Statistical learning in preclinical drug proarrhythmic assessment.

Torsades de pointes (TdP) is an irregular heart rhythm characterized by faster beat rates and potentially could lead to sudden cardiac death. Much effort has been invested in understanding the drug-induced TdP in preclinical studies. However, a comprehensive statistical learning framework that can accurately predict the drug-induced TdP risk from preclinical data is still lacking.

Repolarization studies using human stem cell-derived cardiomyocytes: Validation studies and best practice recommendations.

Human stem cell-derived cardiomyocytes (hSC-CMs) hold great promise as in vitro models to study the electrophysiological effects of novel drug candidates on human ventricular repolarization. Two recent large validation studies have demonstrated the ability of hSC-CMs to detect drug-induced delayed repolarization and "cellrhythmias" (interrupted repolarization or irregular spontaneous beating of myocytes) linked to Torsade-de-Pointes proarrhythmic risk. These (and other) studies have also revealed variability of electrophysiological responses attributable to differences in experimental approaches and experimenter, protocols, technology platforms used, and pharmacologic sensitivity of different human-derived models.

Assessment of Proarrhythmic Potential of Drugs in Optogenetically Paced Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Cardiac side-effects are one of the major reasons for failure of drugs during preclinical development. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been proposed as a model for predicting drug-induced arrhythmias under the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Field potential duration (FPD) in spontaneously beating iPSC-CMs is commonly corrected for beating rate using formulas originally derived from the clinical QT-RR relationship that have not been thoroughly validated for use with iPSC-CMs.

Assay sensitivity in "Hybrid thorough QT/QTc (TQT)" study.

A concurrent positive control should be included in a thorough QTc clinical trial to validate the study according to ICH E14 guidance. Some pharmaceutical companies have started to use "hybrid TQT" study to meet ICH E14 regulatory requirements since the release of ICH E14 Q&A (R3). The "hybrid TQT" study includes the same treatment arms (therapeutic and/or supratherapeutic dose of investigational drug, placebo, and positive control) with sample size less than traditional TQT studies, but use concentration-QTc (C-QTc) analysis as primary analysis and assay sensitivity analysis.

International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment.

To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated the concentration dependence and sources of variability of electrophysiologic responses to 28 drugs linked to low, intermediate, and high torsades de pointes (TdP) risk categories using two commercial cell lines and standardized protocols in a blinded multisite study using multielectrode array or voltage-sensing optical approaches. Logistical and ordinal linear regression models were constructed using drug responses as predictors and TdP risk categories as outcomes. Three of seven predictors (drug-induced arrhythmia-like events and prolongation of repolarization at either maximum tested or maximal clinical exposures) categorized drugs with reasonable accuracy (area under the curve values of receiver operator curves ∼0.

Evaluation of dependent variable, time effect, covariates, and covariation structure in concentration-QTc modeling: A simulation study.

The revised ICH E14 Question and Answer (R3) document issued in December 2015 enables pharmaceutical companies to use concentration-QTc (C-QTc) modeling as the primary analysis for assessing QTc prolongation risk of new drugs. A new approach by including the time effect into the current C-QTc model is introduced. Through a simulation study, we evaluated performances of different C-QTc modeling with different dependent variables, covariates, and covariance structures.

Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays: Results from a Blinded CiPA Pilot Study.

Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC-CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies).

Correction to: Scientific white paper on concentration-QTc modeling.

The original version of this article unfortunately contained an error in Equation 1 under the section "Pre-specified linear mixed effects model". The correct equation has given below.

Scientific white paper on concentration-QTc modeling.

The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies.

Baseline correction in parallel thorough QT studies.

Background: In parallel thorough QT (TQT) studies, it has been speculated that either baseline correction should be omitted, under the assumption that it only adds noise to the data, or a time-averaged baseline instead of a time-matched baseline correction should be considered in order to reduce the study variability.

Objective: This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review.

Data And Methods: 57 parallel TQT studies conducted between 2002 and 2009 in 5591 healthy volunteers were evaluated.

Validation of QT Interval Correction Methods When a Drug Changes Heart Rate.

The QT interval is correlated with heart rate; therefore, the QT interval is usually corrected by heart rate when drug-induced QT effect is studied. Currently, there are many correction methods that use either fixed or data-driven approaches. The effectiveness of correction methods depends on many factors and varies from study to study.

Statistical characteristics of moxifloxacin-induced QTc effect.

Moxifloxacin has been the most commonly used positive control in "thorough" QTc (TQT) studies. In a TQT study, the assay sensitivity is often considered to be established if the baseline corrected mean difference in QTc between moxifloxacin and placebo is greater than 5 ms in common practice at one or more prespecified time points and the observed moxifloxacin induced QTc effect over time follows the proper pharmacokinetics profile. To better understand the statistical characteristics of moxifloxacin-induced QTc prolongation and to provide guidance for future studies, 20 TQT studies that involved moxifloxacin have been evaluated.

Comparison of sleep/wake behavior in CKD stages 4 to 5 and hemodialysis populations using wrist actigraphy.

Background: Patients with kidney failure have more sleep symptoms than the general population, but the contribution to sleep symptoms of kidney failure versus its treatment with thrice-weekly hemodialysis has been unclear. We assessed the influence of hemodialysis on sleep/wake behavior by using wrist actigraphy and self-reported sleep quality compared with patients with chronic kidney disease (CKD) stages 4 to 5.

Study Design: Cross-sectional study.

Pulmonary embolism incidence is increasing with use of spiral computed tomography.

Background: Pulmonary embolism causes significant morbidity in hospitalized patients, yet few studies have explored the impact of spiral computed tomography (CT) scanning on diagnosis and clinical outcome.

Methods: Incidence rates of pulmonary embolism, chest and spiral CT rates, D-dimer assay, anticoagulation, and in-hospital mortality were assessed on statewide pulmonary embolism discharge data (1997-2001) from the Pennsylvania Health Care Cost Containment Council.

Results: The incidence of pulmonary embolism increased from 47 to 63 per 100,000 patients from 1997 to 2001 (mean of 0.

Sample size and power calculations based on generalized linear mixed models with correlated binary outcomes.

The generalized linear mixed model (GLIMMIX) provides a powerful technique to model correlated outcomes with different types of distributions. The model can now be easily implemented with SAS PROC GLIMMIX in version 9.1.

The 8-item Short-Form Health Survey and the physical comfort composite score of the quality of recovery 40-item scale provide the most responsive assessments of pain, physical function, and mental function during the first 4 days after ambulatory knee surgery with regional anesthesia.

Background: We evaluated the validity and responsiveness of three instruments: the numeric rating scale (NRS) pain score, the 8-item Short-Form Health Survey (SF-8), and the 40-item Quality of Recovery from Anesthesia (QoR) Survey in 154 outpatients undergoing anterior cruciate ligament reconstruction (ACLR). The objective was to provide a robust psychometric basis for outcome survey selection for surgical outpatients undergoing regional anesthesia without general anesthesia.

Methods: Patients undergoing ACLR with a standardized spinal anesthesia plan were randomized to receive a perineural catheter with either placebo injection-infusion, or injection-infusion with levobupivacaine.

Daily smoking patterns, their determinants, and implications for quitting.

In this article, the authors examine daily temporal patterns of smoking in relation to environmental restrictions on smoking and cessation outcomes. Time-series methods were used for analyzing cycles in 351 smokers who monitored their smoking in real time for 2 weeks. The waking day was divided into 8 "bins" of approximately 2 hr, cigarette counts were tallied for each bin, and temporal patterns of smoking and restriction were analyzed.

Religious beliefs and practices are associated with better mental health in family caregivers of patients with dementia: findings from the REACH study.

Objective: Providing care to a loved one with dementia and the death of that loved one are generally considered two of the most stressful human experiences. Each puts family caregivers at risk of psychologic morbidity. Although research has suggested that religious beliefs and practices are associated with better mental health, little is known about whether religion is associated with better mental health in family caregivers.

Preparedness for the death of a loved one and mental health in bereaved caregivers of patients with dementia: findings from the REACH study.

Background: Although it has been suggested that family and friends who are prepared for the death of a loved one have less distress, the relationship between preparedness and bereavement mental health is inconclusive.

Objectives: To determine the relationship between preparedness for the death and mental health in bereaved caregivers of dementia patients and explore predictors of preparedness.

Design: A prospective study of family caregivers of persons with dementia.

Analyzing milestones in smoking cessation: illustration in a nicotine patch trial in adult smokers.

Tests of addiction treatments seldom reveal where treatment exercises its effect (i.e., promoting initial abstinence, preventing lapses, and/or impeding progression from lapse to relapse).

Relationship of communication and information measures to colorectal cancer screening utilization: results from HINTS.

Utilization of colorectal cancer screening tests is suboptimal. Knowledge of colorectal cancer screening has been associated with completion of screening. Thus, increasing awareness of colorectal cancer screening may lead to significant improvements in screening rates.

Using trajectories from a bivariate growth curve as predictors in a Cox regression model.

An important research objective in most psychiatric clinical trials of maintenance treatment is to find predictors of recurrence of illness. In those trials, patients are first admitted into an open treatment period also called acute treatment. If they respond to the treatment and are considered to have stable remission from the illness, they enter the second phase of the trial where they are randomized into different arms of the 'maintenance treatments'.

Trypsin and splanchnic protein turnover during feeding and fasting in human subjects.

Knowledge of the stimulatory effects of enteral and parenteral (intravenous) feeding on the synthesis and turnover of trypsin would help in the management of acute pancreatitis, because the disease is caused by the premature activation of trypsin. To investigate this, we labeled intravenous infusions with [1-(13)C]leucine and enterals with [(2)H]leucine and measured isotope enrichment of plasma, secreted trypsin, and duodenal mucosal proteins over 6 h by duodenal perfusion/aspiration and endoscopic biopsy. Thirty healthy volunteers were studied during fasting (n = 7), intravenous feeding (n = 6), or postpyloric enteral feeding [duodenal polymeric (n = 6), elemental duodenal (n = 6), and jejunal elemental (n = 5)].

Immediate antecedents of cigarette smoking: an analysis of unrestricted smoking patterns.

Theory suggests that cigarette smoking is under stimulus control and that affect is a key trigger for smoking. A previous study (S. Shiftman et al.