Placebo response characteristic in sequential parallel comparison design studies

The placebo response can affect inference in analysis of data from clinical trials. It can bias the estimate of the treatment effect, jeopardize the effort of all involved in a clinical trial and ultimately deprive patients of potentially efficacious treatment. The Sequential Parallel Comparison Design (SPCD) is one of the novel approaches addressing placebo response in clinical trials. The analysis of SPCD clinical trial data typically involves classification of subjects as ‘placebo responders’ or ‘placebo non-responders’. This classification is done using a specific criterion and placebo response is treated as a measurable characteristic. However, the use of criterion may lead to subject misclassification due to measurement error or incorrect criterion selection. Subsequently, misclassification can directly affect SPCD treatment effect estimate. We propose to view placebo response as an unknown random characteristic that can be estimated based on information collected during the trial. Two strategies are presented here. First strategy is to model placebo response using criterion classification as a starting point or the observed data, and to include the placebo response estimate into the treatment effect estimation. Second strategy is to jointly model latent placebo response and the observed data, and estimate treatment effect from the joint model. We evaluate both strategies on a wide range of simulated data scenarios in terms of type I error control, mean squared error and power. We then evaluate the strategies in presence of missing data and propose a method for missing data imputation under the non-informative missingness assumption. The data from a recent SPCD clinical trial is used to compare results of the proposed methods with reported results of the trial.2018-01-01T00:00:00

Evaluation of a web-based asthma self-management system: a randomised controlled pilot trial

Background Asthma is the most common chronic condition of childhood and disproportionately affects inner-city minority children. Low rates of asthma preventer medication adherence is a major contributor to poor asthma control in these patients. Web-based methods have potential to improve patient knowledge and medication adherence by providing interactive patient education, monitoring of symptoms and medication use, and by facilitation of communication and teamwork among patients and health care providers. Few studies have evaluated web-based asthma support environments using all of these potentially beneficial interventions. The multidimensional website created for this study, BostonBreathes, was designed to intervene on multiple levels, and was evaluated in a pilot trial. Methods An interactive, engaging website for children with asthma was developed to promote adherence to asthma medications, provide a platform for teamwork between caregivers and patients, and to provide primary care providers with up-to-date symptom information and data on medication use. Fifty-eight (58) children primarily from inner city Boston with persistent-level asthma were randomised to either usual care or use of BostonBreathes. Subjects completed asthma education activities, and reported their symptoms and medication use. Primary care providers used a separate interface to monitor their patients’ website use, their reported symptoms and medication use, and were able to communicate online via a discussion board with their patients and with an asthma specialist. Results After 6-months, reported wheezing improved significantly in both intervention and control groups, and there were significant improvements in the intervention group only in night-time awakening and parental loss of sleep, but there were no significant differences between intervention and control groups in these measures. Emergency room or acute visits to a physician for asthma did not significantly change in either group. Among the subgroup of subjects with low controller medication adherence at baseline, adherence improved significantly only in the intervention group. Knowledge of the purpose of controller medicine increased significantly in the intervention group, a statistically significant improvement over the control group. Conclusions This pilot study suggests that a multidimensional web-based educational, monitoring, and communication platform may have positive influences on pediatric patients’ asthma-related knowledge and use of asthma preventer medications

Routine use of completion imaging after infrainguinal bypass is not associated with higher bypass graft patency

BackgroundSignificant variability exists in completion imaging (CIM) after infrainguinal lower extremity bypass (LEB). We evaluated the use of CIM and compared graft patency in patients treated by surgeons who performed routine CIM vs those who performed selective CIM.MethodsWe reviewed the Vascular Study Group of New England database (2003-2010) and assessed the use of CIM (angiography or duplex ultrasound) among patients undergoing LEB. The surgeon-specific CIM strategy was categorized as routine (≥80% of LEBs) vs selective (<80% of LEBs). Exclusion criteria included acute limb ischemia, bilateral procedures, and surgeon volume <10 cases per study period. Primary graft patency at discharge and at 1 year was analyzed on the basis of CIM use and surgeon-specific CIM strategy. Multivariable analyses were performed using Poisson regression.ResultsAmong 2032 LEB procedures performed by 48 surgeons, CIM was used in 1368 cases (67.3%). CIM was performed in 72% of autogenous LEBs and 52% of prosthetic grafts. Dialysis (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.1-2.6; P = .01), elective LEB (OR, 2.6; 95% CI, 1.4-4.8; P = .002), great saphenous vein conduit (OR, 2.0; 95% CI, 1.6-2.5; P < .001), and tibial or pedal target artery (OR, 1.8; 95% CI, 1.4-2.3; P < .001) were associated with CIM use. In multivariate models, CIM was not associated with improved primary graft patency at discharge (OR, 1.1; 95% CI, 0.7-1.7; P = .64) or at 1 year (OR, 0.9; 95% CI, 0.7-1.2; P = .47). Sixteen surgeons (33%) were routine users and 32 (67%) were selective users of CIM. Among patients of routine vs selective CIM users, primary graft patency at discharge and at 1 year was 96% vs 94% (P = .21) and 68% vs 72% (P = .09), respectively. In multivariate analysis, routine or selective CIM strategy was not associated with improved discharge (rate ratio, 0.8; 95% CI, 0.6-1.1; P = .31) or 1-year (rate ratio, 1.1; 95% CI, 0.9-1.2; P = .56) graft patency.ConclusionsIn our observational cohort, CIM does not improve short-term and 1-year bypass graft patency in infrainguinal LEB. The surgeon-specific strategy of selective CIM after LEB has outcomes comparable to those of routine CIM

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway : a meta-analysis

Aims/hypothesis Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Methods Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. Results In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (beta +/- SE 0.014 +/- 0.004 [mmol/l], p = 1.5 x 10(-3)) and higher fasting insulin (0.030 +/- 0.005 [log(e) pmol/l], p = 2.0 x 10(-10)). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the beta-Klotho (KLB) locus on fasting insulin (0.030 +/- 0.011 log(e) pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. Conclusions/interpretation In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.Peer reviewe

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D

Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

Background and aims Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT