Christina Rabe | Searcharxiv

arXiv2026

Improving Variance Estimation for Covariate Adjustment with Binary Outcomes

Covariate adjustment is a general method for improving precision when estimating treatment effects in randomized trials and is recommended by the FDA in its 2023 guidance when baseline variables are prognostic for the primary outcome. We focus on a method highlighted in that guidance called ``standardization" (or ``g-computation") for estimating the marginal treatment effect. We address the question of how to reliably estimate variance for binary outcomes when marginal outcome probabilities are close to 0 or 1. We propose an influence function-based leave-one-out cross-validated (IF-LOO) variance estimator for the standardized difference-in-means average treatment effect. Through simulation studies, we show that this estimator provides appropriate type-I error control and performs reliably in challenging settings where existing methods can yield inflated type-I error or fail entirely, such as when outcome events are rare or sample sizes are small. In addition to having desirable statistical properties, we derive a closed-form expression for the proposed estimator, enabling straightforward and reliable implementation by study statisticians. The robust finite-sample performance and ease of implementation suggest the IF-LOO variance estimator is a prudent default choice for standardization in clinical trials.

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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.

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