arXiv subjects

Franklin Fuller

Publications and source records attributed to Franklin Fuller.

3 recordsLinked to original sources

arXiv2026

FRESH: Information-Geometric Calibration of Patient-Level Models to Aggregate Evidence

This note introduces FRESH (Fusion of Recent Evidence and Subject Histories), a method for incorporating population-level summary results -- published clinical trials, registry summaries, prior natural-history studies, and peer-reviewed indirect comparisons -- into predictive models trained on patient-level data. This method provides a principled means of combining both patient-level and aggregate-level data types into a unified data-efficient model for clinical decision making. FRESH assumes access to a generative model trained on patient-level data sources (e.g. clinical trial or real-world data). The method produces patient-level predictions from a re-calibrated model that matches a set of specified aggregate statistics for a target population. This can be understood as a patient-level recapitulation of the aggregate source -- with the key property that the recalibration is a minimal perturbation of the original joint distribution in a specific information-geometric sense. The resulting samples can be analyzed directly or combined into a post-training procedure to update the original generative model. This approach enables several applications where rigorously incorporating patient-level data with summary information is valuable, including (i) contextualizing single-arm trial results with respect to recent standard-of-care, (ii) clinical-trial simulations for design and probability-of-technical-success estimation, and (iii) comparative-effectiveness analyses of on-market therapies.

stat.ME↗

arXiv2026

Digital Twins as Synthetic Controls in Single-Arm Trials

Single-arm trials are an important study design for evaluating drug efficacy and safety without enrolling patients into a control arm. Although they do not provide the gold-standard evidence of randomized controlled trials, they are increasingly used in clinical development as they offer an efficient, ethical, and practical alternative. A wide variety of approaches can be used to construct control comparators and estimate treatment effects, from fixed comparators informed by clinical knowledge to data-based and model-based patient-level comparators, also known as synthetic controls. Powerful and flexible machine learning models can allow outcome-model-based synthetic controls to overcome key limitations of direct data-based approaches, yield more robust estimates of treatment effects, and provide a principled way to incorporate corrections or encode additional assumptions when external data are not directly comparable. In this work, we argue that outcome-model-based synthetic control arms are an important tool for single-arm trials. We focus on digital twins, personalized predictions of disease progression generated from machine learning models trained on historical datasets, which naturally leverage these flexible approaches. We review doubly robust estimators, present power and sample size formulas, and discuss trade-offs in selecting historical data for training and analysis. We also outline practical considerations for deploying digital twins within the framework of recent FDA draft guidance on the use of artificial intelligence in drug development. Finally, we reanalyze data from trials in amyotrophic lateral sclerosis and Huntington's disease to demonstrate the proposed methods.

stat.AP↗

arXiv2024

Digital Twin Generators for Disease Modeling

A patient's digital twin is a computational model that describes the evolution of their health over time. Digital twins have the potential to revolutionize medicine by enabling individual-level computer simulations of human health, which can be used to conduct more efficient clinical trials or to recommend personalized treatment options. Due to the overwhelming complexity of human biology, machine learning approaches that leverage large datasets of historical patients' longitudinal health records to generate patients' digital twins are more tractable than potential mechanistic models. In this manuscript, we describe a neural network architecture that can learn conditional generative models of clinical trajectories, which we call Digital Twin Generators (DTGs), that can create digital twins of individual patients. We show that the same neural network architecture can be trained to generate accurate digital twins for patients across 13 different indications simply by changing the training set and tuning hyperparameters. By introducing a general purpose architecture, we aim to unlock the ability to scale machine learning approaches to larger datasets and across more indications so that a digital twin could be created for any patient in the world.

cs.LG↗