Individualized Treatment Rules Research Articles

Learning Individualized Treatment Rules for Multiple-Domain Latent Outcomes

For many mental disorders, latent mental status from multiple-domain psychological or clinical symptoms may perform as a better characterization of the underlying disorder status than a simple summary score of the symptoms, and they may also serve as more reliable and representative features to differentiate treatment responses. Therefore, to address the complexity and heterogeneity of treatment responses for mental disorders, we provide a new paradigm for learning optimal individualized treatment rules (ITRs) by modeling patients’ latent mental status. We first learn the multi-domain latent states at baseline from the observed symptoms under a restricted Boltzmann machine (RBM) model, which encodes patients’ heterogeneous symptoms using an economical number of latent variables and yet remains flexible. We then optimize a value function defined by the latent states after treatment by exploiting a transformation of the observed symptoms based on the RBM without modeling the relationship between the latent mental states before and after treatment. The optimal treatment rules are derived using a weighted large margin classifier. We derive the convergence rate of the proposed estimator under the latent models. Simulation studies are conducted to test the performance of the proposed method. Finally, we apply the developed method to real world studies and we demonstrate the utility and advantage of our method in tailoring treatments for patients with major depression, and identify patient subgroups informative for treatment recommendations. Supplementary materials for this article are available online.

Net benefit index: Assessing the influence of a biomarker for individualized treatment rules.

One central task in precision medicine is to establish individualized treatment rules (ITRs) for patients with heterogeneous responses to different therapies. Motivated from a randomized clinical trial for Type 2 diabetic patients on a comparison of two drugs, that is, pioglitazone and gliclazide, we consider a problem: utilizing promising candidate biomarkers to improve an existing ITR. This calls for a biomarker evaluation procedure that enables to gauge added values of individual biomarkers. We propose an assessment analytic, termed as net benefit index (NBI), that quantifies a contrast between the resulting gain and loss of treatment benefits when a biomarker enters ITR to reallocate patients in treatments. We optimize reallocation schemes via outcome weighted learning (OWL), from which the optimal treatment group labels are generated by weighted support vector machine (SVM). To account for sampling uncertainty in assessing a biomarker, we propose an NBI-based test for a significant improvement over the existing ITR, where the empirical null distribution is constructed via the method of stratified permutation by treatment arms. Applying NBI to the motivating diabetes trial, we found that baseline fasting insulin is an important biomarker that leads to an improvement over an existing ITR based only on patient's baseline fasting plasma glucose (FPG), age, and body mass index (BMI) to reduce FPG over a period of 52 weeks.

Learning Optimal Distributionally Robust Individualized Treatment Rules

Recent development in the data-driven decision science has seen great advances in individualized decision making. Given data with individual covariates, treatment assignments and outcomes, policy makers best individualized treatment rule (ITR) that maximizes the expected outcome, known as the value function. Many existing methods assume that the training and testing distributions are the same. However, the estimated optimal ITR may have poor generalizability when the training and testing distributions are not identical. In this article, we consider the problem of finding an optimal ITR from a restricted ITR class where there are some unknown covariate changes between the training and testing distributions. We propose a novel distributionally robust ITR (DR-ITR) framework that maximizes the worst-case value function across the values under a set of underlying distributions that are “close” to the training distribution. The resulting DR-ITR can guarantee the performance among all such distributions reasonably well. We further propose a calibrating procedure that tunes the DR-ITR adaptively to a small amount of calibration data from a target population. In this way, the calibrated DR-ITR can be shown to enjoy better generalizability than the standard ITR based on our numerical studies. Supplementary materials for this article are available online.

A Two-Part Framework for Estimating Individualized Treatment Rules From Semicontinuous Outcomes

Health care payments are an important component of health care utilization and are thus a major focus in health services and health policy applications. However, payment outcomes are semicontinuous in that over a given period of time some patients incur no payments and some patients incur large costs. Individualized treatment rules (ITRs) are a major part of the push for tailoring treatments and interventions to patients, yet there is a little work focused on estimating ITRs from semicontinuous outcomes. In this article, we develop a framework for estimation of ITRs based on two-part modeling, wherein the ITR is estimated by separately targeting the zero part of the outcome and the strictly positive part. To improve performance when high-dimensional covariates are available, we leverage a scientifically plausible penalty that simultaneously selects variables and encourages the signs of coefficients for each variable to agree between the two components of the ITR. We develop an efficient algorithm for computation and prove oracle inequalities for the resulting estimation and prediction errors. We demonstrate the effectiveness of our approach in simulated examples and in a study of a health system intervention. Supplementary materials for this article are available online.

Improved Doubly Robust Estimation in Learning Optimal Individualized Treatment Rules

Individualized treatment rules (ITRs) recommend treatment according to patient characteristics. There is a growing interest in developing novel and efficient statistical methods in constructing ITRs. We propose an improved doubly robust estimator of the optimal ITRs. The proposed estimator is based on a direct optimization of an augmented inverse-probability weighted estimator of the expected clinical outcome over a class of ITRs. The method enjoys two key properties. First, it is doubly robust, meaning that the proposed estimator is consistent when either the propensity score or the outcome model is correct. Second, it achieves the smallest variance among the class of doubly robust estimators when the propensity score model is correctly specified, regardless of the specification of the outcome model. Simulation studies show that the estimated ITRs obtained from our method yield better results than those obtained from current popular methods. Data from the Sequenced Treatment Alternatives to Relieve Depression study is analyzed as an illustrative example. Supplementary materials for this article are available online.

A nonparametric method for value function guided subgroup identification via gradient tree boosting for censored survival data.

In randomized clinical trials with survival outcome, there has been an increasing interest in subgroup identification based on baseline genomic, proteomic markers, or clinical characteristics. Some of the existing methods identify subgroups that benefit substantially from the experimental treatment by directly modeling outcomes or treatment effect. When the goal is to find an optimal treatment for a given patient rather than finding the right patient for a given treatment, methods under the individualized treatment regime framework estimate an individualized treatment rule that would lead to the best expected clinical outcome as measured by a value function. Connecting the concept of value function to subgroup identification, we propose a nonparametric method that searches for subgroup membership scores by maximizing a value function that directly reflects the subgroup-treatment interaction effect based on restricted mean survival time. A gradient tree boosting algorithm is proposed to search for the individual subgroup membership scores. We conduct simulation studies to evaluate the performance of the proposed method and an application to an AIDS clinical trial is performed for illustration.

A constrained single-index regression for estimating interactions between a treatment and covariates.

We consider a single-index regression model, uniquely constrained to estimate interactions between a set of pretreatment covariates and a treatment variable on their effects on a response variable, in the context of analyzing data from randomized clinical trials. We represent interaction effect terms of the model through a set of treatment-specific flexible link functions on a linear combination of the covariates (a single index), subject to the constraint that the expected value given the covariates equals 0, while leaving the main effects of the covariates unspecified. We show that the proposed semiparametric estimator is consistent for the interaction term of the model, and that the efficiency of the estimator can be improved with an augmentation procedure. The proposed single-index regression provides a flexible and interpretable modeling approach to optimizing individualized treatment rules based on patients' data measured at baseline, as illustrated by simulation examples and an application to data from a depression clinicaltrial.

A rank-based approach to estimating monotone individualized two treatment regimes

Developing effective individualized treatment rules (ITRs) for diseases is an important goal of clinical research. Much effort has been devoted to estimating individualized treatment effects in the recent literature. However, there have not been systematic studies on the robust inference for individualized treatment effects when there exist potential outliers. We propose a monotone ITR in the framework of a semiparametric generalized regression with two treatments and estimate the treatment effects via a smoothed maximum rank correlation procedure. We provide sufficient conditions under which the proposed estimator has an asymptotically normal distribution whose variance can be consistently estimated based on a resampling procedure. We evaluate the finite-sample properties of our proposed approach via simulation studies. We also illustrate the proposed method by applying it to a data set from an AIDS clinical trials study.

On using electronic health records to improve optimal treatment rules in randomized trials.

Individualized treatment rules (ITRs) tailor medical treatments according to patient-specific characteristics in order to optimize patient outcomes. Data from randomized controlled trials (RCTs) are used to infer valid ITRs using statistical and machine learning methods. However, RCTs are usually conducted under specific inclusion/exclusion criteria, thus limiting their generalizability to a broader patient population in real-world practice settings. Because electronic health records (EHRs) document treatment prescriptions in the real world, transferring information in EHRs to RCTs, if done appropriately, could potentially improve the performance of ITRs, in terms of precision and generalizability. In this work, we propose a new domain adaptation method to learn ITRs by incorporating information from EHRs. Unless we assume that there is no unmeasured confounding in EHRs, we cannot directly learn the optimal ITR from the combined EHR and RCT data. Instead, we first pretrain "super" features from EHRs that summarize physician treatment decisions and patient observed benefits in the real world, as these are likely to be informative of the optimal ITRs. We then augment the feature space of the RCT and learn the optimal ITRs by stratifying by super features using subjects enrolled in RCT. We adopt Q-learning and a modified matched-learning algorithm for estimation. We present heuristic justification of our method and conduct simulation studies to demonstrate the performance of super features. Finally, we apply our method to transfer information learned from EHRs of patients with type 2 diabetes to learn individualized insulin therapies from RCTdata.

Optimal Individualized Decision Rules Using Instrumental Variable Methods

There is an extensive literature on the estimation and evaluation of optimal individualized treatment rules in settings where all confounders of the effect of treatment on outcome are observed. We study the development of individualized decision rules in settings where some of these confounders may not have been measured but a valid binary instrument is available for a binary treatment. We first consider individualized treatment rules, which will naturally be most interesting in settings where it is feasible to intervene directly on treatment. We then consider a setting where intervening on treatment is infeasible, but intervening to encourage treatment is feasible. In both of these settings, we also handle the case that the treatment is a limited resource so that optimal interventions focus the available resources on those individuals who will benefit most from treatment. Given a reference rule, we evaluate an optimal individualized rule by its average causal effect relative to a prespecified reference rule. We develop methods to estimate optimal individualized rules and construct asymptotically efficient plug-in estimators of the corresponding average causal effect relative to a prespecified reference rule. Supplementary materials for this article are available online.

Optimal individualized decision rules from a multi-arm trial: A comparison of methods and an application to tailoring inter-donation intervals among blood donors in the UK.

There is a growing interest in precision medicine where individual heterogeneity is incorporated into decision-making and treatments are tailored to individuals to provide better healthcare. One important aspect of precision medicine is the estimation of the optimal individualized treatment rule (ITR) that optimizes the expected outcome. Most methods developed for this purpose are restricted to the setting with two treatments, while clinical studies with more than two treatments are common in practice. In this work, we summarize methods to estimate the optimal ITR in the multi-arm setting and compare their performance in large-scale clinical trials via simulation studies. We then illustrate their utilities with a case study using the data from the INTERVAL trial, which randomly assigned over 20,000 male blood donors from England to one of the three inter-donation intervals (12-week, 10-week, and eight-week) over two years. We estimate the optimal individualized donation strategies under three different objectives. Our findings are fairly consistent across five different approaches that are applied: when we target the maximization of the total units of blood collected, almost all donors are assigned to the eight-week inter-donation interval, whereas if we aim at minimizing the low hemoglobin deferral rates, almost all donors are assigned to donate every 12 weeks. However, when the goal is to maximize the utility score that “discounts” the total units of blood collected by the incidences of low hemoglobin deferrals, we observe some heterogeneity in the optimal inter-donation interval across donors and the optimal donor assignment strategy is highly dependent on the trade-off parameter in the utility function.

Selecting and Ranking Individualized Treatment Rules With Unmeasured Confounding

It is common to compare individualized treatment rules based on the value function, which is the expected potential outcome under the treatment rule. Although the value function is not point-identified when there is unmeasured confounding, it still defines a partial order among the treatment rules under Rosenbaum’s sensitivity analysis model. We first consider how to compare two treatment rules with unmeasured confounding in the single-decision setting and then use this pairwise test to rank multiple treatment rules. We consider how to, among many treatment rules, select the best rules and select the rules that are better than a control rule. The proposed methods are illustrated using two real examples, one about the benefit of malaria prevention programs to different age groups and another about the effect of late retirement on senior health in different gender and occupation groups. Supplementary materials for this article are available online.

Development and Validation of a Machine Learning Individualized Treatment Rule in First-Episode Schizophrenia

Little guidance exists to date on how to select antipsychotic medications for patients with first-episode schizophrenia. To develop a preliminary individualized treatment rule (ITR) for patients with first-episode schizophrenia. This prognostic study obtained data from Taiwan's National Health Insurance Research Database on patients with prescribed antipsychotic medications, ambulatory claims, or discharge diagnoses of a schizophrenic disorder between January 1, 2005, and December 31, 2011. An ITR was developed by applying a targeted minimum loss-based ensemble machine learning method to predict treatment success from baseline clinical and demographic data in a 70% training sample. The model was validated in the remaining 30% of the sample. The probability of treatment success was estimated for each medication for each patient under the model. The analysis was conducted between July 16, 2018, and July 15, 2019. Fifteen different antipsychotic medications. Treatment success was defined as not switching medication and not being hospitalized for 12 months. Among the 32 277 patients in the analysis, the mean (SD) age was 36.7 (14.3) years, and 15 752 (48.8%) were male. In the validation sample, the treatment success rate (SE) was 51.7% (1.0%) under the ITR and was 44.5% (0.5%) in the observed population (Z = 7.1; P < .001). The estimated treatment success if all patients were given a prescription for 1 medication was significantly lower for each of the 13 medications than under the ITR (Z = 4.2-16.8; all P < .001). Aripiprazole (3088 [31.9%]) and amisulpride (2920 [30.2%]) were the medications most often recommended by the ITR. Only 1054 patients (10.9%) received ITR-recommended medications. Observed treatment success, although lower than the success under the ITR, was nonetheless significantly higher than if medications had been randomized (44.5% [SE, 0.55%] vs 41.3% [SE, 0.4%]; Z = 6.9; P < .001), although only marginally higher than if medications had been randomized in their observed population proportions (44.5% [SE, 0.5%] vs 43.5% [SE, 0.4%]; Z = 2.2; P = .03]). These results suggest that an ITR may be associatded with an increase in the treatment success rate among patients with first-episode schizophrenia, but experimental evaluation is needed to confirm this possibility. If confirmed, model refinement that investigates biomarkers, clinical observations, and patient reports as additional predictors in iterative pragmatic trials would be needed before clinical implementation.

Estimating individualized treatment rules with risk constraint.

Individualized treatment rules (ITRs) recommend treatments based on patient-specific characteristics in order to maximize the expected clinical outcome. At the same time, the risks caused by various adverse events cannot be ignored. In this paper, we propose a method to estimate an optimal ITR that maximizes clinical benefit while having the overall risk controlled at a desired level. Our method works for a general setting of multi-category treatment. The proposed procedure employs two shifted ramp losses to approximate the 0-1 loss in the objective function and constraint, respectively, and transforms the estimation problem into a difference of convex functions (DC) programming problem. A relaxed DC algorithm is used to solve the nonconvex constrained optimization problem. Simulations and a real data example are used to demonstrate the finite sample performance of the proposedmethod.

Entropy Learning for Dynamic Treatment Regimes.

Estimating optimal individualized treatment rules (ITRs) in single or multi-stage clinical trials is one key solution to personalized medicine and has received more and more attention in statistical community. Recent development suggests that using machine learning approaches can significantly improve the estimation over model-based methods. However, proper inference for the estimated ITRs has not been well established in machine learning based approaches. In this paper, we propose a entropy learning approach to estimate the optimal individualized treatment rules (ITRs). We obtain the asymptotic distributions for the estimated rules so further provide valid inference. The proposed approach is demonstrated to perform well in finite sample through extensive simulation studies. Finally, we analyze data from a multi-stage clinical trial for depression patients. Our results offer novel findings that are otherwise not revealed with existing approaches.

Learning Personalized Treatment Rules from Electronic Health Records Using Topic Modeling Feature Extraction.

To address substantial heterogeneity in patient response to treatment of chronic disorders and achieve the promise of precision medicine, individualized treatment rules (ITRs) are estimated to tailor treatments according to patient-specific characteristics. Randomized controlled trials (RCTs) provide gold standard data for learning ITRs not subject to confounding bias. However, RCTs are often conducted under stringent inclusion/exclusion criteria, and participants in RCTs may not reflect the general patient population. Thus, ITRs learned from RCTs lack generalizability to the broader real world patient population. Real world databases such as electronic health records (EHRs) provide new resources as complements to RCTs to facilitate evidence-based research for personalized medicine. However, to ensure the validity of ITRs learned from EHRs, a number of challenges including confounding bias and selection bias must be addressed. In this work, we propose a matching-based machine learning method to estimate optimal individualized treatment rules from EHRs using interpretable features extracted from EHR documentation of medications and ICD diagnoses codes. We use a latent Dirichlet allocation (LDA) model to extract latent topics and weights as features for learning ITRs. Our method achieves confounding reduction in observational studies through matching treated and untreated individuals and improves treatment optimization by augmenting feature space with clinically meaningful LDA-based features. We apply the method to EHR data collected at New York Presbyterian Hospital clinical data warehouse in studying optimal second-line treatment for type 2 diabetes (T2D) patients. We use cross validation to show that ITRs outperforms uniform treatment strategies (i.e., assigning same treatment to all individuals), and including topic modeling features leads to more reduction of post-treatment complications.

Suicide prediction models: a critical review of recent research with recommendations for the way forward.

Suicide is a leading cause of death. A substantial proportion of the people who die by suicide come into contact with the health care system in the year before their death. This observation has resulted in the development of numerous suicide prediction tools to help target patients for preventive interventions. However, low sensitivity and low positive predictive value have led critics to argue that these tools have no clinical value. We review these tools and critiques here. We conclude that existing tools are suboptimal and that improvements, if they can be made, will require developers to work with more comprehensive predictor sets, staged screening designs, and advanced statistical analysis methods. We also conclude that although existing suicide prediction tools currently have little clinical value, and in some cases might do more harm than good, an even-handed assessment of the potential value of refined tools of this sort cannot currently be made because such an assessment would depend on evidence that currently does not exist about the effectiveness of preventive interventions. We argue that the only way to resolve this uncertainty is to link future efforts to develop or evaluate suicide prediction tools with concrete questions about specific clinical decisions aimed at reducing suicides and to evaluate the clinical value of these tools in terms of net benefit rather than sensitivity or positive predictive value. We also argue for a focus on the development of individualized treatment rules to help select the right suicide-focused treatments for the right patients at the right times. Challenges will exist in doing this because of the rarity of suicide even among patients considered high-risk, but we offer practical suggestions for how these challenges can be addressed.

Multicategory Outcome Weighted Margin-based Learning for Estimating Individualized Treatment Rules.

Due to heterogeneity for many chronic diseases, precise personalized medicine, also known as precision medicine, has drawn increasing attentions in the scientific community. One main goal of precision medicine is to develop the most effective tailored therapy for each individual patient. To that end, one needs to incorporate individual characteristics to detect a proper individual treatment rule (ITR), by which suitable decisions on treatment assignments can be made to optimize patients' clinical outcome. For binary treatment settings, outcome weighted learning (OWL) and several of its variations have been proposed recently to estimate the ITR by optimizing the conditional expected outcome given patients' information. However, for multiple treatment scenarios, it remains unclear how to use OWL effectively. It can be shown that some direct extensions of OWL for multiple treatments, such as one-versus-one and one-versus-rest methods, can yield suboptimal performance. In this paper, we propose a new learning method, named Multicategory Outcome weighted Margin-based Learning (MOML), for estimating ITR with multiple treatments. Our proposed method is very general and covers OWL as a special case. We show Fisher consistency for the estimated ITR, and establish convergence rate properties. Variable selection using the sparse l 1 penalty is also considered. Analysis of simulated examples and a type 2 diabetes mellitus observational study are used to demonstrate competitive performance of the proposed method.

Robust outcome weighted learning for optimal individualized treatment rules

ABSTRACTPersonalized medicine has received increasing attentions among scientific communities in recent years. Because patients often have heterogenous responses to treatments, discovering individualized treatment rules (ITR) is an important component of precision medicine. To that end, one needs to develop a proper decision rule using patient-specific characteristics to maximize the expected clinical outcome, i.e. the optimal ITR. Recently, outcome weighted learning (OWL) has been proposed to estimate optimal ITR under a weighted classification framework. Since most of commonly used loss functions are unbounded, the resulting ITR may suffer similar effects of outliers as the corresponding classifiers. In this paper, we propose robust OWL (ROWL) to build more stable ITRs using a new family of bounded and non-convex loss functions. Moreover, we extend the proposed ROWL method to the multiple treatment setting under the angle-based classification structure. Our theoretical results show that ROWL is Fisher consistent, and can provide the estimation of rewards’ ratios for the resulting ITRs. We develop an efficient difference of convex functions algorithm (DCA) to solve the corresponding nonconvex optimization problem. Through analysis of simulated examples and a real medical dataset, we demonstrate that the proposed ROWL method yields more competitive performance in terms of the empirical value function and the misclassification error than several existing methods.

Assessment of a Precision Medicine Analysis of a Behavioral Counseling Strategy to Improve Adherence to Diabetes Self-management Among Youth

The Flexible Lifestyles Empowering Change (FLEX) trial, an 18-month randomized clinical trial testing an adaptive behavioral intervention in adolescents with type 1 diabetes, showed no overall treatment effect for its primary outcome, change in hemoglobin A1c (HbA1c) percentage of total hemoglobin, but demonstrated benefit for quality of life (QoL) as a prespecified secondary outcome. To apply a novel statistical method for post hoc analysis that derives an individualized treatment rule (ITR) to identify FLEX participants who may benefit from intervention based on changes in HbA1c percentage (primary outcome), QoL, and body mass index z score (BMIz) (secondary outcomes) during 18 months. This multisite clinical trial enrolled 258 adolescents aged 13 to 16 years with type 1 diabetes for 1 or more years, who had literacy in English, HbA1c percentage of total hemoglobin from 8.0% to 13.0%, a participating caregiver, and no other serious medical conditions. From January 5, 2014, to April 4, 2016, 258 adolescents were recruited. The post hoc analysis excluded adolescents missing outcome measures at 18 months (2 participants [0.8%]) or continuous glucose monitoring data at baseline (40 participants [15.5%]). Data were analyzed from April to December 2018. The FLEX intervention included a behavioral counseling strategy that integrated motivational interviewing and problem-solving skills training to increase adherence to diabetes self-management. The control condition entailed usual diabetes care. Subgroups of FLEX participants were derived from an ITR estimating which participants would benefit from intervention, which would benefit from control conditions, and which would be indifferent. Multiple imputation by chained equations and reinforcement learning trees were used to estimate the ITR. Subgroups based on ITR pertaining to changes during 18 months in 3 univariate outcomes (ie, HbA1c percentage, QoL, and BMIz) and a composite outcome were compared by baseline demographic, clinical, and psychosocial characteristics. Data from 216 adolescents in the FLEX trial were reanalyzed (166 [76.9%] non-Hispanic white; 108 teenaged girls [50.0%]; mean [SD] age, 14.9 [1.1] years; mean [SD] diabetes duration, 6.3 [3.7] years). For the univariate outcomes, a large proportion of FLEX participants had equivalent predicted outcomes under intervention vs usual care settings, regardless of randomization, and were assigned to the muted group (HbA1c: 105 participants [48.6%]; QoL: 63 participants [29.2%]; BMIz: 136 participants [63.0%]). Regarding the BMIz univariate outcome, mean baseline BMIz of participants assigned to the muted group was lower than that of those assigned to the intervention and control groups (muted vs intervention: mean difference, 0.48; 95% CI, 0.21 to 0.75; P = .002; muted vs control: mean difference, 0.86; 95% CI, 0.61 to 1.11; P < .001); this group also had a higher proportion of individuals with underweight or normal weight using weight status cutoffs (95 [69.9%] in muted group vs 24 [54.6%] in intervention group and 11 [30.6%] in control group; χ24 = 24.67; P < .001). The approach identified subgroups estimated to benefit based on HbA1c percentage (54 participants [25.0%]), QoL (89 participants [41.2%]), and BMIz (44 participants [20.4%]). Regarding the HbA1c percentage outcome, participants expected to benefit from the intervention did not have significantly higher baseline HbA1c percentages than those expected to benefit from usual care (9.4% vs 9.2%; difference, 0.2%; 95% CI, -0.16% to 0.56%; P = .44). However, participants in the muted group had higher mean HbA1c percentages at baseline than those assigned to the intervention or control groups (muted vs intervention: 9.9% vs 9.4%; difference, 0.5%; 95% CI, 0.13% to 0.89%; P = .02; muted vs control; 9.9% vs 9.2%; difference, 0.7%; 95% CI, 0.34% to 1.08%; P = .001). No significant differences were found between subgroups estimated to benefit in terms of the composite outcome from the FLEX intervention (91 participants [42.1%]) vs usual care (125 participants [57.9%]). The precision medicine approach represents a conceptually and analytically novel approach to post hoc subgroup identification. More work is needed to understand markers of positive response to the FLEX intervention. ClinicalTrial.gov identifier: NCT01286350.