Determining the Suitability of Registries for Embedding Clinical Trials in the United States: A Project of the Clinical Trials Transformation Initiative.

Background: Patient registries are organized systems that use observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition, or exposure. Data collected in registries often coincide with data that could support clinical trials. Integrating clinical trials within registries to create registry-embedded clinical trials offers opportunities to reduce duplicative data collection, identify and recruit patients more efficiently, decrease time to database lock, accelerate time to regulatory decision-making, and reduce clinical trial costs.

Methods and Issues to Consider for Detection of Safety Signals From Spontaneous Reporting Databases: A Report of the DIA Bayesian Safety Signal Detection Working Group.

Spontaneous reporting (SR) adverse event system databases, large observational databases, large clinical trials, and large health records databases comprise repositories of information that may be useful for early detection of potential harms associated with drugs, devices, and vaccines. All of the data sources include many different adverse events and many medical products, so that any approach designed to detect "important" signals of potential harm must have adequate specificity to protect against false alarms yet provide satisfactory sensitivity for detecting issues that really need further investigation. Algorithms for evaluating potential risks using information from these sources, especially SR databases, have been described in the literature.

Recent Statistical Contributions to Medical Device Development.

Clinical trials in the development of new medical device products are in many ways analogous to clinical trials in the development of new drug or biologic products. However, the differences are important and not always intuitive to a statistician with only experience supporting development of drug and biologic products. In this paper we discuss some of the interesting differences with focus on the statistical innovation that is coming out of the medical device area.

Semiparametric Bayesian commensurate survival model for post-market medical device surveillance with non-exchangeable historical data.

Trial investigators often have a primary interest in the estimation of the survival curve in a population for which there exists acceptable historical information from which to borrow strength. However, borrowing strength from a historical trial that is non-exchangeable with the current trial can result in biased conclusions. In this article we propose a fully Bayesian semiparametric method for the purpose of attenuating bias and increasing efficiency when jointly modeling time-to-event data from two possibly non-exchangeable sources of information.

Bayesian adaptive design for device surveillance.

Background: Postmarket device surveillance studies often have important primary objectives tied to estimating a survival function at some future time $$T$$ with a certain amount of precision.

Purpose: This article presents the details and various operating characteristics of a Bayesian adaptive design for device surveillance, as well as a method for estimating a sample size vector (determined by the maximum sample size and a preset number of interim looks) that will deliver the desired power.

Methods: We adopt a Bayesian adaptive framework, which recognizes the fact that persons enrolled in a study report their results over time, not all at once.

Longitudinal inspiratory capacity changes in chronic obstructive pulmonary disease.

Background: The changes in inspiratory capacity (IC) over time in chronic obstructive pulmonary disease (COPD) patients are unknown. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial included IC measurements.

Methods: IC analysis from UPLIFT® (N = 5992) was performed at 1 and 6 months, and every 6 months through 4 years.

Efficacy of tiotropium in COPD patients with FEV1 ≥ 60% participating in the UPLIFT® trial.

GOLD stage II COPD encompasses patients with FEV₁ 50-80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV₁ <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT® trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60% predicted from UPLIFT®.

Premature discontinuation during the UPLIFT study.

Rationale: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available.

Objective: To obtain better insight into the phenomenon of premature discontinuation.

Preliminary report: Zn-alpha2-glycoprotein genotype and serum levels are associated with serum lipids.

Zn-alpha2-glycoprotein (ZAG) is a serum protein implicated in cancer cachexia and lipolysis. Our aim was to investigate serum levels of ZAG and polymorphisms in the ZAG gene in relation to serum lipids in man. Serum levels of ZAG correlated with serum levels of cholesterol (P = .

Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.

Background: The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD.

Acute hyperinsulinemia raises plasma interleukin-6 in both nondiabetic and type 2 diabetes mellitus subjects, and this effect is inversely associated with body mass index.

Hyperinsulinemia is a characteristic of type 2 diabetes mellitus (T2DM) and is believed to play a role in the low-grade inflammation seen in T2DM. The main aim was to study the effect of hyperinsulinemia on adipokines in individuals with different levels of insulin resistance, glycemia, and obesity. Three groups of sex-matched subjects were studied: young healthy subjects (YS; n = 10; mean age, 26 years; body mass index [BMI], 22 kg/m(2)), patients with T2DM (DS; n = 10; 61 years; BMI, 27 kg/m(2)), and age- and BMI-matched controls to DS (CS; n = 10; 60 years; BMI, 27 kg/m(2)).

Cell death-inducing DFF45-like effector C is reduced by caloric restriction and regulates adipocyte lipid metabolism.

Members of the cell death-inducing DFF45-like effector (CIDE) gene family have been shown to regulate lipid metabolism. In this article, we report that the third member of the human CIDE family, CIDEC, is down-regulated in response to a reduced caloric intake. The down-regulation was demonstrated by microarray and real-time polymerase chain reaction analysis of subcutaneous adipose tissue in 2 independent studies on obese patients undergoing treatment with a very low calorie diet.

Three definitions of the metabolic syndrome: relations to mortality and atherosclerotic morbidity.

Background: Different definitions of the metabolic syndrome are used, and at least one of these does not include indices of glucose intolerance and/or insulin resistance as obligatory components. In this paper, we examine the predictive power of indices having and not having these obligatory components.

Methods: A total of 1135 men and women, aged 37-61 years, were randomly selected from the populations of Mölndal and Orebro, Sweden.

Relations of adipose tissue CIDEA gene expression to basal metabolic rate, energy restriction, and obesity: population-based and dietary intervention studies.

Context: Cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA) could be a potential target for the treatment of obesity via the modulation of metabolic rate, based on the findings that CIDEA inhibits the brown adipose tissue uncoupling process in rodents.

Objectives: Our objects were to investigate the putative link between CIDEA and basal metabolic rate in humans and to elucidate further the role of CIDEA in human obesity.

Design: We have explored CIDEA gene expression in adipose tissue in two different human studies: a cross-sectional and population-based study assessing body composition and metabolic rate (Mölndal Metabolic study, n = 92); and a longitudinal intervention study of obese subjects treated with a very low calorie diet (VLCD) (VLCD study, n = 24).

Postnatal testosterone exposure results in insulin resistance, enlarged mesenteric adipocytes, and an atherogenic lipid profile in adult female rats: comparisons with estradiol and dihydrotestosterone.

Postnatal events contribute to features of the metabolic syndrome in adulthood. In this study, postnatally administered testosterone reduced insulin sensitivity and increased the mesenteric fat depot, the size of mesenteric adipocytes, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and the atherogenic index in adult female rats. To assess the involvement of estrogen and androgen receptors in these programming effects, we compared testosterone-exposed rats to rats exposed to estradiol or dihydrotestosterone (DHT).

Dissociation between adipose tissue expression and serum levels of adiponectin during and after diet-induced weight loss in obese subjects with and without the metabolic syndrome.

The study aimed to examine if dysmetabolic subjects (MetS+) have lower adiponectin gene expression and lower circulating adiponectin levels than non-dysmetabolic obese subjects (MetS-) at baseline, if adiponectin expression and adiponectin concentration rise more in the dysmetabolic group during weight loss, and if v-SNARE Vti1a (vesicle transport soluble NSF attachment protein receptor vps10p tail interacting 1a) expression increases during the weight loss, as a mechanism for increased adiponectin secretion. Twenty-one obese MetS+ and 19 obese MetS- subjects underwent a very low-energy diet for 16 weeks followed by 2 weeks of refeeding. Abdominal subcutaneous adipose tissue biopsies and blood samples were taken before, during, and after dieting for DNA microarray, reverse transcriptase-polymerase chain reaction, and biochemical analyses.

A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome.

The expression of NAD(P)H:quinone oxidoreductase 1 is high in human adipose tissue, reduced by weight loss, and correlates with adiposity, insulin sensitivity, and markers of liver dysfunction.

Context: We have previously identified nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1), an enzyme involved in the protection against oxidative stress, as a gene predominantly expressed in human adipocytes. Studies in mice deficient in NQO1 activity suggest that NQO1 may also play an important role in metabolism.

Objective: The aim of this study was to explore the expression and regulation of NQO1 in human adipose tissue (AT) and isolated adipocytes.

Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression.

Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+/-3.

The expression of inhibin beta B is high in human adipocytes, reduced by weight loss, and correlates to factors implicated in metabolic disease.

Adipose tissue is an endocrine organ that produces and secretes adipokines. The aim of this study was to identify genes predominantly expressed in human subcutaneous adipocytes. For this purpose, an algorithm was developed and DNA microarray expression profiles from 33 human tissues and cell types were used to select genes.

A microarray search for genes predominantly expressed in human omental adipocytes: adipose tissue as a major production site of serum amyloid A.

To identify genes predominantly expressed in omental adipocytes, microarray expression profiles from 33 human tissues or cell types were analyzed, using an algorithm developed for identification of transcripts predominantly expressed in a certain tissue. Both known adipocyte-specific and more unexpected genes were among the 28 genes identified. To validate the approach, adipocyte expression of three of these genes, acute-phase serum amyloid A (A-SAA), aquaporin 7, and transport secretion protein-2.

Mice deficient in apolipoprotein E but not LDL receptors are resistant to accelerated atherosclerosis associated with obesity.

The aims of this study were to determine whether mice induced to become obese also exhibited accelerated atherosclerosis, and to determine whether obesity itself or dyslipidemia associated with obesity enhanced atherosclerosis. Wild-type (C57BL/6) mice and mice deficient for the low density lipoprotein receptor (LDLR-/-) or apolipoprotein E (apoE-/-) were fed a low fat, rodent chow diet or a high fat, high sucrose (diabetogenic) diet to induce obesity. As compared with wild-type mice, diabetogenic diet-fed LDLR-/- mice became more obese and developed severe dyslipidemia.

Adjusted P values for genome-wide scans.

Genome-wide scans for quantitative trait loci (QTL) have traditionally been summarized with plots of logarithm of odds (LOD) scores. A valuable modification is to supplement such plots with an additional vertical axis displaying quantiles of adjusted P values and labeling local maxima of the LOD scores with location-specific adjusted P values. This provides a visible gradation of genome-wide significance for the LOD score curve, instead of the stark dichotomy that a single threshold yields.

LDL receptor but not apolipoprotein E deficiency increases diet-induced obesity and diabetes in mice.

The aim of this study was to determine whether phenotypes associated with type 2 diabetes are altered in dyslipidemic obese mice. C57BL/6 wild-type, low-density lipoprotein (LDL) receptor-deficient (LDLR-/-), and apolipoprotein E-deficient (apoE-/-) mice were fed a high-fat, high-carbohydrate diet (diabetogenic diet), and the development of obesity, diabetes, and hypertriglyceridemia was examined. Wild-type mice became obese and developed hyperglycemia, but not hypertriglyceridemia, in response to this diet.