Comparing Cognitive Decision Models of Iowa Gambling Task in Indivituals Following Temporal Lobectomy

This study examined the theoretical basis for decision making behavior of patients with right or left temporal lobectomy and a control group when they participated in the Iowa Gambling Task. Two cognitive decision models, Expectancy Valence Model and Strategy Switching Heuristic Choice Model, were compared for best fit. The best fitting model was then chosen to provide the basis for parameter estimation (sources of decision making, i.e. cognitive, motivational, and response processes) and interpretation. Both models outperformed the baseline model. However comparison of G2 means between the two cognitive decision models showed the expectancy valence model having a higher mean and thus a better model between the two. Decision parameters were analyzed for the expectancy valence model. The analysis revealed that the parameters were not significant between the three groups. The data was simulated from the baseline model to determine whether the models are different from baseline

Constructing Empirical Likelihood Confidence Intervals for Medical Cost Data with Censored Observations

Medical cost analysis is an important part of treatment evaluation. Since resources are limited in society, it is important new treatments are developed with proper costconsiderations. The mean has been mostly accepted as a measure of the medical cost analysis. However, it is well known that cost data is highly skewed and the mean could be highly influenced by outliers. Therefore, in many situations the mean cost alone cannot offer complete information about medical costs. The quantiles (e.g., the first quartile, median and third quartile) of medical costs could better represent the typical costs paid by a group of individuals, and could provide additional information beyond mean cost. For a specified patient population, cost estimates are generally determined from the beginning of treatments until death or end of the study period. A number of statistical methods have been proposed to estimate medical cost. Since medical cost data are skewed to the right, normal approximation based confidence intervals can have much lower coverage probability than the desired nominal level when the cost data are moderately or severely skewed. Additionally, we note that the variance estimators of the cost estimates are analytically complicated. In order to address some of the above issues, in the first part of the dissertation we propose two empirical likelihood-based confidence intervals for the mean medical costs: One is an empirical likelihood interval (ELI) based on influence function, the other is a jackknife empirical likelihood (JEL) based interval. We prove that under very general conditions, −2log (empirical likelihood ratio) has an asymptotic standard chi squared distribution with one degree of freedom for mean medical cost. Also we show that the log-jackknife empirical likelihood ratio statistics follow standard χ2 distribution with one degree of freedom for mean medical cost. In the second part of the dissertation, we propose an influence function-based empirical likelihood method to construct a confidence region for the vector of regression parameters in mean cost regression models with censored data. The proposed confidence region can be used to obtain a confidence interval for the expected total cost of a patient with given covariates. The new method has sound asymptotic property (Wilks Theorem). In the third part of the dissertation we propose empirical likelihood method based on influence function to construct confidence intervals for quantile medical costs with censored data. We prove that under very general conditions, −2log (empirical likelihood ratio) has an asymptotic standard chi squared distribution with one degree of freedom for quantile medical cost. Simulation studies are conducted to compare coverage probabilities and interval lengths of the proposed confidence intervals with the existing confidence intervals. The proposed methods are observed to have better finite sample performances than existing methods. The new methods are also illustrated through a real example

Modeling Endoscopic Improvement after Induction Treatment With Mesalamine in Patients With Mild-to-Moderate Ulcerative Colitis

Background & Aims: Endoscopic improvement is an important treatment target for mild-to-moderate ulcerative colitis (UC). However, early endoscopic evaluation is not always feasible. We aimed to develop a clinical decision support tool to discriminate patients who have achieved endoscopic improvement from those with more severe inflammation following mesalamine induction therapy. Methods: We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 726 adults with mild-to-moderate UC treated with mesalamine. Multivariable logistic regression modeling determined associations between candidate variables and endoscopic improvement (Mayo endoscopic subscore=0-1 according to blinded central reading) at Week 8. Internal model validation was performed using bootstrap resampling. A clinical decision support tool was developed to stratify patients into low, intermediate, and high probability groups for endoscopic improvement. Results: Variables associated with endoscopic improvement at Week 8 included 50% reduction in fecal calprotectin from baseline (odds ratio [OR] 2.64, 95% CI:, 1.81, 3.85), reduction in rectal bleeding (OR 1.79 per point reduction, 95% CI: 1.35, 2.39), and improvement in physician global assessment (OR 2.32 per point improvement, 95% CI: 1.88, 2.85). The baseline Geboes score (OR 0.74 per grade, 95% CI: 0.65, 0.85) and prolonged disease duration (OR 0.95 per year, 95% CI: 0.92, 0.98) were negatively associated with endoscopic improvement. This model strongly discriminated endoscopic improvement in the development dataset (area under the curve [AUC] 0.84, 95% CI: 0.81, 0.87) and during validation (AUC 0.83). Conclusions: We developed and validated a clinical decision support tool that has good discriminative performance for induction of endoscopic improvement in patients with mild-to-moderate UC treated with mesalamine. ClinicalTrials.gov Registration: NCT01903252

Evaluation of optimal biopsy location for assessment of histological activity, transcriptomic and immunohistochemical analyses in patients with active Crohn’s disease

Background: The appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown. Aim: To explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells. Methods: Fifty-one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins-6, -8 and -23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase-positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient. Results: Histological disease activity scores (P < 0.0001), proinflammatory gene expression levels (P < 0.005) and numbers of myeloperoxidase-positive cells (P < 0.0001) were highest in biopsies from the ulcer edge in the colon and ileum, with decreasing gradients observed with distance from the edge (P < 0.05). No differences between colonic and ileal samples were detected for the parameters measured at any location. Conclusions: Biopsies from the ulcer edge in patients with Crohn's disease yielded the greatest histological disease activity and mRNA levels and had similar readouts in the colon and ileum. Research is needed to confirm this conclusion for other measures

Lower Plasma Magnesium, Measured by Nuclear Magnetic Resonance Spectroscopy, is Associated with Increased Risk of Developing Type 2 Diabetes Mellitus in Women: Results from a Dutch Prospective Cohort Study

Background: Low circulating magnesium (Mg) is associated with an increased risk of developing type 2 diabetes mellitus (T2DM). We aimed to study the performance of a nuclear magnetic resonance (NMR)-based assay that quantifies ionized Mg in EDTA plasma samples and prospectively investigate the association of Mg with the risk of T2DM. Methods: The analytic performance of an NMR-based assay for measuring plasma Mg was evaluated. We studied 5747 subjects free of T2DM at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Results: Passing&#8315;Bablok regression analysis, comparing NMR-measured ionized Mg with total Mg measured by the Roche colorimetric assay, produced a correlation of r = 0.90, with a slope of 1.08 (95% CI: 1.00&#8315;1.13) and an intercept of 0.02 (95% CI: &#8722;0.02&#8315;0.08). During a median follow-up period of 11.2 (IQR: 7.7&#8315;12.0) years, 289 (5.0%) participants developed T2DM. The association of NMR-measured ionized Mg with T2DM risk was modified by sex (Pinteraction = 0.007). In women, we found an inverse association between Mg and the risk of developing T2DM, independent of adjustment for potential confounders (HR: 1.80; 95% CI: 1.20&#8315;2.70). In men, we found no association between Mg and the risk of developing T2DM (HR: 0.90; 95%: 0.67&#8315;1.21). Conclusion: Lower NMR-measured plasma ionized Mg was independently associated with a higher risk of developing T2DM in women, but not in men

Centrally Determined Standardization of Flow Cytometry Methods Reduces Interlaboratory Variation in a Prospective Multicenter Study

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Centrally Determined Standardization of Flow Cytometry Methods Reduces Interlaboratory Variation in a Prospective Multicenter Study

OBJECTIVES: Flow cytometry (FC) aids in characterization of cellular and molecular factors involved in pathologic immune responses. Although FC has potential to facilitate early drug development in inflammatory bowel disease, interlaboratory variability limits its use in multicenter trials. Standardization of methods may address this limitation. We compared variability in FC-aided quantitation of T-cell responses across international laboratories using three analytical strategies. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from three healthy donors, stimulated with phorbol 12-myristate 13-acetate and ionomycin at a central laboratory, fixed, frozen, and shipped to seven international laboratories. Permeabilization and staining was performed in triplicate at each laboratory using a common protocol and centrally provided reagents. Gating was performed using local gating with a local strategy (LGLS), local gating with a central strategy (LGCS), and central gating (CG). Median cell percentages were calculated across triplicates and donors, and reported for each condition and strategy. The coefficient of variation (CV) was calculated across laboratories. Between-strategy comparisons were made using a two-way analysis of variance adjusting for donor. RESULTS: Mean interlaboratory CV ranged from 1.8 to 102.1% depending on cell population and gating strategy (LGLS, 4.4-102.1%; LGCS, 10.9-65.6%; CG, 1.8-20.9%). Mean interlaboratory CV differed significantly across strategies and was consistently lower with CG. CONCLUSIONS: Central gating was the only strategy with mean CVs consistently lower than 25%, which is a proposed standard for pharmacodynamic and exploratory biomarker assay

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo