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1.  Polymorphisms of an Innate Immune Gene, Toll-Like Receptor 4, and Aggressive Prostate Cancer Risk: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(10):e110569.
Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews.
We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls.
Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity.
TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.
PMCID: PMC4215920  PMID: 25360682
2.  Waist-to-Height Ratio as a Predictor of Coronary Heart Disease among Women 
Epidemiology (Cambridge, Mass.)  2009;20(3):361-366.
The aim of our study is to prospectively evaluate and compare the waist circumference-to-height ratio (WHtR) to waist-hip ratio, waist circumference, and body mass index as predictors of subsequent coronary heart disease (CHD) in a group of predominantly post-menopausal women.
The data comes from a prospective cohort study. The included subjects were 45563 women from the Nurses' Health Study cohort, aged 40-65 years in 1986, who were free of heart disease, stroke and cancer. Waist circumference, hip circumference, height, weight, age, and other covariates were collected by questionnaire. The primary endpoint was incident coronary heart disease that was reported by June 2002. Areas under the receiver operating characteristic curves (AUC) were estimated non-parametrically for each of anthropometric measures, and differences between that for WHtR and the other measures, and corresponding 95% confidence intervals were estimated. Cox proportional hazard models were used to estimate the relationships with risk of CHD.
Waist-height ratio, waist-hip ratio and waist circumference were similar in predicting subsequent risk of CHD. All three waist derived measures were superior to BMI in predicting CHD. The unadjusted AUC (95% Confidence Interval) were 0.62 (0.60,0.64) for WHtR, 0.63 (0.61,0.65) for waist-hip ratio, 0.62 (0.60,0.64) for waist-circumference, and 0.57 (0.55,0.59) for body mass index.
Waist-height ratio is comparable to waist circumference and waist-hip ratio for prediction of coronary heart disease incidence among middle-aged and older women, but superior to BMI. Future studies are warranted to corroborate these results in other populations.
PMCID: PMC4012298  PMID: 19289960
3.  Plasma Insulinlike Growth Factor 1 and Binding-Protein 3 and Risk of Myocardial Infarction in Women: A Prospective Study 
Clinical chemistry  2008;54(10):1682-1688.
The aim of this study was to prospectively evaluate relationships between plasma concentrations of insulinlike growth factor 1 (IGF1) and insulinlike growth factor binding protein 3 (IGFBP3) and subsequent myocardial infarction (MI) in women.
We used case-control sampling to select study participants from women who had already been selected for inclusion in the prospective Nurses’ Health Study cohort. Blood samples were collected from 32 826 women in 1989–1990. During the follow-up period from sample collection through June 1998, MI (fatal and nonfatal) was diagnosed in 245 women. Cases were matched to controls 1:2 by age, cigarette-smoking status, and month and fasting status at the time of blood collection. Conditional logistic regression was used to adjust for potential confounders (menopausal status, parental history of MI, postmenopausal hormone use, diabetes mellitus, hypertension, hypercholesterolemia, aspirin use, alcohol use, body mass index, and physical activity).
Multivariable adjusted analyses did not reveal a statistically significant linear relationship between IGF1 or IGFBP3 concentrations or their molar ratio and risk of MI. Women in the highest IGF1 quartile had a multivariable-adjusted rate ratio of 1.46 (95% CI 0.79, 2.72; P for trend = 0.46) for MI, compared with those in the lowest. The corresponding rate ratios (95% CI) for IGFBP3 and the IGF1:IGFBP3 mol/L ratio were 1.24 (0.71, 2.17) and 1.29 (0.70, 2.37), respectively.
We did not observe a monotonic relationship between IGF1 or IGFBP3 and MI among predominantly postmenopausal women. Future studies are warranted to evaluate these relationships in other demographic groups including younger women.
PMCID: PMC3964447  PMID: 18703768
4.  Structural Nested Cumulative Failure Time Models to Estimate the Effects of Interventions 
Journal of the American Statistical Association  2012;107(499):10.1080/01621459.2012.682532.
In the presence of time-varying confounders affected by prior treatment, standard statistical methods for failure time analysis may be biased. Methods that correctly adjust for this type of covariate include the parametric g-formula, inverse probability weighted estimation of marginal structural Cox proportional hazards models, and g-estimation of structural nested accelerated failure time models. In this article, we propose a novel method to estimate the causal effect of a time-dependent treatment on failure in the presence of informative right-censoring and time-dependent confounders that may be affected by past treatment: g-estimation of structural nested cumulative failure time models (SNCFTMs). An SNCFTM considers the conditional effect of a final treatment at time m on the outcome at each later time k by modeling the ratio of two counterfactual cumulative risks at time k under treatment regimes that differ only at time m. Inverse probability weights are used to adjust for informative censoring. We also present a procedure that, under certain “no-interaction” conditions, uses the g-estimates of the model parameters to calculate unconditional cumulative risks under nondynamic (static) treatment regimes. The procedure is illustrated with an example using data from a longitudinal cohort study, in which the “treatments” are healthy behaviors and the outcome is coronary heart disease.
PMCID: PMC3860902  PMID: 24347749
Causal inference; Coronary heart disease; Epidemiology; G-estimation; Inverse probability weighting
5.  Plasma total Cysteine and total Homocysteine and Risk of Myocardial Infarction in Women: A prospective study 
American heart journal  2010;159(4):599-604.
Cysteine is a glutathione precursor, but is also a homocysteine byproduct. We prospectively evaluated relationships between fasting plasma concentrations of total cysteine and total homocysteine, and subsequent myocardial infarction (MI) in women.
Among 32826 women who provided blood samples between 1989 and 1990, 239 were diagnosed with incident MI after blood collection, but before July 1998. Of these women, 144 had provided a post-fast sample. We matched controls to cases 2:1 by age, cigarette smoking status, and month and fasting status at the time of blood collection. We used conditional logistic regression to adjust for confounding.
Fasting total cysteine was positively related to MI risk in matching factor-adjusted analyses [RR for highest vs. lowest quartile 3.50 (95% CI 1.44, 8.52)]. However, after controlling for conventional risk factors of MI, it was not independently associated with risk [RR for highest vs. lowest quartile 1.32 (95% CI 0.42, 4.12; P trend=0.10)]. Fasting homocysteine was positively associated with MI risk; the multivariable adjusted rate ratio (RR) for the highest versus the lowest quartile was 3.37 (95% CI 1.30, 8.70; P trend=0.014).
Fasting plasma concentration of total homocysteine, but not total cysteine was positively associated with MI risk.
PMCID: PMC3046067  PMID: 20362718
6.  Plasma Vitamin B6 and Risk of Myocardial Infarction in Women 
Circulation  2009;120(8):649-655.
Vitamin B6 is widely involved in amino acid metabolism and is a modulator of several reactions important to cardiovascular health. We prospectively evaluated relationships between fasting plasma levels of vitamin B6, as pyridoxal phosphate (PLP), to subsequent myocardial infarction risk in women. We also evaluated the predictors of fasting plasma concentration of pyridoxal phosphate.
Participants were adult nurses who completed questionnaires, and updated exposures every 2 years since 1976. Subjects for this analysis were selected by a nested case control design. Blood samples were collected between 1989 and 1990. We restricted our analysis to those women who had provided fasting blood samples (≥10 hours since last meal). During follow-up through June 1998, 144 were diagnosed with myocardial infarction (fatal and non-fatal). Cases were matched 1:2 by age, cigarette smoking status, and month and fasting status at the time of blood collection. Conditional logistic regression was used to adjust for potential confounders, including anthropometric factors, dietary intake, and selected biomarkers. Linear regression was used to determine which variables predict fasting total PLP concentration among control women.
Median age at blood collection was 63. Among controls, lower estimated creatinine clearance, plasma total homocysteine and body mass index were statistically significant predictors of higher plasma PLP, as were higher dietary vitamin B6, and folate intake (all P <0.05). Plasma levels of pyridoxal phosphate were inversely associated with risk of MI, the multivariable adjusted rate ratio (RR) between extreme quarters was 0.22 (95% CI 0.09,0.55; Ptrend=0.05). The effect of plasma PLP varied by age. Among women who were aged less than 60 at blood sampling, the RR (95%CI) comparing top vs. bottom quarter was 0.03 (0.002,0.48), whereas among older women the corresponding RR (95%CI) was 0.43 (0.15,1.25).
Fasting plasma concentration of pyridoxal phosphate was inversely associated with MI risk. Plasma PLP is positively correlated with dietary vitamin B6, and is inversely correlated with renal function and body mass index. Future studies are needed to better understand both dietary and non-dietary determinants of plasma and tissue vitamin B6 status, and how these can be optimized to prevent MI and other diseases.
PMCID: PMC2833014  PMID: 19667235
vitamins; nutrition; women; myocardial infarction; risk factors
7.  Estimation of the disease-specific diagnostic marker distribution under verification bias 
We consider the estimation of the parameters indexing a parametric model for the conditional distribution of a diagnostic marker given covariates and disease status. Such models are useful for the evaluation of whether and to what extent a marker’s ability to accurately detect or discard disease depends on patient characteristics. A frequent problem that complicates the estimation of the model parameters is that estimation must be conducted from observational studies. Often, in such studies not all patients undergo the gold standard assessment of disease. Furthermore, the decision as to whether a patient undergoes verification is not controlled by study design. In such scenarios, maximum likelihood estimators based on subjects with observed disease status are generally biased. In this paper, we propose estimators for the model parameters that adjust for selection to verification that may depend on measured patient characteristics and additonally adjust for an assumed degree of residual association. Such estimators may be used as part of a sensitivity analysis for plausible degrees of residual association. We describe a doubly robust estimator that has the attractive feature of being consistent if either a model for the probability of selection to verification or a model for the probability of disease among the verified subjects (but not necessarily both) is correct.
PMCID: PMC3475507  PMID: 23087495
Missing at Random; Nonignorable; Missing Covariate; Sensitivity Analysis; Semiparametric; Diagnosis
8.  Plasma Dehydroepiandrosterone and Risk of Myocardial Infarction in Women 
Clinical Chemistry  2008;54(7):1190-1196.
In this study we prospectively evaluated the relationships between plasma concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) and subsequent myocardial infarction in women.
Using case-control sampling, we selected participants from the Nurses’ Health Study cohort. Blood samples were collected from 1989 to 1990 when the women were 43 to 69 years old. During follow-up through June 1998, 239 women were diagnosed with myocardial infarction (fatal and nonfatal). We matched cases 1:2 by age, cigarette smoking status, fasting status, and month of blood collection and used conditional logistic regression to adjust for potential confounders, including anthropometric factors and dietary intake.
Baseline median (10th, 90th percentiles) concentrations of DHEA were 17.1 (4.3, 46.7) nmol/L among women who subsequently developed myocardial infarction and 16.6 (6.1, 37.9) among controls. The risk of myocardial infarction increased with plasma concentrations of DHEA and its sulfate. Women in the highest DHEA quartile had a rate ratio (RR) of 1.27 (95% CI 0.92–1.74, P for trend = 0.008) for myocardial infarction compared with those in the lowest quartile, after adjusting for covariates. The results did not vary significantly by menopausal status, postmenopausal estrogen therapy, fasting status, or age at time of blood collection. Similar relationships between concentrations of DHEA-S and risk were observed, with an RR of 1.58 (95% CI 1.13–2.21; P for trend = 0.06) for myocardial infarction in the highest vs lowest quartile.
We observed a modest positive relationship between plasma concentrations of DHEA and its sulfate and the risk of subsequent myocardial infarction among predominantly postmenopausal women.
PMCID: PMC3400530  PMID: 18451313
9.  Family History of Prostate and Breast Cancer and the Risk of Prostate Cancer in the PSA era 
The Prostate  2008;68(14):1582-1591.
A family history of prostate cancer (PCa) or breast cancer (BCa) has been associated with the risk of PCa, but the risks were inconsistent in terms of the affected family members, and data in the PSA era are limited.
This study included a subcohort of the Health Professionals Follow-Up Study composed of a highly PSA screened population from 1986 to 2004 with 3,695 PCa cases identified. Questionnaires and a food frequency questionnaire were administered every other and every four years, respectively. Family history of PCa and BCa was ascertained in 1990, 1992, and 1996. All statistics were two-sided.
A family history of PCa in both a father and brother(s) was associated with a 2.3-fold increased risk of PCa [95% confidence interval (CI)=1.76–3.12]. Men with a father or brother(s) with a PCa diagnosis at age<60 and ≥60 had 2.16- and 1.95-fold increased risk of PCa, respectively. A family history of PCa was related to early-onset PCa (<65 years: RR=2.25, 95% CI=1.95–2.60) and weakly to late-onset PCa (≥65 years: RR=1.67, 95% CI=1.52–1.85). History of BCa in a mother or a sister was associated with a 1.22-fold increased risk of PCa (95% CI=1.08–1.38).
A family history of PCa or BCa significantly increases PCa risk. These associations are evident in a population with widespread PSA screening.
PMCID: PMC2574825  PMID: 18646000
Family history; prostate cancer; breast cancer; PSA era

Results 1-9 (9)