Faculty Bibliography

As the world faced the devastation of the COVID-19 pandemic in late 2019 and early 2020, numerous clinical trials were initiated in many locations in an effort to establish the efficacy (or lack thereof) of potential treatments. As the pandemic has been shifting locations rapidly, individual studies have been at risk of failing to meet recruitment targets because of declining numbers of eligible patients with COVID-19 encountered at participating sites. It has become clear that it might take several more COVID-19 surges at the same location to achieve full enrollment and to find answers about what treatments are effective for this disease. This paper proposes an innovative approach for pooling patient-level data from multiple ongoing randomized clinical trials (RCTs) that have not been configured as a network of sites. We present the statistical analysis plan of a prospective individual patient data (IPD) meta-analysis (MA) from ongoing RCTs of convalescent plasma (CP). We employ an adaptive Bayesian approach for continuously monitoring the accumulating pooled data via posterior probabilities for safety, efficacy, and harm. Although we focus on RCTs for CP and address specific challenges related to CP treatment for COVID-19, the proposed framework is generally applicable to pooling data from RCTs for other therapies and disease settings in order to find answers in weeks or months, rather than years.

We consider a single-index regression model, uniquely constrained to estimate interactions between a set of pretreatment covariates and a treatment variable on their effects on a response variable, in the context of analyzing data from randomized clinical trials. We represent interaction effect terms of the model through a set of treatment-specific flexible link functions on a linear combination of the covariates (a single index), subject to the constraint that the expected value given the covariates equals zero, while leaving the main effects of the covariates unspecified. We show that the proposed semiparametric estimator is consistent for the interaction term of the model, and that the efficiency of the estimator can be improved with an augmentation procedure. The proposed single-index regression provides a flexible and interpretable modeling approach to optimizing individualized treatment rules based on patients' data measured at baseline, as illustrated by simulation examples and an application to data from a depression clinical trial. This article is protected by copyright. All rights reserved.

In a regression model for treatment outcome in a randomized clinical trial, a treatment effect modifier is a covariate that has an interaction with the treatment variable, implying that the treatment efficacies vary across values of such a covariate. In this paper, we present a method for determining a composite variable from a set of baseline covariates, that can have a nonlinear association with the treatment outcome, and acts as a composite treatment effect modifier. We introduce a parsimonious generalization of the single-index models that targets the effect of the interaction between the treatment conditions and the vector of covariates on the outcome, a single-index model with multiple-links (SIMML) that estimates a single linear combination of the covariates (i.e., a single-index), with treatment-specific nonparametric link functions. The approach emphasizes a focus on the treatment-by-covariates interaction effects on the treatment outcome that are relevant for making optimal treatment decisions. Asymptotic results for estimator are obtained under possible model misspecification. A treatment decision rule based on the derived single-index is defined, and it is compared to other methods for estimating optimal treatment decision rules. An application to a clinical trial for the treatment of depression is presented.

Differences in motivation during adolescence relative to childhood and adulthood in autism was tested in a cross-sectional study. 156 Typically developing individuals and 79 individuals with autism ages 10-30 years of age completed a go/nogo task with social and non-social cues. To assess age effects, linear and quadratic models were used. Consistent with prior studies, typically developing adolescents and young adults demonstrated more false alarms for positive relative to neutral social cues. In autism, there were no changes in attention across age for social or non-social cues. Findings suggest reduced orienting to motivating cues during late adolescence and early adulthood in autism. The findings provide a unique perspective to explain the challenges for adolescents with autism transitioning to adulthood.

In this paper we propose a unified Bayesian joint modeling framework for studying association between a binary treatment outcome and a baseline matrix-valued predictor. Specifically, a joint modeling approach relating an outcome to a matrix-valued predictor through a probabilistic formulation of multilinear principal component analysis (MPCA) is developed. This framework establishes a theoretical relationship between the outcome and the matrix-valued predictor although the predictor is not explicitly expressed in the model. Simulation studies are provided showing that the proposed method is superior or competitive to other methods, such as a two-stage approach and a classical principal component regression (PCR) in terms of both prediction accuracy and estimation of association; its advantage is most notable when the sample size is small and the dimensionality in the imaging covariate is large. Finally, our proposed joint modeling approach is shown to be a very promising tool in an application exploring the association between baseline EEG data and a favorable response to treatment in a depression treatment study by achieving a substantial improvement in prediction accuracy in comparison to competing methods. This article is protected by copyright. All rights reserved.

Hutson and Vexler (2018) demonstrate an example of aliasing with the beta and normal distribution. This letter presents another illustration of aliasing using the beta and normal distributions via an infinite mixture model, inspired by the problem of modeling placebo response.

This tutorial introduces recent developments in precision medicine for estimating treatment decision rules. The objective of these developments is to advance personalised healthcare by identifying an optimal treatment option for each individual patient based on each patient's characteristics. The methods detailed in this tutorial define composite variables from the patient measures that can be viewed as 'biosignatures' for differential treatment response, which we have termed 'generated effect modifiers'. In contrast to most machine learning approaches to precision medicine, these biosignatures are derived from linear and non-linear regression models and thus have the advantage of easy visualisation and ready interpretation. The methods are illustrated using examples from randomised clinical trials.

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45

Smartphones offer a flexible tool to collect data about mental health, but less is known about their effectiveness as a method to assess variability in children's problem behaviors. Caregivers of children with autism completed daily questions about irritability, anxiety and mood delivered via smartphones across 8-weeks. Smartphone questions were consistent with subscales on standard caregiver questionnaires. Data collection from 7 to 10 days at the beginning and 7 to 10 days at the end of the study were sufficient to capture similar amounts of variance as daily data across 8-weeks. Other significant findings included effects of caregiver socioeconomic status and placebo-like effects from participation even though the study included no specific treatment. Nevertheless, single questions via smartphones collected over relatively brief periods reliably represent subdomains in standardized behavioral questionnaires, thereby decreasing burden on caregivers.

Treatment response heterogeneity poses serious challenges for selecting treatment for many diseases. To better understand this heterogeneity and to help in determining the best patient-specific treatments for a given disease, many clinical trials are collecting large amounts of patient-level data prior to administering treatment in the hope that some of these data can be used to identify moderators of treatment effect. These data can range from simple scalar values to complex functional data such as curves or images. Combining these various types of baseline data to discover "biosignatures" of treatment response is crucial for advancing precision medicine. Motivated by the problem of selecting optimal treatment for subjects with depression based on clinical and neuroimaging data, we present an approach that both (1) identifies covariates associated with differential treatment effect and (2) estimates a treatment decision rule based on these covariates. We focus on settings where there is a potentially large collection of candidate biomarkers consisting of both scalar and functional data. The validity of the proposed approach is justified via extensive simulation experiments and illustrated using data from a placebo-controlled clinical trial investigating antidepressant treatment response in subjects with depression.