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1.  Differential Associations of Oral Glucose Tolerance Test–Derived Measures of Insulin Sensitivity and Pancreatic β-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes 
Diabetes Care  2013;37(1):124-133.
We evaluated relationships of oral glucose tolerance testing (OGTT)–derived measures of insulin sensitivity and pancreatic β-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease.
A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and β-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria.
The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio −0.78 [95% CI −1.51 to −0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30–0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes.
Lower β-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.
PMCID: PMC3867998  PMID: 23949560
2.  Racial Differences in Longitudinal Changes in Serum Prostate-Specific Antigen Levels: The Olmsted County Study and The Flint Men’s Health Study 
Urology  2013;83(1):88-93.
To determine the distribution of and racial differences in changes in PSA from a population-based sample of men.
Materials and Methods
Data from two prospective cohort studies of a random sample of Caucasian men, ages 40–79 in 1990, followed biennially through 2007 and African-American men, ages 40–79 in 1996, followed through 2000 were examined to assess longitudinal changes in PSA concentrations. Serum PSA levels were determined at each examination for both cohorts and observations after a diagnosis of prostate cancer or treatment for benign prostatic hyperplasia (BPH) were censored. Observed and estimated annual percentage change in serum PSA levels were examined by race.
At baseline, the median PSA level in Caucasian men did not differ from the median level observed in African-American men (Caucasian men: 0.9 ng/mL; African-American men: 0.9 ng/mL; P value=0.48). However, African-American men had a much more rapid increase in PSA level over time compared to Caucasian men (median annual percent change in PSA Caucasian men: 3.6%/year; African-American men: 7.9%/year; P value<0.001).
These data suggest that African-American men have more rapid rates of change in PSA levels over time. If the difference in rate of changes between African-American and Caucasian men is an early indicator of future prostate cancer diagnosis, earlier detection in African-American men could help to alleviate the racial disparities in prostate cancer diagnosis and mortality.
PMCID: PMC3896508  PMID: 24139354
Prostate cancer; PSA; racial differences; epidemiology
3.  Variable Selection for Propensity Score Models When Estimating Treatment Effects on Multiple Outcomes: a Simulation Study 
It is often preferable to simplify the estimation of treatment effects on multiple outcomes by using a single propensity score (PS) model. Variable selection in PS models impacts the efficiency and validity of treatment effects. However, the impact of different variable selection strategies on the estimated treatment effects in settings involving multiple outcomes is not well understood. The authors use simulations to evaluate the impact of different variable selection strategies on the bias and precision of effect estimates to provide insight into the performance of various PS models in settings with multiple outcomes.
Simulated studies consisted of dichotomous treatment, two Poisson outcomes, and eight standard-normal covariates. Covariates were selected for the PS models based on their effects on treatment, a specific outcome, or both outcomes. The PSs were implemented using stratification, matching, and weighting (IPTW).
PS models including only covariates affecting a specific outcome (outcome-specific models) resulted in the most efficient effect estimates. The PS model that only included covariates affecting either outcome (generic-outcome model) performed best among the models that simultaneously controlled measured confounding for both outcomes. Similar patterns were observed over the range of parameter values assessed and all PS implementation methods.
A single, generic-outcome model performed well compared with separate outcome-specific models in most scenarios considered. The results emphasize the benefit of using prior knowledge to identify covariates that affect the outcome when constructing PS models and support the potential to use a single, generic-outcome PS model when multiple outcomes are being examined.
PMCID: PMC3540180  PMID: 23070806
propensity scores; simulation; variable selection; instrumental variables; pharmacoepidemiology
4.  Use of Systems Biology Approaches to Analysis of Genome-Wide Association Studies of Myocardial Infarction and Blood Cholesterol in the Nurses' Health Study and Health Professionals’ Follow-Up Study 
PLoS ONE  2013;8(12):e85369.
With the advance of genome-wide association studies and newly identified SNP (single-nucleotide polymorphism) associations with complex disease, important discoveries have emerged focusing not only on individual genes but on disease-associated pathways and gene sets. The authors used prospective myocardial infarction case-control studies nested in the Nurses’ Health and Health Professionals Follow-Up Studies to investigate genetic variants associated with myocardial infarction or LDL, HDL, triglycerides, adiponectin and apolipoprotein B (apoB). Using these case-control studies to illustrate an integrative systems biology approach, the authors applied SNP set enrichment analysis to identify gene sets where expression SNPs representing genes from these sets show enrichment in their association with endpoints of interest. The authors also explored an aggregate score approach. While power limited one’s ability to detect significance for association of individual loci with myocardial infarction, the authors found significance for loci associated with LDL, HDL, apoB and triglycerides, replicating previous observations. Applying SNP set enrichment analysis and risk score methods, the authors also found significance for three gene sets and for aggregate scores associated with myocardial infarction as well as for loci-related to cardiovascular risk factors, supporting the use of these methods in practice.
PMCID: PMC3873433  PMID: 24386469
5.  Potential role for plasma placental growth factor in predicting coronary heart disease risk in women 
To examine placental growth factor’s (PlGF) predictive value in relation to coronary heart disease (CHD) risk in healthy women.
Methods and results
Among 32,826 women from the Nurses’ Health Study who provided blood samples at baseline, 453 CHD events were documented during 14 years of follow-up. Controls were matched to cases (2:1) for age, smoking, fasting status, and date of blood sampling. PlGF was inversely correlated with HDL-cholesterol (HDL-C), and positively correlated with several coronary risk factors. In multivariate models, women in the highest versus lowest quintile of PlGF had a greater risk of CHD (RR:1.58;95%CI:1.03-2.41). Additional adjustment for many coronary risk factors did not substantively alter this relationship, but HDL-C attenuated the association (RR:1.25;95%CI:0.81-1.94). In exploratory time to event analysis, higher PlGF levels, measured > 10 years prior to CHD event, but not < 10 years pre-clinical event, were associated with increased risk of CHD, even after adjustment for co-morbid conditions and HDL-C levels (RR:2.79;95%CI:1.19-6.56).
Elevated prediagnostic PlGF levels were modestly associated with subsequent risk of CHD events and results were attenuated after controlling for HDL-C. PlGF may be most strongly associated with long term prediction of CHD, consistent with a potential role in early plaque formation and growth.
PMCID: PMC3789235  PMID: 18927470
PlGF; CHD; women
6.  Integrating Genetic Association, Genetics of Gene Expression, and Single Nucleotide Polymorphism Set Analysis to Identify Susceptibility Loci for Type 2 Diabetes Mellitus 
American Journal of Epidemiology  2012;176(5):423-430.
Large-scale genome-wide association studies (GWAS) have identified over 40 genomic regions significantly associated with type 2 diabetes mellitus. However, GWAS results are not always straightforward to interpret, and linking these loci to meaningful disease etiology is often difficult without extensive follow-up studies. The authors expanded on previously reported type 2 diabetes mellitus GWAS from the nested case-control studies of 2 prospective US cohorts by incorporating expression single nucleotide polymorphism (SNP) information and applying SNP set enrichment analysis to identify sets of SNPs associated with genes that could provide further biologic insight to traditional genome-wide analysis. Using data collected between 1989 and 1994 in these previous studies to form a nested case-control study, the authors found that 3 of the most significantly associated SNPs to type 2 diabetes mellitus in their study are expression SNPs to the lymphocyte antigen 75 gene (LY75), the ubiquitin-specific peptidase 36 gene (USP36), and the phosphatidylinositol transfer protein, cytoplasmic 1 gene (PITPNC1). SNP set enrichment analysis of the GWAS results identified enrichment for expression SNPs to the macrophage-enriched module and the Gene Ontology (GO) biologic process fat cell differentiation human, which includes the transcription factor 7-like 2 gene (TCF7L2), as well as other type 2 diabetes mellitus-associated genes. Integrating genome-wide association, gene expression, and gene set analysis may provide valuable biologic support for potential type 2 diabetes mellitus susceptibility loci and may be useful in identifying new targets or pathways of interest for the treatment and prevention of type 2 diabetes mellitus.
PMCID: PMC3499116  PMID: 22865700
expression single nucleotide polymorphism; gene set enrichment analysis; genome-wide association study; integrative genomic analysis; single nucleotide polymorphism; type 2 diabetes
7.  Nocturia is associated with an increased risk of coronary heart disease and death 
BJU international  2012;110(6):848-853.
To determine whether nocturia is associated with the development of diabetes mellitus, hypertension, coronary heart disease (CHD) and occurrence of death.
We studied data obtained from a retrospective cohort of randomly selected men, aged 40–79 years in 1990, from Olmsted County, MN, USA.
Nocturia was defined as waking to urinate ≥2 times per night.
Men were followed every 2 years through repeated questionnaires and community medical records to assess development of diabetes mellitus and hypertension, and occurrence of death. CHD was ascertained through ongoing surveillance of heart disease in Olmsted County.
Cox proportional hazard models were used to estimate associations between baseline nocturia and each of the outcomes.
A total of 2447 men were followed for a median of 17.1 years (25th and 75th percentiles: 15.0, 17.4 years).
Nocturia was not significantly associated with the later development of diabetes mellitus or hypertension in this study.
Younger men (<60 years of age) with moderate nocturia were more likely to develop CHD later in life than younger men without nocturia (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.13, 2.49). This association was no longer significant when adjusted for age, body mass index (BMI) and urological medications (HR: 1.36; 95% CI: 0.87, 2.22).
Older men (≥60 years of age) with moderate nocturia were more likely to die than older men without moderate nocturia, even after adjusting for age, BMI, urological medications and CHD (HR: 1.48; 95% CI: 1.15, 1.91).
Nocturia may be a marker for increased risk of CHD in younger men, and death in older men.
PMCID: PMC3508707  PMID: 22233166
nocturia; diabetes mellitus; cardiovascular disease; hypertension; cohort
8.  Longitudinal changes of benign prostate-specific antigen and [-2]pro-prostate-specific antigen over 7 years in a community-based sample of men 
Urology  2012;79(3):655-661.
Introduction and Objectives
Benign prostate-specific antigen (BPSA) and [-2]pro-prostate-specific antigen ([-2]proPSA) have been shown to be predictive of prostate cancer and benign prostatic hyperplasia treatment, but little is known about longitudinal changes in these markers and how they relate to outcomes.
In 1990, a 25% subsample from a cohort of Caucasian men aged 40–79 years randomly selected from Olmsted County, MN residents completed a detailed clinical examination. BPSA and [-2]proPSA were measured from frozen sera. Subjects were evaluated biennially (median follow-up 7 years; range: 0–8.8 years). Mixed-effects regression models were used to estimate longitudinal changes in BPSA and [-2]proPSA levels overall and by outcomes. Spearman correlations were used to compare these changes with baseline levels and annualized changes in urologic measures.
Median (25th, 75th percentiles) annualized percent change for [-2]proPSA and BPSA were 3.7% (2.5%, 5.2%) and 7.3% (6.8%, 7.7%), respectively. Annualized percent change for both markers were correlated with baseline and annualized changes in PSA and prostate volume. Annualized percent change increased with increasing age decade for [-2]proPSA, but not BPSA. The median (25th, 75th percentiles) rate of increase in [-2]proPSA was significantly greater for men who developed enlarged prostates (3.5% (2.6%, 4.4%)) or prostate cancer (8.1% (6.6%, 9.8%)) compared to those who did not develop enlarged prostates (1.9% (0.9%, 3.0%)) or prostate cancer (3.5% (2.3%, 4.8%)).
BPSA and [-2]proPSA levels increase over time. The annualized percent change in [-2]proPSA increases with age and may be a useful predictor of development of prostate cancer.
PMCID: PMC3297985  PMID: 22386420
The Journal of Urology  2011;187(1):87-91.
To describe the cross-sectional associations of benign prostate-specific antigen (BPSA) with clinical urologic measures, and to examine the risk of future urologic outcomes in two population-based cohorts of black and white men.
Materials and Methods
Two population-based, cohort studies were established to characterize the natural history and risk factors for progression of prostate disease in white and black male residents of Olmsted County, Minnesota and Genesee County, Michigan, respectively.
The distribution of BPSA levels was similar in blacks (median (25th, 75th percentiles) =32.9 (17.3, 68.0) pg/mL) and whites (median=32.2 (16.6,68.9) pg/mL), p=0.71, but much lower than previous reports. For Olmsted County men in the upper quartile of BPSA, there was a 15-fold increased risk of prostate cancer (CaP; hazard ratio (HR): 14.6 95% confidence interval (CI): 3.1, 68.6) and a 2-fold higher risk of treatment for benign prostatic hyperplasia (BPH; HR: 2.2, 95% CI: 1.2, 4.2) after adjusting for age. After additional adjustment for baseline PSA, the association between BPSA and CaP risk was attenuated, but remained nearly 9-fold higher for men in the upper BPSA quartile (HR: 8.7, 95% CI: 1.8, 42.4). The 2-fold higher risk of treatment for BPH also remained after adjustment for baseline PSA for men in the upper BPSA quartile (HR: 1.9, 95% CI: 0.9, 4.0).
These results suggest that elevated BPSA level may help to identify men at risk of treatment for BPH and identify men with prostate cancer.
PMCID: PMC3307095  PMID: 22093190
prostate enlargement; prostate cancer; biomarkers; BPSA
The Journal of Urology  2011;187(1):92-96.
To provide cross-sectional normative data for [-2]pro-prostate-specific antigen ([-2]proPSA) from the Olmsted County Study of Urinary Symptoms and Health Status among Men (OCS) and the Flint Men’s Health Study (FMHS) and to describe the associations with clinical urologic measures and risk of prostate cancer diagnosis.
Materials and Methods
Measurements of [-2]proPSA were obtained from n=420 white men from Olmsted County, Minnesota and n=328 black men from Genesee County, Michigan. Cross-sectional associations between [-2]proPSA and prostate enlargement / elevated PSA level were assessed. Cox proportional hazard models were used to assess associations between [-2]proPSA and incident diagnosis of prostate cancer.
Baseline [-2]proPSA level was slightly higher among black men (median (25th, 75th percentiles) =6.3 (4.1, 8.9) pg/mL) than among white men (median=5.6 (3.9, 7.7) pg/mL), p=0.01. Baseline [-2]proPSA level was highly predictive of biopsy-confirmed prostate cancer (CaP) in the OCS cohort. Relative to men in the lower quartile of [-2]proPSA, men in the upper quartile had almost an 8-fold increase in the risk of CaP (hazard ratio (HR): 7.8, 95% confidence interval (CI): 2.2, 27.8) after adjustment for age and baseline PSA.
Levels of [-2]proPSA in these cohorts of community-dwelling black and white men are much lower than seen in previous studies. These data suggest that levels of [-2]proPSA may help identify prostate cancer in men with serum PSA levels in an indeterminate range, although the reference ranges for white and black men may differ slightly.
PMCID: PMC3307097  PMID: 22093189
prostate enlargement; prostate cancer; biomarkers; proPSA
11.  Plasma total and high molecular weight adiponectin levels and risk of coronary heart disease in women 
Atherosclerosis  2011;219(1):322-329.
To examine prospectively the association of total and high molecular weight (HMW) adiponectin, and HMW/total adiponectin ratio with risk of incident coronary heart disease (CHD) in women, and to examine to what extent adjustment for potentially intermediary variables would explain this association.
Methods and Results
Among 30,111 women from the Nurses’ Health Study, 468 women developed non-fatal myocardial infarction or fatal CHD during 14 years of follow-up. Using risk set sampling, controls were selected 2:1 matched on age, smoking, and date of blood draw. Adjusted for matching factors, parental history of myocardial infarction, hormone replacement therapy, alcohol consumption, physical activity, body mass index, hypertension, and low-density lipoprotein cholesterol levels, the relative risk in the highest versus lowest quintile was 0.50 (95%-CI 0.33-0.75; p trend=0.001) for total adiponectin, 0.53 (95%-CI 0.35-0.80; p trend=0.004) for HMW adiponectin, and 0.63 (95%-CI 0.43-0.93; p trend=0.03) for HMW/total adiponectin ratio. After adjustment for diabetes, HDL-cholesterol, HbA1c, and CRP these associations were attenuated and no longer significant (RRs, 0.84; 95%-CI 0.53-1.33; p trend=0.62; 0.95; 95%-CI 0.60-1.52; p trend=0.98; 0.97; 95%-CI 0.64-1.47; p trend=0.80).
High levels of total and HMW adiponectin, and HMW/total adiponectin ratio are associated with a lower risk of CHD among women. HMW adiponectin and HMW/total adiponectin ratio are not more closely related to risk than total adiponectin. These associations are largely mediated by parameters related to glucose and lipid metabolism and inflammation, especially HDL-cholesterol levels.
PMCID: PMC3206156  PMID: 21813129
adiponectin; cohort study; coronary disease; epidemiology; risk factors
12.  Protein Interaction-Based Genome-Wide Analysis of Incident Coronary Heart Disease 
Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions are enriched in genes associated with risk of coronary heart disease (CHD).
Methods and Results
GWA analyses of ~700,000 SNPs in 899 incident CHD cases and 1,823 age- and sex-matched controls within the Nurses’ Health and the Health Professionals Follow-Up Studies were used to assign gene-wise p-values. A large database of protein-protein interactions (PPI) was used to assemble 8,300 unbiased protein complexes and corresponding gene-sets. Superimposed gene-wise p-values were used to rank gene-sets based on their enrichment in genes associated with CHD. After correcting for the number of complexes tested, one gene-set was overrepresented in CHD-associated genes (p-value=0.002). Centered on the beta-1-adrenergic receptor gene (ADRB1), this complex included 18 protein interaction partners that, so far, have not been identified as candidate loci for CHD. Five of the 19 genes in the top-complex are reported to be involved in abnormal cardiovascular system physiology based on knock-out mice (4-fold enrichment; p-value, Fisher’s exact test= 0.006). Ingenuity pathway analysis revealed that especially canonical pathways related to blood pressure regulation were significantly enriched in the genes from the top complex.
The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis.
PMCID: PMC3197770  PMID: 21880673
Genetics of cardiovascular disease; acute myocardial infarction; epidemiology
13.  Sixteen-Year Longitudinal Changes in Serum Prostate-Specific Antigen Levels: The Olmsted County Study 
Mayo Clinic Proceedings  2012;87(1):34-40.
To determine the distribution of longitudinal changes in serum prostate-specific antigen (PSA) levels from a population-based sample of men.
Patients and Methods
In this prospective cohort study, a random sample of Olmsted County, Minnesota, men aged 40 to 79 years in 1990 were followed up biennially from January 1, 1990, through August 29, 2007. Serum PSA levels were determined at each examination, and men were censored for follow-up with a diagnosis of prostate cancer or treatment for benign prostatic hyperplasia. The empirical distributions of annual percent change and annual absolute change in serum PSA level were calculated and tabulated, including the median and 75th and 95th percentiles.
For men with PSA measurements 2 years apart, the median annual percent change in serum PSA level was 4.83% and the 95th percentile was about 49.76%. The variability in estimated annual change decreased with increasing time between assessments, with a 95th percentile of 21.82% after 8 or more years between assessments. Although the median absolute change per year increased with increasing age, the median percent change per year was fairly consistent across age groups.
These data demonstrate that, with shorter intervals between assessments, greater variability should be expected. These distributions should prove helpful to patients and clinicians in interpreting changes in serum PSA levels observed in typical clinical practices.
PMCID: PMC3538390  PMID: 22212966
14.  Associations Between Longitudinal Changes in Serum Estrogen, Testosterone, and Bioavailable Testosterone and Changes in Benign Urologic Outcomes 
American Journal of Epidemiology  2011;173(7):787-796.
Some men have rapid increases in benign prostatic enlargement and lower urinary tract symptoms (LUTS), and it is not clear how sex steroid hormones contribute to the rates of change in these urologic outcomes. Therefore, the authors conducted a population-based cohort study of 648 men residing in Olmsted County, Minnesota, from 1990 to 2007, to examine associations between baseline sex steroid hormones, the rate of change in these hormones, and the rates of change in LUTS, maximum urinary flow rate, and prostate volume. Annual changes in hormone levels and urologic outcomes were calculated using mixed-effects regression models. Associations between hormone variables and rates of change in urologic outcomes were assessed with linear regression models. Higher baseline estradiol levels and rapid declines in estradiol over time were associated with rapid increases in LUTS and rapid decreases in maximum flow rate. Lower baseline bioavailable testosterone levels and more rapid declines in bioavailable testosterone were associated with more rapid increases in prostate volume. These results suggest that both absolute sex steroid hormone levels and the rates at which the levels change may be important in the development of urologic conditions in aging men.
PMCID: PMC3070494  PMID: 21367876
estradiol; prostatic hyperplasia; testosterone
16.  Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms 
BJU international  2010;107(3):443-450.
To determine whether statin use is associated with a decreased risk of developing benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS).
We conducted a retrospective, population-based cohort study of 2447 men, 40–79 years of age, residing in Olmsted County, MN, USA, in 1990, and followed these men biennially through 2007.Cox proportional hazard models were used to assess associations between statin use and new onset of moderate/severe LUTS (American Urologic Association Symptom Index score > 7), a decreased maximum urinary flow rate (< 12 mL/s) or BPE (prostate volume > 30 mL).
Statin use was inversely associated with new onset of LUTS (Hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.31–0.49), a decreased maximum flow rate (HR 0.53; 95% CI 0.34–0.82) and BPE (HR 0.40; 95% CI 0.23–0.69) after adjustment for base-line age and body mass index, diabetes, hypertension, coronary heart disease, smoking, alcohol use, activity level and non-steroidal anti-inflammatory use.The longest duration of statin use was associated with the lowest risk of developing each outcome (all tests for trend: P < 0.001).
In this study, statin use was associated with a 6.5- to 7-year delay in the new onset of moderate/severe LUTS or BPE.While men typically take statin medications to prevent coronary heart disease events and related outcomes, these data suggest that men who use statins may also receive urologic benefits.
PMCID: PMC2997141  PMID: 20804476
Statins; BPH; prostate
17.  Estimation of Prostate Size in Community-Dwelling Men 
Urology  2010;77(2):422-426.
Previous investigators have demonstrated the ability to use serum prostate-specific antigen (PSA) levels to estimate prostate volume (PV) in men without prostate cancer; however, the ability of additional clinical variables to further enhance PV estimation in these men remains unclear. Motivated by this, we utilized two population-based samples of prostate cancer-free men to develop and validate a novel, multivariable equation for estimating PV.
We applied linear regression modeling to data from an 80% random sample (n=366) of the baseline cohort from the Olmsted County Study of Urinary Symptoms and Health Status among Men (OCS) to develop an equation for estimating PV in men without prostate cancer. We then evaluated the predictive ability of this equation by comparing estimated and measured PV values in three additional validation sets of men.
The final linear regression model included PSA, age, and weight as independent predictors of PV. For prediction in baseline OCS men, the multiple correlation coefficients increased from 0.62 PSA alone to 0.71 full model. Additionally, the area under the curve estimates from the receiver operating characteristic curves increased from 0.79 PSA alone to 0.85 full model for predicting PV >30 mL.
Our data suggest that PV can be estimated with easily obtained clinical variables. Moreover, we demonstrate that age and weight can be added to PSA level to achieve greater accuracy in predicting PV. This methodology may prove useful for estimating PV in men in settings where costs and practicality preclude the use of imaging techniques.
PMCID: PMC3010416  PMID: 20800880
Prostate volume; PSA; prediction
18.  Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes 
Human Molecular Genetics  2010;19(13):2706-2715.
To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case–control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10 870 cases and 73 735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR = 0.90, 95% CI = 0.86–0.93; P = 3.7 × 10−8). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P < 0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance.
PMCID: PMC2883345  PMID: 20418489
19.  Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels 
Human Molecular Genetics  2010;19(9):1846-1855.
Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < 5 × 10−8); all mapping to the leptin receptor gene (LEPR). Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genome-wide significance level. Of these 132 SNPs (including two non-synonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 × 10−9, 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 × 10−4). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits.
PMCID: PMC2850621  PMID: 20167575
20.  Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes 
Human Molecular Genetics  2010;19(9):1856-1862.
Blood soluble E-selectin (sE-selectin) levels have been related to various conditions such as type 2 diabetes. We performed a genome-wide association study among women of European ancestry from the Nurses' Health Study, and identified genome-wide significant associations between a cluster of markers at the ABO locus (9q34) and plasma sE-selectin concentration. The strongest association was with rs651007, which explained ∼9.71% of the variation in sE-selectin concentrations. SNP rs651007 was also nominally associated with soluble intracellular cell adhesion molecule-1 (sICAM-1) (P = 0.026) and TNF-R2 levels (P = 0.018), independent of sE-selectin. In addition, the genetic-inferred ABO blood group genotypes were associated with sE-selectin concentrations (P = 3.55 × 10−47). Moreover, we found that the genetic-inferred blood group B was associated with a decreased risk (OR = 0.44, 0.27–0.70) of type 2 diabetes compared with blood group O, adjusting for sE-selectin, sICAM-1, TNF-R2 and other covariates. Our findings indicate that the genetic variants at ABO locus affect plasma sE-selectin levels and diabetes risk. The genetic associations with diabetes risk were independent of sE-selectin levels.
PMCID: PMC2850622  PMID: 20147318
21.  Multinational Internet-based survey of patient preference for newer oral or injectable Type 2 diabetes medication 
The prevalence of Type 2 diabetes mellitus continues to rise. Although glucagon-like peptide-1 (GLP-1) analog and dipeptidyl peptidase-4 (DPP-4) inhibitor medications are effective, there are differences between these products, including method of administration (injectable versus oral). The objective of this study was to examine patient preferences (and predictors of preferences) for two different medication profiles, one similar to a GLP-1 analog (liraglutide) and another similar to a DPP-4 inhibitor (sitagliptin).
Internet survey data were collected in two waves (wave 1, n = 2402; wave 2, n = 1340) using patients from the US and Europe. Patients were presented with two hypothetical medication profiles (“drug A” and “drug B”, resembling sitagliptin and liraglutide, respectively) and asked to report their preferences.
Most patients in wave 1 and wave 2 reported that overall they would prefer a drug with the sitagliptin-like profile (81.9% and 84.4%, respectively) over a drug with the liraglutide-like profile (18.1% and 15.6%, respectively), and >80% of patients reported that they would be able to take a drug with the sitagliptin-like profile as directed by their physician for a longer period. The likelihood of preferring the sitagliptin-like profile significantly increased as age (odds ratio [OR] = 1.02) and importance placed on method of administration (OR = 1.32) increased (P < 0.05). Although the sitagliptin-like profile was preferred by the majority of patients in all subgroups, a lower proportion of patients with obesity, with weight gain, with A1C values above target, and who exercised preferred the sitagliptin-like profile compared with those without obesity (77.0% versus 87.9%), without weight gain (77.8% versus 86.7%), with A1C values at or below target (79.0% versus 86.5%), and who did not exercise (81.6% versus 86.4%), respectively (P < 0.05).
This research suggests that patients (across geographies) prefer an oral medication with a profile resembling sitagliptin to an injectable medication with a profile resembling liraglutide.
PMCID: PMC3003606  PMID: 21206515
Type 2 diabetes; medication preference; sitagliptin; liraglutide
22.  Three-Dimensional Ultrasound Bladder Characteristics and Their Association with Prostate Size and Lower Urinary Tract Dysfunction among Men in the Community 
Urology  2009;74(4):908-913.
To characterize ultrasound bladder measures, and to determine if these measures were associated with Measures of lower urinary tract dysfunction.
Three-dimensional ultrasounds were used to assess bladder surface area (SA), bladder wall thickness (BWT), and estimated bladder weight (EBW) in a random sample of the Olmsted County, Minnesota male population. Uroflowometry was used to determine maximum urinary flow rates, and ultrasound was used to assess post-void residual volume. Prostate volume was assessed with transrectal ultrasound and prostate specific antigen (PSA) levels were assessed from serum samples. Correlation and linear regression analyses assessed relationships between bladder measures and prostate volume, PSA, maximum flow rate, and post-void residual.
Among 259 men, median bladder SA was 228 cm2 (25th, 75th percentiles: 180, 279), median BWT was 2.3 mm (25th, 75th percentiles: 1.8, 2.7), and median EBW was 48.5 g (25th, 75th percentiles: 43.7, 53.0). Decreased bladder SA was correlated with increased PSA level, increased prostate volume, higher AUASI scores (rs=-0.13 to -0.21; p values=0.03 to 0.001), and decreased maximum flow rate (rs=0.21, p=0.001). Increased BWT was correlated with increased PSA level (rs=0.22, p=0.0003), increased prostate volume (rs=0.17, p=0.01), and decreased maximum flow rate (rs=-0.14, p=0.03). EBW was correlated with increased maximum flow rate (rs=0.14, p=0.03), and decreased AUASI score (rs=-0.13, p=0.04).
Decreased SA and EBW were modestly associated with decreased maximum flow rate and increased AUASI scores, suggesting that such measures may provide insight into detrusor dysfunction.
PMCID: PMC2757487  PMID: 19647300
bladder; prostatic hyperplasia; urinary retention
23.  Associations Between C-Reactive Protein and Benign Prostatic Hyperplasia/Lower Urinary Tract Symptom Outcomes in a Population-based Cohort 
American Journal of Epidemiology  2009;169(11):1281-1290.
Inflammation may play a role in the development of benign prostatic hyperplasia and/or lower urinary tract symptoms (LUTS). Higher levels of C-reactive protein (CRP) may therefore be associated with the development of these outcomes. The authors examined the association of CRP levels measured in 1996 with rapid increases in prostate volume, prostate-specific antigen levels, and LUTS as well as rapid decreases in peak flow rates (through 2005) in a population-based cohort of men residing in Olmsted County, Minnesota. Men with CRP levels of ≥3.0 mg/L were more likely to have rapid increases in irritative LUTS (odds ratio (OR) = 2.14, 95% confidence interval (CI): 1.18, 3.85) and rapid decreases in peak flow rates (OR = 2.54, 95% CI: 1.09, 5.92) compared with men with CRP levels of <3.0 mg/L. CRP levels were not significantly associated with rapid increases in prostate volume, obstructive LUTS, or prostate-specific antigen levels. Associations were attenuated after adjusting for age, body mass index, hypertension, and smoking history (irritative LUTS: OR = 2.00, 95% CI: 1.04, 3.82; peak flow rate: OR = 2.45, 95% CI: 0.73, 8.25). These results suggest that rapid increases in irritative LUTS and rapid decreases in peak flow rates may be due to inflammatory processes.
PMCID: PMC2727252  PMID: 19395697
C-reactive protein; inflammation; prostatic hyperplasia; signs and symptoms; urinary tract
24.  The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study 
Transcription factor 7-like 2 (TCF7L2) has emerged as a consistently replicated susceptibility gene for type 2 diabetes, however, whether the TCF7L2 gene also has similar effects on the retinal microvasculature is less clear. We therefore aimed to investigate the association between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and retinal microvascular phenotypes in the Atherosclerosis Risk in Communities (ARIC) Study (1993-1995).
This was a population-based, cross-sectional study of 10,320 middle-aged African American (n = 2,199) and Caucasian (n = 8,121) men and women selected from four United States communities to examine the association between TCF7L2 rs7903146 polymorphism and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, arteriolar and venular calibers). Photographs on one randomly selected eye were graded for presence of retinal microvascular signs and used to measure retinal vessel calibres.
After adjusting for age, sex, study center, mean arterial blood pressure, total serum cholesterol, triglycerides, and other covariates, few associations of TCF7L2 rs7903146 and retinal microvascular signs were noted. TCF7L2 rs7903146 T risk allele was significantly associated with focal arteriolar narrowing in Caucasians with hypertension [odds ratio (OR)CT vs. CC (95% CI) = 1.25 (1.09-1.44); ORTT vs. CC = 1.56 (1.18-2.06); P = 0.002] and in Caucasians without diabetes [OR CT vs. CC = 1.18 (1.06-1.32); OR TT vs. CC = 1.40 (1.12, 1.75); P = 0.003]. No significant association of the TCF7L2 rs7903146 polymorphism and retinal vascular signs was noted among African American individuals.
TCF7L2 rs7903146 is not consistently associated with retinal microvascular signs. However, we report an association between the TCF7L2 rs7903146 polymorphism and focal arteriolar narrowing in Caucasians with hypertension or without diabetes. Further research in other large, population-based studies is needed to replicate these findings.
PMCID: PMC2879252  PMID: 20478041
25.  Intravesical Prostatic Protrusion in Men in Olmsted County, Minnesota 
The Journal of urology  2009;182(6):2819-2824.
Ultrasonically measured intravesical prostatic protrusion may be a promising noninvasive method of assessing bladder outlet obstruction. Previous investigations of this technique focused on patients with acute urinary retention and symptomatic men identified in urology clinics, which may not reflect the distribution of intravesical prostatic protrusion in community dwelling men.
Materials and Methods
In 2006 a total of 322 white men residing in Olmsted County, Minnesota underwent transrectal ultrasound examination which permitted direct measurement of intravesical prostatic protrusion. Cross-sectional associations between lower urinary tract symptoms/benign prostatic enlargement and intravesical prostatic protrusion were measured. Rapid increases in lower urinary tract symptoms/benign prostatic enlargement measures as predictors of severe intravesical prostatic protrusion were also assessed.
Overall 10% of these men had an intravesical prostatic protrusion of 10 mm or greater. Greater intravesical prostatic protrusion was weakly correlated with greater prostate volume (rs = 0.28), higher obstructive symptoms (rs = 0.18) and lower peak urinary flow rate (rs = −0.18). Men with the most rapidly growing prostate before intravesical prostatic protrusion measurement were 3 times more likely to have an intravesical prostatic protrusion of 10 mm or greater. Men with an intravesical prostatic protrusion of 10 mm or greater were more likely to use medications for lower urinary tract symptoms/benign prostatic enlargement compared to those with an intravesical prostatic protrusion less than 10 mm (adjusted OR 2.95, 95% CI 1.23–7.06).
These population based data provide reference ranges for future studies of intravesical prostatic protrusion as a predictor of adverse urological outcomes. Intravesical prostatic protrusion is significantly correlated with greater prostate volume, higher obstructive symptoms and lower peak urinary flow rate, suggesting that it may have clinical usefulness in predicting the need for treatment.
PMCID: PMC2864147  PMID: 19837429
urinary tract; prostate; urinary retention; organ size; prostatic hyperplasia

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