SMART: an integral part of the Multiphase Optimization Strategy (MOST)

1. Presented by Linda M. Collins, Ph.D. The Methodology Center Penn State Presented at the 6th Annual Conference on Statistical Issues in Clinical Trials Center for Clinical Epidemiology and Biostatistics University of Pennsylvania April 17, 2013 SMART: an integral part of the Multiphase Optimization Strategy (MOST)

2. Collaborators • Inbal (Billie) Nahum-Shani • Daniel Almirall • Susan A. Murphy All at University of Michigan and • William Pelham, Florida International University

3. Outline • Definitions • Development of behavioral interventions: business as usual • Development of behavioral interventions: the Multiphase Optimization Strategy (MOST) • Using a SMART for optimization • Ongoing research, open areas and future directions

4. Definition: behavioral intervention • A program aimed at modifying behavior for the purpose of treating or preventing disease, promoting health, and/or enhancing well-being. • Examples: • Clinic-based smoking cessation • Weight loss/management program • School-based drug abuse prevention • Note that according to this definition, most behavioral interventions are treatment packages made up of multiple components.

5. Definition: Intervention component • Any aspect of an intervention that can be separated out for study • Parts of intervention content • e.g. : topics in a drug abuse prevention curriculum • Features that promote compliance/adherence • e.g.: use of mems caps on medication • Features aimed at improving fidelity • e.g.: 800 number for program delivery staff to call with questions

6. Definition: Intervention component • Any aspect of an intervention that can be separated out for study • A decision rule in a dynamic treatment regime • e.g.: “If more than one heavy drinking day in a two-week period, increase clinic visits to three per week” • A tailoring variable in a dynamic treatment regime • e.g.: “If more than one heavy drinking day in a two-week period, increase clinic visits to three per week” • The review interval in a dynamic treatment regime • e.g.: “If more than one heavy drinking day in a two-week period, increase clinic visits to three per week”

7. Definition: Intervention component • Any aspect of an intervention that can be separated out for study • The sequencing of components can itself be considered a component, particularly in a dynamic treatment regime • e.g. what should be tried first in treatment of ADHD, behavioral modification or medication?

8. More about intervention components • Can impact effectiveness, efficiency, economy, burden, scalability, etc. • Some may be pharmaceutical • Can be defined at any level: individual, family, school, etc.

9. Outline • Definitions • Development of behavioral interventions: business as usual • Development of behavioral interventions: the Multiphase Optimization Strategy (MOST) • Using a SMART for optimization • Ongoing research, open areas and future directions

10. How behavioral inventions are typically developed • Intervention components are chosen based on scientific theory, clinical experience, etc. • Combined into a treatment package • Package is evaluated via a randomized controlled trial (RCT) • The treatment package approach

11. Treatment package approach component component component component component Behavioral intervention Evaluation via RCT

12. What’s wrong with evaluating a treatment package via an RCT? Absolutely nothing!

13. The RCT is best suited for • Determining whether a treatment package performs better than • A control or comparison group • An alternative intervention

14. Treatment package approach component component component component component Behavioral intervention Evaluation via RCT

15. The RCT does not tell us An RCT that finds a significant effect DOES NOT tell us • Which components are making positive contributions to overall effect • Whether the inclusion of one component has an impact on the effect of another • Whether a component’s contribution offsets its cost • Whether all the components are really needed • How to make the intervention more effective, efficient, and scalable

16. What the RCT does not tell us An RCT that finds a non-significant effect DOES NOT tell us • Whether any components are worth retaining • Whether one component had a negative effect that offset the positive effect of others • Specifically what went wrong and how to do it better the next time

17. Reliance on the treatment package approach has encouraged… …stuffing the behavioral intervention with many components to get a significant effect …downplaying considerations such as efficiency cost-effectiveness time-effectiveness participant burden scalability

18. Reliance on the treatment package approach has encouraged… …focusing primarily on attaining statistical significance …paying insufficient attention to meeting clinically meaningful criteria

19. What’s the alternative? • When engineers build products they take an approach that is • Systematic • Efficient • Focused on the clear objective of optimizing the product • We can borrow ideas from engineering… • … and build optimized behavioral interventions

20. Outline • Definitions • Development of behavioral interventions: business as usual • Development of behavioral interventions: the Multiphase Optimization Strategy (MOST) • Using a SMART for optimization • Ongoing research, open areas and future directions

21. The Multiphase Optimization Strategy (MOST) • An engineering-inspired framework for development, optimization, and evaluation of behavioral interventions • Using MOST it is possible to engineer a behavioral intervention to meet a specific optimization criterion • Three phases: Preparation, Optimization, Evaluation Collins, Murphy, Nair, & Strecher, 2005; Collins, Murphy, & Strecher, 2007; Collins, Baker, Mermelstein, Piper, Jorenby, Smith, Schlam, Cook, & Fiore, 2011

22. MOST: Preparation, Optimization, Evaluation • Preparation • Purpose: to lay groundwork for optimization • Review prior research, take stock of clinical experience, conduct secondary analyses, etc. • Derive theoretical model • Select intervention components to examine • Conduct pilot/feasibility work • Identify clearly operationalized optimization criterion

23. Definition: Optimization • “The process of finding the best possible solution… subject to given constraints” (The Concise Oxford Dictionary of Mathematics) • Optimized does not mean best in an absolute or ideal sense • Instead, realistic because it includes constraints • Optimization always involves a clearly stated optimization criterion

24. Selecting an optimization criterion • Your definition of “best possible, given constraints” • This is the goal you want to achieve • Implicit constraint: the set of components under consideration

25. One possible optimization criterion: • Efficient intervention with no “dead wood” • Select higher/more intense/more expensive level only when empirically demonstrated to be more effective • CONSIDER a school-based drug abuse prevention program. • Suppose: So that they can justify the use of classroom time and to reduce waste of resources, the investigators want to be confident that every component is necessary. • Achieve this by selecting only active intervention components.

26. This optimization criterion for a dynamic treatment regime… • Efficient intervention with no “dead wood” • Tailoring variables and decision rules that produce the most effective dynamic treatment regime • Select higher/more intense/more expensive tailoring variables and decision rules only when empirically demonstrated to be more effective • Will go over an example later

27. Another possible optimization criterion • Most effective intervention that can be delivered for ≤ some $$ • CONSIDER a dynamic smoking cessation intervention. • Suppose: Insurers say they will pay for a smoking cessation intervention that costs no more than $500/person to deliver, including materials, pharmaceuticals, and staff time. • Achieve this by identifying a set of tailoring variables and decision rules that represents the most effective intervention that can be delivered for ≤ $500.

28. Other possible optimization criteria • Most effective intervention that can be delivered in ≤ some amount of time • Cost-effectiveness • A criterion based on a combination of cost and time • Most effective without exceeding a specified level of participant burden • Or any other relevant criterion

29. MOST: Preparation, Optimization, Evaluation • Preparation • Purpose: to lay groundwork for optimization • Review prior research, take stock of clinical experience, conduct secondary analyses, etc. • Derive theoretical model • Select intervention components to examine • Conduct pilot/feasibility work • Identify optimization criterion

30. MOST: Preparation, Optimization, Evaluation • Optimization • Objective: To form a treatment package that meets the optimization criterion • Collect and analyze empirical data on performance of individual intervention components • Efficient randomized experimentation • e.g. fractional factorial, SMART • Augment by secondary analyses • Based on information gathered, select components and levels that meet optimization criterion.

31. MOST: Preparation, Optimization, Evaluation • Evaluation • Objective: To establish whether the optimized intervention has a statistically significant effect compared to a control or alternative intervention • Conduct a randomized clinical trial

32. Treatment package approach component component component component component Behavioral intervention Evaluation via RCT

33. Treatment package approach component component component component component Evaluation via RCT

34. Multiphase Optimization Strategy (MOST) component component component Optimizedbehavioral intervention component component component component Evaluation via RCT Empirically-based optimization component

35. Multiphase Optimization Strategy (MOST) component component component Optimizedbehavioral intervention component component component component Evaluation via RCT Empirically-based optimization component

36. Multiphase Optimization Strategy (MOST) component component component Optimizedbehavioral intervention component component component component Evaluation via RCT Empirically-based optimization component

38. Outline • Definitions • Development of behavioral interventions: business as usual • Development of behavioral interventions: the Multiphase Optimization Strategy (MOST) • Using a SMART for optimization • Ongoing research, open areas and future directions

39. Example • Dynamic treatment regime for children with ADHA • W. Pelham is the intervention scientist • Optimization criterion: Efficient dynamic treatment regime with no “dead wood”

40. Dynamic treatment regimes for children with ADHD • Two approaches to treatment of ADHD • Behavior modification (BMOD) • Medication • They can be combined into a dynamic treatment regime • What is the best set of decision rules?

41. Dynamic treatment regimes for children with ADHD • Research questions that must be addressed for optimization: • Is it better to start with BMOD or medication? • Note: BMOD much more expensive • For those who do not respond to initial treatment, is it better to • Remain with the same strategy but enhance • Augment with the other strategy • What is the best overall strategy?

42. SMART Continue Med (SG1) Response Medication Response Enhance (SG2) Enhance (SG5) Non-Response R R Non-Response R Augment (SG3) Augment (SG6) Continue BMOD (SG4) BMOD

43. Questions we can address with SMART • Is it better to start with BMOD or MED? • (SG1+SG2+SG3) vs. (SG4+SG5+SG6) • Medicationvs.BMOD • Averaging over subsequent treatment Continue (SG1) Response Enhance (SG2) MED Non-Response R Augment (SG3) R Continue (SG4) Response BMOD Enhance (SG5) Non-Response R Augment (SG6)

44. Questions we can address with SMART • Is it better to Enhance or Augment for non-responders? • (SG2+SG5)vs.(SG3+SG6) • Enhancevs.Augment Continue (SG1) Response Enhance (SG2) MED Non-Response R Augment (SG3) R Continue (SG4) Response BMOD Enhance (SG5) Non-Response R Augment (SG6)

45. Questions we can address with SMART • What is the best overall strategy? There are FOUR embedded here. Stage 1 = {BMOD}, IF response = {NO} THEN stage 2 = {AUGMENT} ELSE continue stage 1 Stage 1 = {MED}, IF response = {NO} THEN stage 2 = {AUGMENT} ELSE continue stage 1 Stage 1 = {MED}, IF response = {NO} THEN stage 2 = {ENHANCE} ELSE continue stage 1 Continue (SG1) Response Enhance (SG2) MED Non-Response R Augment (SG3) Stage 1 = {BMOD}, IF response = {NO} THEN stage 2 = {ENHANCE} ELSE continue stage 1 R Continue (SG4) Response BMOD Enhance (SG5) Non-Response R Augment (SG6)

46. After the SMART • Results of analyses will be used to decide on best decision rules, i.e. optimized intervention • This does not tell us whether the optimized intervention has a statistically significant effect as compared to a control • Must move to the Evaluation phase for that

47. Outline • Definitions • Development of behavioral interventions: business as usual • Development of behavioral interventions: the Multiphase Optimization Strategy (MOST) • Using a SMART for optimization • Ongoing research, open areas and future directions

48. Ongoing research, open areas, and future directions • Q-learning (Watkins, 1989; Murphy, 2005) • Popular method from computer science. • Regression-based: • Sequence of regressions • One regression for each stage • Rationale: • Base your decision on what you know up to that point • Assume best future decisions Nahum-Shani et al., (2012). Q-learning: A secondary data analysis method for developing adaptive interventions. Psychological Methods, 17(4), 478-494

49. Ongoing research, open areas, and future directions • Building a controller using techniques from engineering • In much the same way any other controller would be built • Requires intensive longitudinal data • Must be able identify system • Usually will require experimentation • Potential for m-health interventions Zafra-Cabeza, A., Rivera, D.E., Collins, L.M., Ridao, M.A., & Camacho, E.F. (2011). A risk-based model predictive control approach to adaptive interventions in behavioral health. IEEE Transactions on Control Systems Technology, 19, 891-901. Trail, J.B., Collins, L.M., Rivera, D.E.,Li, R., Piper, M., & Baker, T. (almost in press). Functional Data Analysis for the system identification of behavioral processes. Psychological Methods. Nahum-Shani, I., ISR, University of Michigan

50. Ongoing research, open areas, and future directions • Q-learning as a secondary data analysis approach for data from SMART’s (Nahum-Shani et al., 2012) • Clarification about optimization criteria, particularly with dynamic treatment regimes • Experimental designs that mix adaptive (dynamic) and fixed components • More applications of MOST, particularly including SMARTs