Introduction to Adaptive Interventions and SMART Study Design Principles Daniel Almirall1;2 Linda M Collins2;3;5 Susan A Murphy1;2;4 1Institute for Social Research, University of Michigan 2The Methodology Center, Penn State University 3Human Development and Family Studies, Pennsylvania State University 4Department of Statistics, University of Michigan 5Department of Statistics, Pennsylvania State University COPTR Workshop on Adaptive Interventions; June 29, 2011 Almirall, Collins, Murphy Building Adaptive Interventions 1 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) SMART Design Principles Discussion Outline Adaptive Interventions What? Why? Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What are SMARTs? SMART Design Principles Keep it Simple Choosing Primary and Secondary Hypotheses Discussion Almirall, Collins, Murphy Building Adaptive Interventions 2 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What? Why? SMART Design Principles Discussion ADAPTIVE INTERVENTIONS Almirall, Collins, Murphy Building Adaptive Interventions 3 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What? Why? SMART Design Principles Discussion Definition: An Adaptive Intervention is I a sequence of individually tailored decision rules I that specify whether, how, and/or when I to alter the intensity, type, dosage, or delivery of treatment I at critical decision points in the course of care. Adaptive Interventions operationalize sequential decision making with the aim of improving clinical practice. Almirall, Collins, Murphy Building Adaptive Interventions 4 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What? Why? SMART Design Principles Discussion Concrete Example of Adaptive Intervention Pediatric Anxiety Example (SAD, GAD, SoP) First-line Txt Tailoring Variable Second-line Txt Maintain: Responder CBT s CBT Add Treatment: Non-Responders CBT + MED I Goal is to minimize the child’s symptom profile/trajectory. Almirall, Collins, Murphy Building Adaptive Interventions 5 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What? Why? SMART Design Principles Discussion What makes up an Adaptive Intervention? 1. Critical decisions: treatment options and more 2. Tailoring variables: to decide how to adapt treatment 3. FirstDecision-line Txt rules: inputsTailoring tailoring Variable variable, outputsSecond one or-line Txt more recommended treatments Maintain: Responder CBT s CBT Add Treatment: Non-Responders CBT + MED Adaptive interventions AKA: dynamic treatment regimes, adaptive treatment strategies, treatment algorithms, structured treatment interruptions, practice parameters, ASAM criteria... Almirall, Collins, Murphy Building Adaptive Interventions 6 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What? Why? SMART Design Principles Discussion Why Adaptive Interventions? Necessary because... I Chronic nature of substance use/mental health disorders I Waxing and waning course (multiple relapse, recurrence) I Genetic and non-genetic factors influence course I Co-occuring disorders may arise I High patient heterogeneity in response to treatment I Within person (over time) differential response to treatment I Between person differential response to treatment All require sequences of treatment decisions. Almirall, Collins, Murphy Building Adaptive Interventions 7 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) SMART Design Principles Discussion EVALUATING VERSUS BUILDING VERSUS GENERATING HYPOTHESES ABOUT ADAPTIVE INTERVENTIONS? Almirall, Collins, Murphy Building Adaptive Interventions 8 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) SMART Design Principles Discussion 3 Different Research Questions/Aims = 3 Different Research Designs I Aim 1: When evaluating a particular Adaptive Intervention: e.g. Does the AI have a statistically significant effect as compared to control intervention? I Aim 2: When building an Adaptive Intervention: e.g, What are the best tailoring variables and/or decision rules? I Aim 3: When generating hypotheses to build an Adaptive Intervention: e.g., Does augmenting txt (as observed in a previous trial) for non-responders correlate with better outcomes? Almirall, Collins, Murphy Building Adaptive Interventions 9 / 42 3 Different Research Questions/Aims = 3 Different Research Designs Ex. Q1: Does the Adaptive Intervention have a statistically significant effect as compared to control intervention? Ex. Q2: What are the best tailoring variables or decision rules? Ex. Q3: Does augmenting txt for non-responders (as observed in a previous trial) correlate with better outcomes? Analysis of RCT SMART Previous RCT Question Aim (Experimental) (Observational) p 1 Evaluating XX p 2 Building X ∼ p 3 Hypothesis Gen. X X Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What are SMARTs? SMART Design Principles Discussion SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMIZED TRIALS (SMARTs) Almirall, Collins, Murphy Building Adaptive Interventions 11 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What are SMARTs? SMART Design Principles Discussion What is a Sequential Multiple Assignment Randomized Trial (SMART)? I Multi-stage trials; same participants throughout I Each stage corresponds to a critical decision point I At each stage, subjects randomized to set of treatment options I The goal of a SMART is to inform the development of adaptive interventions. I will give you an example SMART, but first... Almirall, Collins, Murphy Building Adaptive Interventions 12 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Sequential Multiple Assignment Randomized Trial (SMART) What are SMARTs? SMART Design Principles Discussion Motivation for an Example SMART Child-Adolescent Anxiety Multi-modal Study (CAMS) I CAMS: acute-phase, efficacy, RCT for child anxiety I CBT+MED > MED ≈ CBT > Placebo I However, some families and clinicians remain concerned about the use of MED in this population I So an important next question for clinical practice is “Can we delay the use of MED?” I Some children may do fine w/ CBT only and not need MED. Almirall, Collins, Murphy Building Adaptive Interventions 13 / 42 Concrete Example of a SMART: Pediatric Anxiety Courtesy of Scott N Compton, Duke University Medical Center O2 + Primary O1 First-line Txt Second-line Txt Y Tailoring Variable Add Treatment: Non-Responders CBT + MED + FT CBT + MED Maintain: CBT + MED Responders R Step Down: CBT Only R Maintain: Responders CBT CBT Add Treatment: CBT + MED Non-Responders R Switch Treatment: MED One Adaptive Intervention Within the SMART O2 + Primary O1 First-line Txt Second-line Txt Y Tailoring Variable Add Treatment: Non-Responders CBT + MED + FT CBT + MED Maintain: CBT + MED Responders R Step Down: CBT Only R Maintain: Responders CBT CBT Add Treatment: CBT + MED Non-Responders R Switch Treatment: MED Another Adaptive Intervention Within the SMART O2 + Primary O1 First-line Txt Second-line Txt Y Tailoring Variable Add Treatment: Non-Responders CBT + MED + FT CBT + MED Maintain: CBT + MED Responders R Step Down: CBT Only R Maintain: Responder CBT s CBT Add Treatment: CBT + MED Non-Responders R Switch Treatment: MED 4 Embedded Adaptive Interventions in this SMART Add Treatment: Non‐Responders CBT + MED + FT 1 CBT + MED AI Responders Step Down: CBT Boost Add Treatment: Non‐Responders CBT + MED + FT 2 CBT + MED AI Responders Maintain: CBT + MED Maintain: Responders CBT Boost 3 CBT AI Non‐Responders Add Treatment: CBT + MED Maintain: Responders CBT Boost 4 CBT AI Non‐Responders Switch Treatment: MED Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Keep it Simple Sequential Multiple Assignment Randomized Trial (SMART) Choosing Primary and Secondary Hypotheses SMART Design Principles Discussion SMART DESIGN PRINCIPLES Almirall, Collins, Murphy Building Adaptive Interventions 18 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Keep it Simple Sequential Multiple Assignment Randomized Trial (SMART) Choosing Primary and Secondary Hypotheses SMART Design Principles Discussion SMART Design Principles I KISS Principle: Keep It Simple, Straightforward I Power for simple important primary hypotheses I Take Appropriate steps to develop an more deeply-individualized Adaptive Intervention Almirall, Collins, Murphy Building Adaptive Interventions 19 / 42 Adaptive Interventions Evaluating versus Building an Adaptive Intervention? Keep it Simple Sequential Multiple Assignment Randomized Trial (SMART) Choosing Primary and Secondary Hypotheses SMART Design Principles Discussion Keep It Simple, Straightforward Overarching Principle At each stage, or critical decision point,... I Use low dimensional summary to