Can metformin prevent cancer relative to sulfonylureas? A target trial emulation accounting for competing risks and poor overlap via double/debiased machine learning estimators.

There is mounting interest in the possibility that metformin, indicated for glycemic control in type 2 diabetes, has a range of additional beneficial effects. Randomized trials have shown that metformin prevents adverse cardiovascular events, and metformin use has also been associated with reduced cognitive decline and cancer incidence. In this paper, we dig more deeply into whether metformin prevents cancer by emulating target randomized trials comparing metformin to sulfonylureas as first line diabetes therapy using data from Clinical Practice Research Datalink, a U.K. primary care database (1987-2018). We included individuals with diabetes, no prior cancer diagnosis, no chronic kidney disease, and no prior diabetes therapy who initiated metformin (N=93353) or a sulfonylurea (N=13864). In our cohort, the estimated overlap weighted additive separable direct effect of metformin compared to sulfonylureas on cancer risk at 6 years was -1% (.95 CI=-2.2%, 0.1%), which is consistent with metformin providing no direct protection against cancer incidence or substantial protection. The analysis faced two methodological challenges-poor overlap, and pre-cancer death as a competing risk. To address these issues while minimizing nuisance model misspecification, we develop and apply double/debiased machine learning estimators of overlap weighted separable effects in addition to more traditional effect estimates.

Machine learning in the estimation of causal effects: targeted minimum loss-based estimation and double/debiased machine learning.

In recent decades, the fields of statistical and machine learning have seen a revolution in the development of data-adaptive regression methods that have optimal performance under flexible, sometimes minimal, assumptions on the true regression functions. These developments have impacted all areas of applied and theoretical statistics and have allowed data analysts to avoid the biases incurred under the pervasive practice of parametric model misspecification. In this commentary, I discuss issues around the use of data-adaptive regression in estimation of causal inference parameters. To ground ideas, I focus on two estimation approaches with roots in semi-parametric estimation theory: targeted minimum loss-based estimation (TMLE; van der Laan and Rubin, 2006) and double/debiased machine learning (DML; Chernozhukov and others, 2018). This commentary is not comprehensive, the literature on these topics is rich, and there are many subtleties and developments which I do not address. These two frameworks represent only a small fraction of an increasingly large number of methods for causal inference using machine learning. To my knowledge, they are the only methods grounded in statistical semi-parametric theory that also allow unrestricted use of data-adaptive regression techniques.