Comparison of causal forest and regression-based approaches to evaluate treatment effect heterogeneity: an application for type 2 diabetes precision medicine.

OBJECTIVE: Precision medicine requires reliable identification of variation in patient-level outcomes with different available treatments, often termed treatment effect heterogeneity. We aimed to evaluate the comparative utility of individualized treatment selection strategies based on predicted individual-level treatment effects from a causal forest machine learning algorithm and a penalized regression model. METHODS: Cohort study characterizing individual-level glucose-lowering response (6 month reduction in HbA1c) in people with type 2 diabetes initiating SGLT2-inhibitor or DPP4-inhibitor therapy. Model development set comprised 1,428 participants in the CANTATA-D and CANTATA-D2 randomised clinical trials of SGLT2-inhibitors versus DPP4-inhibitors. For external validation, calibration of observed versus predicted differences in HbA1c in patient strata defined by size of predicted HbA1c benefit was evaluated in 18,741 patients in UK primary care (Clinical Practice Research Datalink). RESULTS: Heterogeneity in treatment effects was detected in clinical trial participants with both approaches (proportion predicted to have a benefit on SGLT2-inhibitor therapy over DPP4-inhibitor therapy: causal forest: 98.6%; penalized regression: 81.7%). In validation, calibration was good with penalized regression but sub-optimal with causal forest. A strata with an HbA1c benefit > 10 mmol/mol with SGLT2-inhibitors (3.7% of patients, observed benefit 11.0 mmol/mol [95%CI 8.0-14.0]) was identified using penalized regression but not causal forest, and a much larger strata with an HbA1c benefit 5-10 mmol with SGLT2-inhibitors was identified with penalized regression (regression: 20.9% of patients, observed benefit 7.8 mmol/mol (95%CI 6.7-8.9); causal forest 11.6%, observed benefit 8.7 mmol/mol (95%CI 7.4-10.1). CONCLUSIONS: Consistent with recent results for outcome prediction with clinical data, when evaluating treatment effect heterogeneity researchers should not rely on causal forest or other similar machine learning algorithms alone, and must compare outputs with standard regression, which in this evaluation was superior.

Best (but often forgotten) Statistical Practices: Measuring Real-World Intervention Effectiveness using Electronic Health Data.

The evidence base supporting the use of most interventions consists primarily of data from randomized controlled trials (RCTs), but how and to whom interventions are delivered in clinical practice may differ substantially from these foundational RCTs. With the increasing availability of electronic health data, it is now feasible to study the "real-world" effectiveness of a wide range of interventions. However, real-world intervention effectiveness studies using electronic health data face many challenges including data quality, selection bias, confounding by indication, and lack of generalizability. In this article, we describe the key barriers to generating high-quality evidence from real-world intervention effectiveness studies and suggest statistical best practices for addressing them.

Assessing effect heterogeneity of a randomized treatment using conditional inference trees.

Treatment effect heterogeneity occurs when individual characteristics influence the effect of a treatment. We propose a novel approach that combines prognostic score matching and conditional inference trees to characterize effect heterogeneity of a randomized binary treatment. One key feature that distinguishes our method from alternative approaches is that it controls the Type I error rate, that is, the probability of identifying effect heterogeneity if none exists and retains the underlying subgroups. This feature makes our technique particularly appealing in the context of clinical trials, where there may be significant costs associated with erroneously declaring that effects differ across population subgroups. Treatment effect heterogeneity trees are able to identify heterogeneous subgroups, characterize the relevant subgroups and estimate the associated treatment effects. We demonstrate the efficacy of the proposed method using a comprehensive simulation study and illustrate our method using a nutrition trial dataset to evaluate effect heterogeneity within a patient population.

Decision trees in epidemiological research.

BACKGROUND: In many studies, it is of interest to identify population subgroups that are relatively homogeneous with respect to an outcome. The nature of these subgroups can provide insight into effect mechanisms and suggest targets for tailored interventions. However, identifying relevant subgroups can be challenging with standard statistical methods. MAIN TEXT: We review the literature on decision trees, a family of techniques for partitioning the population, on the basis of covariates, into distinct subgroups who share similar values of an outcome variable. We compare two decision tree methods, the popular Classification and Regression tree (CART) technique and the newer Conditional Inference tree (CTree) technique, assessing their performance in a simulation study and using data from the Box Lunch Study, a randomized controlled trial of a portion size intervention. Both CART and CTree identify homogeneous population subgroups and offer improved prediction accuracy relative to regression-based approaches when subgroups are truly present in the data. An important distinction between CART and CTree is that the latter uses a formal statistical hypothesis testing framework in building decision trees, which simplifies the process of identifying and interpreting the final tree model. We also introduce a novel way to visualize the subgroups defined by decision trees. Our novel graphical visualization provides a more scientifically meaningful characterization of the subgroups identified by decision trees. CONCLUSIONS: Decision trees are a useful tool for identifying homogeneous subgroups defined by combinations of individual characteristics. While all decision tree techniques generate subgroups, we advocate the use of the newer CTree technique due to its simplicity and ease of interpretation.