    Journal of Internal Medicine 02/2014; 275(6). DOI:10.1111/joim.12197 · 5.79 Impact Factor

Publication Stats

30k Citations
4,670.63 Total Impact Points

Institutions

  • 1992–2015
    • Brigham and Women's Hospital
      • • Division of Pharmacoepidemiology and Pharmacoeconomics
      • • Division of Preventive Medicine
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1988–2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Otology and Laryngology
      Boston, Massachusetts, United States
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1986–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2009–2012
    • The University of Manchester
      • School of Translational Medicine
      Manchester, ENG, United Kingdom
  • 2011
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 2010
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1987–2010
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2006–2009
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 2008
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2007
    • Schepens Eye Research Institute
      Boston, Massachusetts, United States
  • 2005–2007
    • Florida Atlantic University
      • Department of Biomedical Science
      Boca Raton, Florida, United States
    • McLean Hospital
      • Biological Psychiatry Laboratory
      Cambridge, Massachusetts, United States
  • 2003
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
    • Bristol-Myers Squibb
      New York, New York, United States
  • 2001
    • Duke University
      Durham, North Carolina, United States
  • 2000
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Rush Medical College
      Chicago, Illinois, United States
  • 1999
    • University of Münster
      • Institute of Epidemiology and Social Medicine
      Muenster, North Rhine-Westphalia, Germany
    • University of Massachusetts Medical School
      • Meyers Primary Care Institute
      Worcester, MA, United States
  • 1991–1996
    • Massachusetts Eye and Ear Infirmary
      • • Laryngology Division
      • • Epidemiology Unit
      Boston, Massachusetts, United States