Hopkins PSMG Meeting Randomized Designs for Person, Place, and Time For 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 Support R01-MH40859 (Brown) Methodology for Mental Health / Drug Abuse Prevention & Early Intervention Designs & Analyses for Mental Health Preventive Trials NIMH and NIDA 3R01MH S1 (Brown) Methodology for Population-Based Approaches to the Prevention of Suicide NIMH Office of Rare Diseases CDC Injury Prevention Center R34MH (Wyman) RCT of Gatekeeper Training for Suicide Prevention NIMH P20MH (Caine) Developing Center On Public Health and Population Interventions For The Prevention Of Suicide NIMH

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

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

Hopkins PSMG Meeting 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 Prevention Field Trials Needed to Determine Precise Information about What Works For Whom Under What Conditions Because …

Hopkins PSMG Meeting There are very few Broad Street Pump Handles Left to Remove John Snows Map of London

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

Hopkins PSMG Meeting B. Typology of Research Questions/Designs 1)Efficacy – Impact in optimally controlled settings 2)Effectiveness – Impact in real world settings 3)Implementability – What level of intervention produces what level of impact; what does it take to implement? 4)Adaptability – How does variation in intervention delivered affect impact? 5)Extensibility – What impact is achieved when delivered to different persons/settings? 6)Sustainability – Does impact continue after training ? 7)Scalability– What impact is achieved when the intervention is expanded system wide, or in larger contexts? 8)Disseminability/ Adoptability – What interventions are effective in having new communities adopt such a program?

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

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

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

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

Hopkins PSMG Meeting Three Descriptive Epidemiologic Concepts Viewed Three Different Ways

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

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

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

Hopkins PSMG Meeting Person/Place UnitCombinations of Interventions SchoolAssign Available Services No Available Services Classrm UniversalNo Universal UniversalNo Universal Child Moderate High Moderate High Moderate High Moderate High

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

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

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

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

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

Hopkins PSMG Meeting 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 1 st replicate early intervention schools, then in 2 nd replicate, etc.

Hopkins PSMG Meeting Classic and Dynamic Wait-Listed Design

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

Hopkins PSMG Meeting 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 Added Power from Dynamic Wait Listed Design

Hopkins PSMG Meeting 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 Timing of Universal Classroom and Individual Level Interventions

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

Hopkins PSMG Meeting 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