Targeted Machine Learning to evaluate and optimize HIV prevention strategies in cluster randomized trials

/ABSTRACT Globally, there were 1.3 million new HIV infections in 2023, despite expanded access to biomedical HIV prevention products with high efficacy. Implementation strategies are needed to expand the reach of HIV risk screening and to facilitate the use of biomedical prevention among persons with risk. These implementation strategies are often delivered at the group-level or induce changes at the group-level (e.g., health clinics or health systems). Cluster randomized trials (CRTs) are integral to evaluating and optimizing strategies deployed at the group-level. CRTs provide an exciting opportunity to evaluate strategies aiming to both improve reach into the target population and health outcomes among persons reached. However, these CRTs create a complex missing data problem: the strategy improves outcomes directly and indirectly; yet, outcomes are only measured among persons reached. While machine learning can facilitate adjustment for missing data in simpler CRT settings, new methods are needed to minimize bias arising from this common CRT setting. CRTs also provide an exciting opportunity for intervention optimization by evaluating for whom and in what context the strategy works best. However, existing methods to evaluate effect heterogeneity in CRTs are prone to false conclusions (i.e., Type-I and Type-II errors). While machine learning can facilitate data-driven evaluation of effect modification in individually randomized trials, CRTs present distinct challenges due to their small effective sample sizes. In this proposal, we will address these crucial gaps in the analysis of CRTs. To do so, we will develop, apply, and disseminate new Targeted Machine Learning Estimators (TMLEs) to minimize bias due to missing data and to facilitate data-driven evaluation of effect modification. TMLE combines formal causal modeling, statistical theory, and machine learning to improve the accuracy, precision, and relevance of our findings. This proposal has the following aims. We will develop new TMLEs to minimize bias due to missing data and robustly evaluate overall effectiveness in CRTs of strategies that aim to improve both reach and health outcomes (Aim 1A). We will combine these TMLEs with novel sample-splitting and multiple testing procedures to data-adaptively identify and evaluate effect heterogeneity at multiple levels (Aim 1B). In secondary data analyses of two CRTs, we apply the proposed methods to generate new insights about the effectiveness and implementation of an HIV prevention strategy when offered at scale and when adapted to a new context (Aim 2). We will disseminate the proposed methods through a user-friendly and interactive website – facilitating the rigorous and reproducible use of our new methods (Aim 3). This work is timely and significant given the role of CRTs in evaluating and optimizing strategies to prevent HIV and other chronic conditions, such as hypertension, diabetes, and cardiovascular disease. Project Number: 1R01MH140685-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Laura Balzer | Institution: UNIVERSITY OF CALIFORNIA BERKELEY, BERKELEY, CA | Award Amount: $759,816 | Activity Code: R01 | Study Section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH] View on NIH RePORTER: https://reporter.nih.gov/project-details/11328733