Application of Targeted Maximum Likelihood Estimation in Public Health and Epidemiological Studies: a Systematic Review

Purpose: The targeted maximum likelihood estimation (TMLE) statistical data analysis framework integrates machine learning, statistical theory, and statistical inference to provide a least biased, efficient, and robust strategy for estimation and inference of a variety of statistical and causal parameters. We describe and evaluate the epidemiological applications that have benefited from recent methodological developments.Methods: We conducted a systematic literature review in PubMed for articles that applied any form of TMLE in observational studies. We summarized the epidemiological discipline, geographical location, expertize of the authors, and TMLE methods over time. We used the Roadmap of Targeted Learning and Causal Inference to extract key methodological aspects of the publications. We showcase the contributions to the literature of these TMLE results. Results: Of the 89 publications included, 33% originated from the University of California at Berkeley, where the framework was first developed by Professor Mark van der Laan. By 2022, 59% of the publications originated from outside the United States and explored up to seven different epidemiological disciplines in 2021-2022. Double-robustness, bias reduction, and model misspecification were the main motivations that drew researchers toward the TMLE framework. Through time, a wide variety of methodological, tutorial, and software-specific articles were cited, owing to the constant growth of methodological developments around TMLE. Conclusions: There is a clear dissemination trend of the TMLE framework to various epidemiological disciplines and to increasing numbers of geographical areas. The availability of R packages, publication of tutorial papers, and involvement of methodological experts in applied publications have contributed to an exponential increase in the number of studies that understood the benefits and adoption of TMLE.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).