A Diffusion-Model Subpopulation Digital Twin for Mobile Health Deployment: A Case Study on the HeartSteps Intervention

A digital twin (DT) is a virtual model of a real-world system that can assist decision-making by simulating scenarios induced by different policies. However, typical machine learning-based DTs do not optimise for this use case. We prove that, when model capacity is limited, training DTs to minimise one-step transition errors can produce suboptimal models for ranking sets of policies according to a reward function. We further show that this holds empirically, even with expressive model classes. To address this, we introduce $\text{DT}^2$, a decision-targeted DT training paradigm. Firstly, $\text{DT}^2$ uses fitted Q-evaluation to estimate values of candidate policies from offline data. A DT is then trained to generate rollouts that preserve pairwise policy rankings derived from these proxy ground-truth values with an architecture-agnostic loss function. We empirically demonstrate the efficacy of our method across a range of settings and architectures. $\text{DT}^2$ consistently improves policy ranking and reduces decision regret during policy selection relative to conventional DT training, both for policies used during training and for unseen policies, while maintaining a good level of raw simulation fidelity.

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.

We propose a framework for predicting the effects of mobility introduction measures using a human-flow digital twin. This digital twin incorporates a multi-agent simulator that can represent how visitors choose destinations depending on factors such as their current location and the attractiveness of spots. We extract data on how visitors selected destinations with respect to measured pre-intervention human-flow data, inter-spot distances, spot attractiveness, and travel volumes, and use these data to train each agent's decision model of this simulator. The trained decision model is a function that takes a visitor's current state and surrounding environmental information as input and outputs which spot the visitor will move toward next. By expressing mobility introduction measures as changes to inter-point distances or to spot attractiveness, the framework can reproduce human flows with mobility introduction in the multi-agent simulator and thereby quantify effects such as changes in visitor counts and circulation. We evaluated the proposed method using human-flow data measured with and without introducing mobility within Wakayama Castle Park in Japan. When reproducing flows with mobility introduction using a multi-layer perceptron decision model, the cosine similarity of the spatial population distribution exceeded 0.7, confirming that the approach can replicate the flow changes caused by the mobility introduction.