Randomized Designs for Person, Place, and Time For Effectiveness Trials and Beyond

1. Randomized Designs for Person, Place, and TimeFor Effectiveness Trials and Beyond C Hendricks Brown University of South Florida Peter Wyman U Rochester Jing Guo USF Juan Peña U Rochester Hopkins PSMG Meeting

2. Support R01-MH40859 (Brown) Methodology for Mental Health / Drug Abuse Prevention & Early Intervention Designs & Analyses for Mental Health Preventive Trials NIMH and NIDA     3R01MH040859-15S1 (Brown)Methodology for Population-Based Approaches to the Prevention of Suicide NIMH Office of Rare Diseases CDC Injury Prevention Center R34MH071189-01 (Wyman)  RCT of Gatekeeper Training for Suicide Prevention NIMH P20MH071897-01 (Caine)  Developing Center On Public Health and Population Interventions For The Prevention Of Suicide NIMH Hopkins PSMG Meeting

3. Brown C.H., Wyman P. A., Guo J, and Peña J. (2005). Dynamic wait-listed designs for randomized trials: New designs for prevention of youth suicide. Submitted for publication. Hopkins PSMG Meeting

4. Outline • Types of Scientific Questions • Typology of Trials Matching these Questions • Randomization involving Person, Place, and Time • Dynamic Wait-Listed Design for suicide prevention • Randomizations of Person/Place/Time Hopkins PSMG Meeting

5. A. Types of Questions: Phases of prevention Hopkins PSMG Meeting

6. Do we need random assignment as we move to effectiveness and beyond? Nonrandomized designs • Blueprints Project U Colorado Denver • Alternative Study Designs for Evidence-based Practice: Harnessing Natural Variation for Effectiveness Research Agency for Healthcare Research and Quality (AHRQ), Hopkins PSMG Meeting

7. Prevention Field Trials Needed to Determine Precise Information aboutWhat WorksFor WhomUnder What ConditionsBecause … Hopkins PSMG Meeting

8. There are very few Broad Street Pump Handles Left to Remove John Snow’s Map of London Hopkins PSMG Meeting

9. To Obtain Precise Answers • Need to rely on Very Carefully Designed Intervention Studies • Random Assignment needed, • In novel ways …… Hopkins PSMG Meeting

10. B. Typology of Research Questions/Designs • Efficacy – Impact in optimally controlled settings • Effectiveness – Impact in real world settings • Implementability – What level of intervention produces what level of impact; what does it take to implement? • Adaptability – How does variation in intervention delivered affect impact? • Extensibility – What impact is achieved when delivered to different persons/settings? • Sustainability – Does impact continue after training ? • Scalability– What impact is achieved when the intervention is expanded system wide, or in larger contexts? • Disseminability/ Adoptability – What interventions are effective in having new communities adopt such a program? Hopkins PSMG Meeting

11. Extensibility Trials • Selection Bias -- ASU Braver • Participation Bias – UM, ASU, GW Price/Vinokur/Sandler/Howe -- U Miami Szapocznik Hopkins PSMG Meeting

12. Three Stages of a Trial Design Pre-Intervention Design Intervention Design Post-Intervention Design Hopkins PSMG Meeting Adapted from Brown & Liao, 1999

13. Extensibility Trials Participation Trials Can participation be increased and if so, how do these people benefit compared to those who would normally have participated? Hopkins PSMG Meeting

14. Extensibility Trial with Two Randomizations Trial Inside a Trial U Michigan, GW Sample Can participation be increased, and if so, how do these people benefit compared to those who would normally have participated? Randomize Intervention Control Randomize to Invitation Routine Intensity High Intensity Model Participation and Measure Outcomes MeasureParticipation and Measure Outcomes Hopkins PSMG Meeting

15. Newer Examples of Experimental Manipulations Extensibility Trial – Intervening to Increase Participation Effectiveness Trial -- Combinations of Intervention Components Sustainability Trial – Schedule for Supervision of a defined intervention Scalability Trial – Systems level intervention Hopkins PSMG Meeting

16. C. A General Framework for Randomizing Using Person Place, and Time Person Time Place Hopkins PSMG Meeting

17. Three Descriptive Epidemiologic Concepts Viewed Three Different Ways Hopkins PSMG Meeting

18. Units that can be Randomly Assigned in a Trial • Persons – Inclusion/Exclusion Criteria • Places/Groups – Random assignment at the group level Group/Cluster Randomized Trials- Murray Place-Based Randomized Trials -- Boruch • Time -- when to intervene Hopkins PSMG Meeting

19. Person Level Assignments Persons Target Population Inclusion / Exclusion Criteria Universal, Selective, Indicated, Treated Extensibility Trials: Does intervention work effectively for Prevention Lower risk subjects? Less likely to be identified or participate? Treatment Placebo Nonresponders? Genetic Risk? Hopkins PSMG Meeting

20. Place-Based Randomized Trials Places/Groups – Classroom, Schools, Child Welfare Settings, MH/Drug Abuse Clinics • Schools -- Sloboda 88 HS’s New DARE 7th & 9th • Classrooms within Schools – Balt Prev Pgm Brown & Liao (1999) Am J Commun Psychol • Rural Communities – PROGRESA, Mexico Hopkins PSMG Meeting

21. Time Assignments Time -- when to intervene Wait-listed design: Half initially half later Crossover Design A-B B-A Multiple Baseline Designs Hopkins PSMG Meeting

22. Time (Persons) Randomized Clinical Trial with Blocking on Time A B B A A B B A A B A B Hopkins PSMG Meeting

23. Person-Place Randomizations Interventions at Two Levels Example: Linking Classroom Prevention and an individually based Service Intervention within Schools Hopkins PSMG Meeting

24. Person/Place Hopkins PSMG Meeting

25. Place and Time Group Based, Wait-Listed Design Group Based, Multiple Baseline Design Hopkins PSMG Meeting

26. Randomization in Place and Time: D. Dynamic Wait-Listed Designs • Divide a set of schools into replicates • Randomly assign WHEN a replicate converts from wait-listed to active intervention Brown et al. (under review) Wyman, Brown Ga Gatekeeper Trial: NIMH Hopkins PSMG Meeting

27. Randomization in Place and Time:School-Based Gatekeeper Training for Suicide Prevention QPR: (Quinnett, 1995): • Question a person (showing warning signs) about suicide • Persuade the person to get help • Refer the person to the appropriate resource Identify recognizable behaviors (“threats of suicide”) Develop knowledge and skills to take action Hopkins PSMG Meeting

28. Primary Endpoint Rate of referral of youth by school staff for suicidality QPR should • Increase rate of referral in those schools that have been trained • Maintain this increase rate over the study Hopkins PSMG Meeting

29. Prevalence of Suicidal Behavior in Middle and High School Hopkins PSMG Meeting

30. Proportion of Suicidal Attempters Identified by School System 6% Hopkins PSMG Meeting

31. Probability that a Single Staff Member Would be able to Identify and Refer a Suicidal Child 0.03% Hopkins PSMG Meeting

32. Probability of Referral as Function of Proportion Trained and Training Effectiveness Hopkins PSMG Meeting

33. Comparison of Classic versus Dynamic Wait-Listed Designs Standard Wait-List Design Half are assigned immediately, half later Dynamic Wait-Listed Design Divide into replicates, then assign intervention or wait-listed control within each replicate Train in 1st replicate early intervention schools, then in 2nd replicate, etc. Hopkins PSMG Meeting

34. Classic and Dynamic Wait-Listed Design Hopkins PSMG Meeting

35. Comparing Power of Classic vs Dynamic Wait-Listed Design Assumptions • Poisson Rates of Referral that vary randomly over time but are proportional to time interval • Intervention Effect is Linear on the rate • General least squares analysis • Efficiency in Asymptotic Variance fctn of Intervals 2 / (Intervals 2 – 1) 3 18% 4 25% Limit 33% Hopkins PSMG Meeting

36. More Realistic Setting Poisson counts for each interval with a varying multiplicative rate parameter that has a Gamma distribution Log-Linear model for intervention impact Maximum likelihood analysis Hopkins PSMG Meeting

37. Efficiency Increases with Number of Time Blocks and Low Variability in Rates over Time Hopkins PSMG Meeting

38. Recommendation for the Current Trial Currently completed first half of trial with half receiving intervention, half wait-listed. Switch to a dynamic wait-listed design in the second phase, 4 groups of 4 schools Hopkins PSMG Meeting

39. Added Power from Dynamic Wait Listed Design Hopkins PSMG Meeting

40. E. Randomizations involving Person Place and Time • Timing of Multi Level Interventions • Testing of Intervention in the Presence of Gene by Environment Interactions Hopkins PSMG Meeting

41. Timing of Universal Classroom and Individual Level Interventions Hopkins PSMG Meeting

42. Serotonin Transporter Gene SLC6A4 Long and Short Forms Short form associated with increased depression, bipolar disorder, violent suicide Low CSF serotonin occurs among short allele monkeys who are raised in deprived environments, but not in mother raised environments Hopkins PSMG Meeting

43. Comparison of Interventions for Those with Genetic Risk (Short Alleles) Hopkins PSMG Meeting

44. Summary For Effectiveness Trials and Beyond Often Dictated by Community Needs “Everyone Gets This by a Certain Date” Randomization involving TIME Dynamic Wait-Listed Designs are Efficient Newer Designs often require randomization involving 2 or 3 of PERSON, PLACE, and TIME Hopkins PSMG Meeting