Robert J Glynn

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

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Publications (560)4973.03 Total impact

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    ABSTRACT: Selection and measurement of confounders is critical for successful adjustment in nonrandomized studies. Although the principles behind confounder selection are now well established, variable selection for confounder adjustment remains a difficult problem in practice, particularly in secondary analyses of databases. We present a simulation study that compares the high-dimensional propensity score algorithm for variable selection with approaches that utilize direct adjustment for all potential confounders via regularized regression, including ridge regression and lasso regression. Simulations were based on 2 previously published pharmacoepidemiologic cohorts and used the plasmode simulation framework to create realistic simulated data sets with thousands of potential confounders. Performance of methods was evaluated with respect to bias and mean squared error of the estimated effects of a binary treatment. Simulation scenarios varied the true underlying outcome model, treatment effect, prevalence of exposure and outcome, and presence of unmeasured confounding. Across scenarios, high-dimensional propensity score approaches generally performed better than regularized regression approaches. However, including the variables selected by lasso regression in a regular propensity score model also performed well and may provide a promising alternative variable selection method. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:
    American journal of epidemiology 08/2015; DOI:10.1093/aje/kwv108 · 4.98 Impact Factor
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    ABSTRACT: Oxaliplatin was rapidly adopted for treatment of stage III colon cancer after FDA approval in November 2004, thus providing an opportunity to use calendar time as an instrumental variable in nonexperimental comparative effectiveness research. Assuming instrument validity, instrumental variable analyses account for unmeasured confounding and are particularly valuable in sub-populations of unresolved effectiveness, such as older individuals. We examined stage III colon cancer patients ages 65+ years initiating chemotherapy between 2003 and 2008 using US population-based cancer registry data linked with Medicare claims (N = 3,660). Risk differences for all-cause mortality were derived from Kaplan-Meier survival curves. We examined instrumental variable strength and compared risk differences with propensity score estimates. Calendar time greatly affected oxaliplatin receipt. The calendar time instrument compared patients treated from January 2003 through September 2004 (N = 1,449) with those treated from March 2005 through May 2007 (N = 1,432), resulting in 54% compliance. The 1-, 2-, and 3-year local average treatment effect of the risk differences per 100 patients in the "compliers" (95% confidence intervals) were -4.6 (-8.2, -0.44), -6.3 (-12, -0.16), and -9.2 (-15, -2.5), respectively. Corresponding propensity score-matched results were -1.9 (-4.0, 0.2), -3.4 (-6.2, -0.05), and -4.3 (-7.5, -0.96). Instrumental variable and propensity score analyses both indicate better survival among patients treated with oxaliplatin. As these results are based on different populations and assumptions, the instrumental variable analysis adds to evidence of oxaliplatin's effectiveness in older adults, who bear the greatest burden of colon cancer yet were underrepresented in clinical trials. In nonexperimental comparative effectiveness research of rapidly emerging therapies, the potential to use calendar time as an instrumental variable is worth consideration.
    Epidemiology (Cambridge, Mass.) 07/2015; DOI:10.1097/EDE.0000000000000355 · 6.18 Impact Factor
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    ABSTRACT: Dietary fats have effects on biological pathways that may influence the development and maintenance of atrial fibrillation (AF). However, associations between n-3 (ω-3) polyunsaturated fatty acids and AF are inconsistent, and data on other dietary fats and AF risk are sparse. We examined the association between dietary fatty acid (FA) subclasses and risk of incident AF and whether these associations differed for sustained and paroxysmal AF. We conducted a prospective cohort study in 33,665 women ≥45 y old without cardiovascular disease (CVD) and AF at baseline in 1993. Fat intake was estimated from food frequency questionnaires at baseline and in 2004. Incident AF was confirmed by medical records through October 2013. AF patterns were classified according to the most sustained form of AF within 2 y of diagnosis. Cox proportional hazards models with the use of a competing risk model approach estimated the RR. Over 19.2 y, 1441 cases of incident AF (929 paroxysmal and 467 persistent/chronic) were confirmed. Intake of total fat and FA subclasses was not associated with risk of AF. Saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) were differentially associated with AF patterns. The RR for a 5% increment of energy from SFAs was 1.47 (95% CI: 1.04, 2.09) for persistent/chronic and 0.85 (95% CI: 0.66, 1.08) for paroxysmal AF (P-difference = 0.01). For MUFAs, the RR for a 5% increment was 0.67 (95% CI: 0.46, 0.98) for persistent/chronic and 1.03 (95% CI: 0.78, 1.34) for paroxysmal AF, although the difference between patterns was not significant (P-difference = 0.07). Dietary fat was not associated with risk of incident AF in women without established CVD or AF. High SFA and low MUFA intake was associated with greater risk of persistent or chronic, but not paroxysmal, AF. Improving dietary fat quality may play a role in the prevention of sustained forms of AF. The Women's Health Study was registered at as NCT00000479. © 2015 American Society for Nutrition.
    Journal of Nutrition 07/2015; DOI:10.3945/jn.115.212860 · 4.23 Impact Factor
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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. Identifier: NCT 00239681.
    Circulation 03/2015; 131(21). DOI:10.1161/CIRCULATIONAHA.114.014522 · 14.95 Impact Factor
  • Journal of the American College of Cardiology 03/2015; 65(10):A1362. DOI:10.1016/S0735-1097(15)61362-6 · 15.34 Impact Factor
  • Journal of the American College of Cardiology 03/2015; 65(10):A1358. DOI:10.1016/S0735-1097(15)61358-4 · 15.34 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; 128(6). 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; 137(3). 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; 128(5). 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. Identifier: NCT00239681.
    JAMA Internal Medicine 12/2014; 175(2). 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
  • Cancer Research 10/2014; 74(19 Supplement):3245-3245. DOI:10.1158/1538-7445.AM2014-3245 · 9.28 Impact Factor
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    30th International conference of pharmacoepidemiology, Taipei, Taiwan; 10/2014
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    ABSTRACT: Importance 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.Objective To test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men.Design, Setting, and Participants The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group–coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35 533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11 267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study.Interventions Individual supplements of selenium (200 μg per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-α-tocopheryl acetate).Main Outcomes and Measures Incident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract.Results During a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95 % CI, 0.75-1.11; P = .37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95 % CI, 0.84-1.25; P = .81). Similar results were observed for cataract extraction.Conclusions and Relevance These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract.Trial Registration Identifier: NCT00784225
    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 as NCT00270647.
    American Journal of Clinical Nutrition 07/2014; 100(3). DOI:10.3945/ajcn.114.085480 · 6.92 Impact Factor

Publication Stats

34k Citations
4,973.03 Total Impact Points


  • 1993–2015
    • Brigham and Women's Hospital
      • • Division of Pharmacoepidemiology and Pharmacoeconomics
      • • Division of Preventive Medicine
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1997–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1988–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, 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
    • Rush Medical College
      Chicago, Illinois, United States
  • 1999
    • University of Münster
      • Institute of Epidemiology and Social Medicine
      Muenster, North Rhine-Westphalia, Germany
  • 1988–1997
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1989–1996
    • Massachusetts Eye and Ear Infirmary
      • • Laryngology Division
      • • Epidemiology Unit
      Boston, Massachusetts, United States
  • 1992
    • University of Iowa
      Iowa City, Iowa, United States