arXiv subjects

Michael C. Donohue

Publications and source records attributed to Michael C. Donohue.

6 recordsLinked to original sources

arXiv2025

Alzheimer's Clinical Research Data via R Packages: the alzverse

Sharing clinical research data is essential for advancing research in Alzheimer's disease (AD) and other therapeutic areas. However, challenges in data accessibility, standardization, documentation, usability, and reproducibility continue to impede this goal. In this article, we highlight the advantages of using R packages to overcome these challenges using two examples. The A4LEARN R package includes data from a randomized trial (the Anti-Amyloid Treatment in Asymptomatic Alzheimer's [A4] study) and its companion observational study of biomarker negative individuals (the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study). The ADNIMERGE2 R package includes data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal observational biomarker and imaging study. These packages collect data, documentation, and reproducible analysis vignettes into a portable bundle that can be installed and browsed within commonly used R programming environments. We also introduce the alzverse package which leverages a common data standard to combine study-specific data packages to facilitate meta-analyses. By promoting collaboration, transparency, and reproducibility, R data packages can play a vital role in accelerating clinical research.

stat.CO↗

arXiv2025

A critical evaluation of longitudinal proportional effect models

Nonlinear longitudinal proportional effect models have been proposed to improve power and provide direct estimates of the proportional treatment effect in randomized clinical trials. These models assume a fixed proportional treatment effect over time, which can lead to bias and Type I error inflation when the assumption is violated. Even when the proportional effect assumption holds, these models are biased, and their inference is sensitive to the labeling of treatment groups. Typically, this bias favors the active group, inflates Type I error, and can result in one-sided testing. Conversely, the bias can make it more difficult to detect treatment harm, creating a safety concern.

stat.ME↗

arXiv2021

The Alzheimer's Disease Prediction Of Longitudinal Evolution (TADPOLE) Challenge: Results after 1 Year Follow-up

We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of biomarkers. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

q-bio.PE↗

arXiv2019

The relative efficiency of time-to-progression and continuous measures of cognition in pre-symptomatic Alzheimer's

Pre-symptomatic (or Preclinical) Alzheimer's Disease is defined by biomarker evidence of fibrillar amyloid beta pathology in the absence of clinical symptoms. Clinical trials in this early phase of disease are challenging due to the slow rate of disease progression as measured by periodic cognitive performance tests or by transition to a diagnosis of Mild Cognitive Impairment. In a multisite study, experts provide diagnoses by central chart review without the benefit of in-person assessment. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently compared to models of time-to-progression to an endpoint such as change in diagnosis. Multivariate continuous data are simulated from a Bayesian joint mixed effects model fit to data from the Alzheimer's Disease Neuroimaging Initiative. Simulated progression events are algorithmically derived from the continuous assessments using a random forest model fit to the same data. We find that power is approximately doubled with models of repeated continuous outcomes compared to the time-to-progression analysis. The simulations also demonstrate that a plausible informative missing data pattern can induce a bias which inflates treatment effects, yet 5% Type I error is maintained.

stat.AP↗

arXiv2018

Bayesian latent time joint mixed effect models for multicohort longitudinal data

Characterization of long-term disease dynamics, from disease-free to end-stage, is integral to understanding the course of neurodegenerative diseases such as Parkinson's and Alzheimer's; and ultimately, how best to intervene. Natural history studies typically recruit multiple cohorts at different stages of disease and follow them longitudinally for a relatively short period of time. We propose a latent time joint mixed effects model to characterize long-term disease dynamics using this short-term data. Markov chain Monte Carlo methods are proposed for estimation, model selection, and inference. We apply the model to detailed simulation studies and data from the Alzheimer's Disease Neuroimaging Initiative.

stat.AP↗

arXiv2016

Regression of ranked responses when raw responses are censored

We discuss semiparametric regression when only the ranks of responses are observed. The model is $Y_i = F (\mathbf{x}_i'{\boldsymbolβ}_0 + \varepsilon_i)$, where $Y_i$ is the unobserved response, $F$ is a monotone increasing function, $\mathbf{x}_i$ is a known $p-$vector of covariates, ${\boldsymbolβ}_0$ is an unknown $p$-vector of interest, and $\varepsilon_i$ is an error term independent of $\mathbf{x}_i$. We observe $\{(\mathbf{x}_i,R_n(Y_i)) : i = 1,\ldots ,n\}$, where $R_n$ is the ordinal rank function. We explore a novel estimator under Gaussian assumptions. We discuss the literature, apply the method to an Alzheimer's disease biomarker, conduct simulation studies, and prove consistency and asymptotic normality.

stat.AP↗