Impacts of informant replacement in two industry-sponsored Alzheimer's disease clinical trials.

Introduction: In Alzheimer's disease (AD) clinical trials, participants must enroll with a study partner informant who completes validated study instruments. We hypothesized that mid-trial informant replacement impacts study data in industry-sponsored trials.

Methods: We conducted a retrospective analysis of two industry-sponsored AD clinical trials testing semagacestat in mild-to-moderate AD dementia.

Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease.

Background And Objectives: Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD).

The utility of recruitment incentives in early Alzheimer's disease trials.

Introduction: Amid recent approvals, early Alzheimer's disease (AD) remains an active area of treatment development.

Methods: We performed a conjoint experiment to compare preferences among 26 patients with mild cognitive impairment for four trial features including designs incorporating active aducanumab-control (vs. placebo), returning tau positron emission tomography (PET) results (vs.

Reasons for undergoing amyloid imaging among diverse enrollees in the A4 study.

Introduction: Understanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment.

Methods: Using data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline.

Study Partner Type and Adverse Event Reporting in Mild-to-Moderate Alzheimer's Disease Clinical Trials.

Background: In randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer's disease (AD) RCTs require participants to enroll with a study partner.

Objective: We examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type.

Post-disclosure distress among racial and ethnic groups in a preclinical AD trial.

Introduction: Trialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials.

Methods: We used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants' responses on the Impact of Event Scale (IES) 24 to 72 hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups.

Effects of informant replacement in Alzheimer's disease clinical trials.

Introduction: Alzheimer's disease (AD) trials require enrollment with an informant.

Methods: We assessed relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS-ADL between successive visits.

Retention of American Indian and Alaska Native participants in the National Alzheimer's Coordinating Center Uniform Data Set.

Introduction: The number of American Indian and Alaska Native (AI/AN) elders is expected to double by 2060. Thus it is imperative to retain AI/AN participants in longitudinal research studies to identify novel risk factors and potential targets for intervention for Alzheimer's disease and related dementias in these communities.

Methods: The National Alzheimer's Coordinating Center houses uniformly collected longitudinal data from the network of National Institute on Aging (NIA)-funded Alzheimer's Disease Research Centers (ADRCs).

Estimating attrition in mild-to-moderate Alzheimer's disease and mild cognitive impairment clinical trials.

Background: Participant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer's disease (AD) is an area of active treatment development.

A generalized interrupted time series model for assessing complex health care interventions.

Assessing the impact of complex interventions on measurable health outcomes is a growing concern in health care and health policy. Interrupted time series (ITS) designs borrow from traditional case-crossover designs and function as quasi-experimental methodology able to retrospectively analyze the impact of an intervention. Statistical models used to analyze ITS designs primarily focus on continuous-valued outcomes.

Frameworks for estimating causal effects in observational settings: comparing confounder adjustment and instrumental variables.

To estimate causal effects, analysts performing observational studies in health settings utilize several strategies to mitigate bias due to confounding by indication. There are two broad classes of approaches for these purposes: use of confounders and instrumental variables (IVs). Because such approaches are largely characterized by untestable assumptions, analysts must operate under an indefinite paradigm that these methods will work imperfectly.

Recruitment across two decades of NIH-funded Alzheimer's disease clinical trials.

Background: Timely accrual of a representative sample is a key factor in whether Alzheimer's disease (AD) clinical trials successfully answer the scientific questions under study. Studies in other fields have observed that, over time, recruitment to trials has become increasingly reliant on larger numbers of sites, with declines in the average per-site recruitment rate. Here, we examined the trends in recruitment over a 20-year period of NIH-funded AD clinical trials conducted by the Alzheimer's Disease Cooperative Study (ADCS), a temporally consistent network of sites devoted to interventional research.

Maternal insulin resistance in pregnancy is associated with fetal fat deposition: findings from a longitudinal study.

Background: Newborns exhibit substantial variation in fat mass accretion over gestation. These individual differences in newborn adiposity extend into infancy and childhood and relate to subsequent risk of obesity and metabolic dysregulation. Maternal glucose homeostasis in pregnancy has been proposed as an underlying mechanism; however, the timing in gestation when maternal glucose regulation influences the progression of fetal fat deposition remain unclear.

Effect of Aducanumab Approval on Willingness to Participate in Preclinical Alzheimer's Disease Trials.

Background: Clinical trials now test promising therapies in the preclinical stages of Alzheimer's disease (AD). Participant willingness to enroll in different types of preclinical AD trials is understudied and whether the FDA approval of aducanumab affected these attitudes is unknown.

Objective: To evaluate preferences toward three preclinical AD trial scenarios and whether the FDA approval of aducanumab changed willingness to participate among potential trial participants.

Strategies Associated with Retaining Participants in the Longitudinal National Alzheimer's Coordinating Center Uniform Data Set Study.

Background: Best approaches for retaining research participants in Alzheimer's disease cohort studies are understudied.

Objective: Using data from the National Alzheimer's Coordinating Center Uniform Data Set, we evaluated the associations of unique strategies with participant retention across Alzheimer's Disease Research Centers and explored potential effect modification by race, ethnicity and diagnostic group.

Methods: We examined retention at the first follow-up visit among participants enrolled during 2015-2017.

Dyadic Enrollment in a Phase 3 Mild Cognitive Impairment Clinical Trial.

Background: Dyadic enrollment of a participant and study partner is required in mild cognitive impairment (MCI) clinical trials, despite participants being functionally independent. Research examining how the study partner requirement impacts MCI trials remains limited.

Methods: Using the Alzheimer's Disease Cooperative Study donepezil and vitamin E MCI trial data, we quantified the proportions of enrolled spouse, adult child, and other dyads.

Post-discharge decolonization of patients harboring methicillin-resistant (MRSA) USA300 strains: secondary analysis of the CLEAR Trial.

The CLEAR Trial recently found that decolonization reduced infections and hospitalizations in MRSA carriers in the year following hospital discharge. In this secondary analysis, we explored whether decolonization had a similar benefit in the subgroup of trial participants who harbored USA300, using two different definitions for the USA300 strain-type.

Censoring-robust time-dependent receiver operating characteristic curve estimators.

Time-dependent receiver operating characteristic curves are often used to evaluate the classification performance of continuous measures when considering time-to-event data. When one is interested in evaluating the predictive performance of multiple covariates, it is common to use the Cox proportional hazards model to obtain risk scores; however, previous work has shown that when the model is mis-specified, the estimand corresponding to the partial likelihood estimator depends on the censoring distribution. In this manuscript, we show that when the risk score model is mis-specified, the AUC will also depend on the censoring distribution, leading to either over- or under-estimation of the risk score's predictive performance.

On the design of early-phase Alzheimer's disease clinical trials with cerebrospinal fluid tau outcomes.

Background/aims: The focus of Alzheimer's disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with "prodromal Alzheimer's disease" to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer's disease dementia. The use of these eligibility criteria may affect study power.

RITS: a toolbox for assessing complex interventions via interrupted time series models.

Background: Various interacting and interdependent components comprise complex interventions. These components create difficulty in assessing the true impact of interventions designed to improve patient-centered outcomes. Interrupted time series (ITS) designs borrow from case-crossover designs and serve as quasi-experimental methodology able to retrospectively assess the impact of an intervention while accounting for temporal correlation.

Reasons for undergoing amyloid imaging among cognitively unimpaired older adults.

Objectives: Preclinical Alzheimer's disease (AD) clinical trials screen cognitively unimpaired older adults for biomarker criteria and disclose their results. We examined whether participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease Study with "elevated" and "not elevated" amyloid differed in scores on the "Views and Perceptions of Amyloid Imaging" questionnaire. We hypothesized that, prior to disclosure, those with elevated amyloid would score higher than those with not elevated amyloid.

Evaluation of the Safety and Efficacy of a Novel Thrombin Containing Combination Hemostatic Powder Using a Historical Control.

This clinical study compares 2 hemostatic agents, a novel combination powder (CP) (HEMOBLAST Bellows) and an established polysaccharide starch powder (PP) (Arista AH) to assess the usefulness of CP. Retrospective comparative analysis of CP (July 2018 to July 2019, 68 patients) to PP (January 2011 to January 2013, 94 patients) in cardiothoracic patients was performed using linear regression models adjusting for age, sex, and procedure type for the endpoints: blood loss; protamine to skin closure time (hemostasis time); chest tube output and blood products required 48 hours postoperatively; ICU stay; postoperative comorbidities; and 30 day mortality. 162 patients (108 M: 54 F) underwent 162 cardiothoracic surgical procedures including: transplantation (n = 44), placement of ventricular assist device (n = 87), and others (n = 31).

The ANTsX ecosystem for quantitative biological and medical imaging.

The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality.

Recruitment and retention of participant and study partner dyads in two multinational Alzheimer's disease registration trials.

Background: Early study exit is detrimental to statistical power and increases the risk for bias in Alzheimer's disease clinical trials. Previous analyses in early phase academic trials demonstrated associations between rates of trial incompletion and participants' study partner type, with participants enrolling with non-spouse study partners being at greater risk.

Methods: We conducted secondary analyses of two multinational phase III trials of semagacestat, an oral gamma secretase inhibitor, for mild-to-moderate AD dementia.

Placental Corticotrophin-Releasing Hormone is a Modulator of Fetal Liver Blood Perfusion.

Context: Variation in fetal liver blood flow influences fetal growth and postnatal body composition. Placental corticotrophin-releasing hormone has been implicated as a key mediator of placental-fetal perfusion.

Objective: To determine whether circulating levels of placental corticotrophin-releasing hormone across gestation are associated with variations in fetal liver blood flow.