Machine learning models for estimating counterfactuals in a single-arm inflammatory bowel disease study
Authors: Dan Liu, Fida K. Dankar, Jennifer C. deBruyn, Amanda Ricciuto, Anne M. Griffiths, Thomas D. Walters, Khaled EI Emam
Organizations: Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada · School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada · Alberta Children’s Hospital, Calgary, Alberta, Canada · University of Calgary, Calgary, Alberta, Canada · University of Toronto, Toronto, Ontario, Canada · Hospital for Sick Children, Toronto, Ontario, Canada
Abstract
Single-arm trials accelerate study timelines by reducing the number of patients that must be recruited for a concurrent control group. However, these designs require an alternative comparator to estimate treatment effects. One approach is to construct a virtual control arm using a machine learning (ML) model trained on external control data to predict the counterfactual outcomes of the treatment arm. Our aim in this study was to leverage virtual controls by developing and evaluating ML-based counterfactual outcome models trained on IFX-treated patients to predict 1-year steroid-free clinical remission (SFCR ) and a composite of C-reactive protein remission plus steroid-free clinical remission (CRP-SFCR) for ADA-treated pediatric Crohn's disease patients, and to compare the resulting IFX-versus-ADA treatment effect estimates with those obtained using propensity score matching to external controls. Five ML models were used to train counterfactual models on the observed IFX cohort data. The resulting models were used to predict the counterfactual outcomes for the ADA arm patients. LGBM yields the best OR closest to the propensity score matched reference, and all 95% CI results align with the conclusion from the reference study that no statistical difference in the primary and secondary outcomes has been observed between the patients treated with ADA or IFX. Our study supports virtual controls as a viable and effective substitute for expensive, lengthy or unethical patient recruitment in an inflammatory bowel disease (IBD) trial. The developed gradient boosted prediction model can be used as a pretrained model to generate IFX counterfactual predictions in future studies, pending external validation and assessment of transportability.
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.
Daniele Bertolini, Franklin Fuller, Aaron M. Smith +2
Generative models for counterfactual outcomes have great potential to support decision-making under complex interventions, but existing approaches are limited by unstable estimation, poor generalization across environments, and bias from nuisance model misspecification. We introduce ADIGen, a framework for automatic, debiased, and invariant counterfactual generation under general interventions, including high-dimensional interventions and outcomes. ADIGen combines Riesz regression to avoid unstable density-ratio estimation, causal invariance to improve generalization under distribution shift, and orthogonal statistical learning to obtain doubly robust guarantees against nuisance model misspecification. We provide excess-risk bounds showing that ADIGen controls counterfactual risk under general interventions, with a product-bias nuisance remainder and an invariant risk bound across environments.
We study counterfactual regression, which maps features to outcomes under hypothetical scenarios that differ from those observed in the data. This problem is central to decision-making under distribution shift, where treatment patterns may change at deployment. We develop a semiparametric framework for counterfactual regression along a prespecified incremental-intervention path. The target is a finite-dimensional constrained projection of counterfactual risk, estimated using cross-fitted influence-function representations of the program components. For smooth programs with fixed constraints and finite-dimensional programs with estimated linear constraints, we establish consistency and local stability of the optimizer under class-specific conditions, and derive pointwise and uniform first-order expansions. These results yield asymptotically valid inference, including simultaneous confidence bands for the counterfactual regression path. Simulations and an application to SMS reminders illustrate the finite-sample performance and practical applicability of the proposed approach.