A Partially Randomized Patient Preference, Sequential, Multiple-Assignment, Randomized Trial Design Analyzed via Weighted and Replicated Frequentist and Bayesian Methods.

Results from randomized control trials (RCTs) may not be representative when individuals refuse to be randomized or are excluded for having a preference for which treatment they receive. If trial designs do not allow for participant treatment preferences, trials can suffer in accrual, adherence, retention, and external validity of results. Thus, there is interest surrounding clinical trial designs that incorporate participant treatment preferences.

JOINT MODELING OF MULTISTATE AND NONPARAMETRIC MULTIVARIATE LONGITUDINAL DATA.

It is oftentimes the case in studies of disease progression that subjects can move into one of several disease states of interest. Multistate models are an indispensable tool to analyze data from such studies. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational study of at-risk children from birth to onset of type-1 diabetes (T1D) up through the age of 15.

The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study.

Context: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty.

Objective: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes.

Methods: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort.

Background/objective: Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI.

Research Design And Methods: Genetically at-risk children ( = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually.

Power prior models for estimating response rates in a small n, sequential, multiple assignment, randomized trial.

A small n, sequential, multiple assignment, randomized trial (snSMART) is a small sample, two-stage design where participants receive up to two treatments sequentially, but the second treatment depends on response to the first treatment. The parameters of interest in an snSMART are the first-stage response rates of the treatments, but outcomes from both stages can be used to obtain more information from a small sample. A novel way to incorporate the outcomes from both stages uses power prior models, in which first stage outcomes from an snSMART are regarded as the primary (internal) data and second stage outcomes are regarded as supplemental data (co-data).

HbA1c as a time predictive biomarker for an additional islet autoantibody and type 1 diabetes in seroconverted TEDDY children.

Objective: Increased level of glycated hemoglobin (HbA1c) is associated with type 1 diabetes onset that in turn is preceded by one to several autoantibodies against the pancreatic islet beta cell autoantigens; insulin (IA), glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8). The risk for type 1 diabetes diagnosis increases by autoantibody number. Biomarkers predicting the development of a second or a subsequent autoantibody and type 1 diabetes are needed to predict disease stages and improve secondary prevention trials.

The association of physical activity to oral glucose tolerance test outcomes in multiple autoantibody positive children: The TEDDY Study.

Objective: To examine the association of physical activity (PA), measured by accelerometry, to hemoglobin AIC (HbA1c) and oral glucose tolerance test (OGTT) outcomes in children who were multiple persistent confirmed autoantibody positive for type 1 diabetes (T1D).

Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) multinational study followed children from birth. Children ≥3 years of age who were multiple persistent confirmed autoantibody positive were monitored by OGTTs every 6 months.

Maternal food consumption during late pregnancy and offspring risk of islet autoimmunity and type 1 diabetes.

Aims/hypothesis: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Methods: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n = 8556). A questionnaire on the mother's diet in late pregnancy was completed by 3-4 months postpartum.

Bayesian methods to compare dose levels with placebo in a small n, sequential, multiple assignment, randomized trial.

Clinical trials studying treatments for rare diseases are challenging to design and conduct due to the limited number of patients eligible for the trial. One design used to address this challenge is the small n, sequential, multiple assignment, randomized trial (snSMART). We propose a new snSMART design that investigates the response rates of a drug tested at a low and high dose compared with placebo.

Adherence to oral glucose tolerance testing in children in stage 1 of type 1 diabetes: The TEDDY study.

Objective: To examine adherence to the oral glucose tolerance test (OGTT) in multiple islet autoantibody children in stage 1 of developing type 1 diabetes (T1D).

Methods: Children are followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Completion of an OGTT is recommended every 6 months in children ≥3 years of age who are multiple islet autoantibody positive.

Genetic Subtype-Phenotype Analysis of Growth Hormone Treatment on Psychiatric Behavior in Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a complex multisystemic condition caused by a lack of paternal expression of imprinted genes from the 15q11.2-q13 region. Limited literature exists on the association between molecular classes, growth hormone use, and the prevalence of psychiatric phenotypes in PWS.

Design and analysis considerations for utilizing a mapping function in a small sample, sequential, multiple assignment, randomized trials with continuous outcomes.

Small sample, sequential, multiple assignment, randomized trials (snSMARTs) are multistage trials with the overall goal of determining the best treatment after a fixed amount of time. In snSMART trials, patients are first randomized to one of three treatments and a binary (e.g.

Sample size determination for Bayesian analysis of small n sequential, multiple assignment, randomized trials (snSMARTs) with three agents.

The small n, Sequential, Multiple Assignment, Randomized Trial (snSMART) is a two-stage clinical trial design for rare diseases motivated by the comparison of three active treatments for isolated skin vasculitis in the ongoing clinical trial ARAMIS (a randomized multicenter study for isolated skin vasculitis, NCT09239573). In Stage 1, all patients are randomized to one of three treatments. In Stage 2, patients who respond to their initial treatment receive the same treatment again, while those who fail to respond are re-randomized to one of the two remaining treatments.

Protocol for a randomized multicenter study for isolated skin vasculitis (ARAMIS) comparing the efficacy of three drugs: azathioprine, colchicine, and dapsone.

Background: Skin-limited forms of vasculitis, while lacking systemic manifestations, can persist or recur indefinitely, cause pain, itch, or ulceration, and be complicated by infection or scarring. High-quality evidence on how to treat these conditions is lacking. The aim of this comparative effectiveness study is to determine the optimal management of patients with chronic skin-limited vasculitis.

Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities.

Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS.

Birth seasonality studies in a large Prader-Willi syndrome cohort.

Prader-Willi syndrome (PWS) is generally due to sporadic paternal deletions of the chromosome 15q11-q13 region followed by maternal disomy 15. Advanced maternal age is more commonly seen in those with maternal disomy 15. Environmental factors (e.

Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer.

Background: Trastuzumab is highly effective for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer but is associated with a decline in left ventricular ejection fraction.

Objectives: The purpose of this study was to determine whether angiotensin-converting enzyme inhibitors or beta-blockers reduce the rate of trastuzumab-induced cardiotoxicity (left ventricular ejection fraction decrease >10%, or >5% if below 50%) and limit treatment interruptions.

Methods: In this double-blind, multicenter, placebo-controlled trial, cardiotoxicity and treatment interruptions in patients with HER2-positive breast cancer treated with trastuzumab for 12 months were evaluated over a 2-year period.

Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children.

Objective: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Methods: Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data.

Risk factors for chemotherapy-induced nausea in pediatric patients receiving highly emetogenic chemotherapy.

Background: Little is known regarding risk factors for chemotherapy-induced nausea (CIN) in pediatric patients.

Procedure: A secondary analysis was conducted of a previously published multicenter, prospective, randomized, single-blind, sham-controlled trial assessing the efficacy of acupressure in preventing CIN in pediatric patients receiving highly emetogenic chemotherapy. The primary outcome was nausea severity, self-reported using the Pediatric Nausea Assessment Tool.

Maternal dietary supplement use and development of islet autoimmunity in the offspring: TEDDY study.

Objective: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring.

Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the United States. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA.

A Bayesian analysis of small n sequential multiple assignment randomized trials (snSMARTs).

Designing clinical trials to study treatments for rare diseases is challenging because of the limited number of available patients. A suggested design is known as the small n sequential multiple assignment randomized trial (snSMART), in which patients are first randomized to one of multiple treatments (stage 1). Patients who respond to their initial treatment continue the same treatment for another stage, while those who fail to respond are rerandomized to one of the remaining treatments (stage 2).

Thyroid function in the etiology of fatigue in breast cancer.

Background: Cancer related fatigue (CRF), reported in about 90% of breast cancer patients receiving chemotherapy, and has a profound impact on physical function, psychological distress and quality of life. Although several etiological factors such as anemia, depression, chronic inflammation, neurological pathology and alterations in metabolism have been proposed, the mechanisms of CRF are largely unknown.

Methods: We conducted a pilot, prospective, case-control study to estimate the magnitude of change in thyroid function in breast cancer patients from baseline to 24 months, compared to cancer-free, age-matched controls.

Multicentre study of maternal and neonatal outcomes in individuals with Prader-Willi syndrome.

Introduction: Prader-Willi syndrome (PWS) is a complex genetic disorder associated with three different genetic subtypes: deletion of the paternal copy of 15q11-q13, maternal UPD for chromosome 15 and imprinting defect. Patients are typically diagnosed because of neonatal hypotonia, dysmorphism and feeding difficulties; however, data on the prenatal features of PWS are limited.

Objective: The aim of the study was to identify and compare frequencies of prenatal and neonatal clinical features of PWS among the three genetic subtypes.