STAR 3 randomized controlled trial to compare sensor-augmented insulin pump therapy with multiple daily injections in the treatment of type 1 diabetes: research design, methods, and baseline characteristics of enrolled subjects.

BACKGROUND: Sensor-augmented pump therapy (SAPT) integrates real-time continuous glucose monitoring (RT-CGM) with continuous subcutaneous insulin infusion (CSII) and offers an alternative to multiple daily injections (MDI). Previous studies provide evidence that SAPT may improve clinical outcomes among people with type 1 diabetes. Sensor-Augmented Pump Therapy for A1c Reduction (STAR) 3 is a multicenter randomized controlled trial comparing the efficacy of SAPT to that of MDI in subjects with type 1 diabetes. METHODS: Subjects were randomized to either continue with MDI or transition to SAPT for 1 year. Subjects in the MDI cohort were allowed to transition to SAPT for 6 months after completion of the study. SAPT subjects who completed the study were also allowed to continue for 6 months. The primary end point was the difference between treatment groups in change in hemoglobin A1c (HbA1c) percentage from baseline to 1 year of treatment. Secondary end points included percentage of subjects with HbA1c < or =7% and without severe hypoglycemia, as well as area under the curve of time spent in normal glycemic ranges. Tertiary end points include percentage of subjects with HbA1c < or =7%, key safety end points, user satisfaction, and responses on standardized assessments. RESULTS: A total of 495 subjects were enrolled, and the baseline characteristics similar between the SAPT and MDI groups. Study completion is anticipated in June 2010. CONCLUSIONS: Results of this randomized controlled trial should help establish whether an integrated RT-CGM and CSII system benefits patients with type 1 diabetes more than MDI.

Assessment of LD matrix measures for the analysis of biological pathway association.

Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression (Wang et al., 2008). To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis). In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r=0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.

Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review.

BACKGROUND: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel. METHODS AND RESULTS: Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs. CONCLUSIONS: Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.