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

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

Variable selection for propensity score models when estimating treatment effects on multiple outcomes: a simulation study: PS VARIABLE SELECTION FOR MULTIPLE OUTCOMES

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

The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men

The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men.BackgroundBenign prostatic hyperplasia (BPH) and chronic kidney disease are important public health problems in older men. Previous referral-based studies disagree on whether BPH is associated with chronic kidney disease. The objective of this study was to determine the community-based association between clinical measures of BPH and chronic kidney disease.MethodsA community-based sample of 2115 white men (ages 40–79 years) was randomly selected from the Olmsted County, Minnesota population (55% participation rate) in 1990. A random subsample (N = 476) had a detailed clinical evaluation. This evaluation included a questionnaire with similar queries to the International Prostate Symptom Score (IPSS), peak urinary flow rates (uroflowmeter), postvoid residual urine volume (ultrasound), prostate volume (ultrasound), serum prostate specific antigen (PSA), and serum creatinine.ResultsAfter adjustment for age, hypertension, diabetes, leukocyte esterase positive (possible urinary tract infection), and smoking, chronic kidney disease [serum creatinine ≥133 μmol/L (1.5 mg/dL)] was associated with diminished peak urinary flow rate (<15 mL/sec) by an odds ratio (OR) = 2.96 (95% CI 1.30–7.01), moderate-severe lower urinary tract symptoms (IPSS >7) by an OR = 2.91 (95% CI 1.32–6.62), and chronic urinary retention (postvoid residual >100 mL) by an OR = 2.28 (95% CI 0.66–6.68). There was no association with a prostate volume >30 mL by an OR = 0.56 (95% CI 0.22–1.37) or PSA >1.4 ng/mL by an OR = 1.17 (95% CI 0.47–2.81).ConclusionThere was a cross-sectional association between signs and symptoms of bladder outlet obstruction and chronic kidney disease in community-dwelling men. Prostatic enlargement was not associated with chronic kidney disease

Assessing the Impact of Propensity Score Estimation and Implementation on Covariate Balance and Confounding Control Within and Across Important Subgroups in Comparative Effectiveness Research

Researchers are often interested in estimating treatment effects in subgroups controlling for confounding based on a propensity score (PS) estimated in the overall study population

Trends and Determinants of Oral Anti-Diabetic Initiation in Youth with Suspected Type 2 Diabetes

ObjectiveTo evaluate trends and identify predictors of treatment initiation of oral anti-diabetic drugs (OAD) in youth.Patients and MethodsWe identified a select population of children, ages 8–18 years, with at least 13 months of continuous health plan coverage within the years 2001–2012 in a large US commercial insurance claims database. New use of an OAD was defined as the first claim for an outpatient dispensing following a 12-month wash out period. Treatment incidence was estimated monthly over the study period, and stratified by age, gender, geographic region, and provider specialty.ResultsThe median size of the source population during the study period was 2.2 million children. A total of 13,824 initiators (mean monthly incidence of 4.6 (95% CI = 3.6, 5.5) per 100,000 youths) were identified. Initiators were more likely to be females, age 15–18, from the southern region, and have visited a family practitioner (versus a general pediatrician) prior to initiation. Time trends demonstrate a 43% increase in initiation from 2002–2012, with a gradual decrease starting from early 2008.ConclusionIncidence of filled OAD medications in youth increased over time, especially for patients treated by family practitioners. Additional research is needed into factors influencing prescribing by family practitioners and pediatricians

Matching on the disease risk score in comparative effectiveness research of new treatments: Matching on Disease Risk Scores

We use simulations and an empirical example to evaluate the performance of disease risk score (DRS) matching compared with propensity score (PS) matching when controlling large numbers of covariates in settings involving newly introduced treatments

The Role of Prediction Modeling in Propensity Score Estimation: An Evaluation of Logistic Regression, bCART, and the Covariate-Balancing Propensity Score

The covariate-balancing propensity score (CBPS) extends logistic regression to simultaneously optimize covariate balance and treatment prediction. Although the CBPS has been shown to perform well in certain settings, its performance has not been evaluated in settings specific to pharmacoepidemiology and large database research. In this study, we use both simulations and empirical data to compare the performance of the CBPS with logistic regression and boosted classification and regression trees. We simulated various degrees of model misspecification to evaluate the robustness of each propensity score (PS) estimation method. We then applied these methods to compare the effect of initiating glucagonlike peptide-1 agonists versus sulfonylureas on cardiovascular events and all-cause mortality in the US Medicare population in 2007–2009. In simulations, the CBPS was generally more robust in terms of balancing covariates and reducing bias compared with misspecified logistic PS models and boosted classification and regression trees. All PS estimation methods performed similarly in the empirical example. For settings common to pharmacoepidemiology, logistic regression with balance checks to assess model specification is a valid method for PS estimation, but it can require refitting multiple models until covariate balance is achieved. The CBPS is a promising method to improve the robustness of PS models

Responsiveness of the Acne-Specific Quality of Life Questionnaire (Acne-QoL) to treatment for acne vulgaris in placebo-controlled clinical trials

The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to measure the impact of facial acne across four dimensions of patient quality of life. The main objective of the current study was to evaluate the responsiveness of this instrument. Secondarily, this study provided an opportunity to extend the developer's psychometric validation. The Acne-QoL was utilized in two randomized, double-blind, placebo-controlled studies of the efficacy of Estrostep ® (norethindrone acetate/ethinyl estradiol) in the treatment of facial acne; a total of 296 Estrostep ® and 295 placebo patients were evaluated. The Acne-QoL was completed at the beginning, middle (cycle 3), and end (cycle 6) of the 6-month treatment period. The responsiveness of the Acne-QoL was demonstrated through its ability to detect both small (baseline to mid-study) and moderate (baseline to study end) treatment advantages for Estrostep ® patients. Confirmatory factor analysis supported the subscale structure, and internal consistency estimates were excellent. Convergent and discriminant validity were supported by correlations between Acne-QoL scores and clinical measures that were both in the direction and relative magnitude hypothesized. Finally, item response theory analyses confirmed that each item is highly related to its subscale's latent construct and that each subscale is sensitive across a broad range of the underlying continuum. The results of this evaluation confirm that the Acne-QoL is responsive, internally consistent, and valid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43563/1/11136_2004_Article_5089801.pd

Transcription factor 7-like 2 (TCF7L2) polymorphism and context-specific risk of impaired fasting glucose in African American and Caucasian adults: the atherosclerosis risk in communities (ARIC) study

Although variants in the transcription factor 7-like 2 (TCF7L2) gene are consistently associated with impaired fasting glucose (IFG) in Caucasians, data from large population-based studies of African Americans are lacking. Moreover, few studies have investigated the effects of TCF7L2 on IFG in the context of metabolic risk factors for diabetes