Factorial designs in tobacco treatment research: From funding to publication May 17, 2016

Overview Planning Grant writing Implementation Analyses Publishing the findings Next grants

Planning Focused on intervention components that: Addressed phase-specific challenges Prequit and early cessation Needed to be compared head-to-head Would work well together Could be implemented in a real-world clinical context

P50 Center Grant Engineering Effective Interventions for Tobacco Use: A Translational Laboratory 3 R01s Motivation Cessation Maintenance and Adherence 4 Cores Administrative Intervention Optimization Methods Mentoring, Education, and Dissemination More space to set the stage for the methods

Grant Writing Concerns Use of language Intervention component vs. treatment package RCT vs. factorial experiments Rationale for selection of components Components can all work together Plan for program of research, including next steps

Ecological Momentary Assessments Use Graphics Preparation Phase Cessation Phase Maintenance Phase Preparation Patch Preparation Gum Preparation Counseling In-Person Counseling Phone Counseling Extended Medication ( 8 vs. 16 weeks) Ecological Momentary Assessments -3 Wks Target Quit Day 2 Wks 8 Wks 16 Wks 26 Wks

Grant Strengths A major strength of the Center is the integration between theory and intervention methods The authors make a compelling case that current weaknesses in the field include a need for novel interventions This Center’s engineering-based optimization model is a quite innovative way to approach the process of intervention building, in the domain of substance use It proposes a new and perhaps better mousetrap for conducting tests of intervention effectiveness – particularly those relevant to substance abuse treatment.

Grant Strengths The current application develops a methodologically innovative approach to differentiating effective treatment components and combinations at different phases of cessation. There are some considerable strengths in this application—the most compelling of which is the uniqueness of the optimization model and the talents of its core investigators Its novel Cyclical model is an innovative jumping-off point for framing unique directions in smoking cessation interventions---and for the development of intervention processes for multiple domains of risk and distress. The framework proposed is cumbersome, but it offers a principled, systematic way to develop interventions using the scientific method, which is quite significant.

Grant Critiques One drawback of the approach is that the initial cycle runs leave one “stuck’ with the conditions and components that one first inserts in the intervention model. As necessitated by the complexity of the overall methodological approach proposed, there is some lack of detail about the nuts and bolts of the methodology. …if the components do not work especially well, or combine well, the process goes back to the drawing board to try different interventions or combinations of interventions. Failure is progress, too, but there is a level of risk to the use of this reductionist, long-view approach. It would be useful to have more information in the Preliminary Studies section about how this has worked, or had problems, in applications to health and health-related research.

Key Par tners for Translational Research A Large EHR Vendor: Epic Systems Corporation 2 Large Healthcare Systems: Aurora & Dean University-Based Scientists:  UW-CTRI  UI-Chicago  Penn State

Implementation Issues 3 R01’s simultaneously implemented in primary care clinics Smokers not yet ready to quit Smokers ready to quit Training staff and treatment fidelity Taped sessions Coded for compliance Database is key!

Database Issues Separated out 3 studies What to do when Randomized to one of 2 cessation trials Guided phone screens What to do when

Setting Up Study Schedule

Schedule

Setting Up Database Flowsheets

Database Flowsheets

Project 2 Goal To identify promising Pre-Cessation and Cessation intervention components that could be combined in an optimized comprehensive cessation treatment Motivation Pre-Cessation Cessation Maintenance -3 weeks Target Quit Day 2 weeks 26 weeks

Intervention Components Prequit Nicotine Patch 3 weeks patch (ON) vs. None (OFF) 14 mg Prequit Nicotine Gum 3 weeks gum (ON) vs. None (OFF) 2 mg Choice of mint or fruit

Intervention Components Prequit Counseling Intensive (ON) vs. None (OFF) 2 in-person (1 and 3 weeks pre-quit) and 1 call (2 weeks pre-quit) 20 min. sessions Practice quit attempts, reduction, changing patterns

Intervention Components Combination NRT Duration 16 weeks (ON) vs. 8 weeks (OFF) Nicotine patch + nicotine gum Clear that these next 3 are Cessation phase interventions.

Intervention Components InPerson Counseling Intense (ON) vs. Minimal (OFF) Intense: 3, 20-min sessions 1 week pre-quit, Quit day, 1 week post-quit Minimal: 1, 3-min session 1 week pre-quit Phone Counseling 3, 15-min calls Quit day, Day 2 and 7 1, 10-min call Quit day

Fractional Factorial Design 6 interventions = 2x2x2x2x2x2 = 64 conditions Fractional factorial design reduces 64 to 32 conditions Aliasing (confounding) individual higher order effects, which are assumed to be 0, with the individual main effects and 2-way interaction effects Resolution VI fractional factorial design

Example Treatment Conditions   Pre-Cessation Intervention Components Cessation Intervention Components Condition Nicotine Gum Nicotine Patch Pre-Cessation Coaching Medication Duration In-Person Coaching Telephone Coaching 1 Gum Patch None 8 weeks Intensive Minimal 2 No patch Coaching 16 weeks 3 No gum

Sample 637 primary care patients 55% women 88% white; 8% African-American 3% Hispanic 16% college degree or higher 45.8 years old (SD = 12.0) 17.7 cigarettes per day (SD = 8.2)

CONSORT Diagram

Preparation Counseling Descriptives   Total Sample Prequit Gum Prequit Patch Preparation Counseling In-Person Counseling Phone Counseling Medication Duration On Off Women (%) 54.6 54.3 55.0 55.3 53.9 54.7 55.4 53.8 55.5 56.3 53.2 Age (mean, SD) 45.8 (12.0) 45.3 (11.9) 46.2 (12.2) 45.2 (11.8) 46.3 (12.3) 45.8 (12.2) 45.7 (11.9) 45.1 (12.0) 46.4 (12.0) 45.1 (12.2) 46.4 (11.6) High School diploma or GED only (%) 31.4 32.0 30.7 31.5 34.5 28.4 30.1 32.7 32.5 30.4 30.6 32.2 At least some college (%) 58.7 57.2 60.2 57.6 59.7 55.7 61.5 58.2 58.1 59.1 60.1 57.3 White (%) 87.8 87.7 88.5 87.0 89.5 86.0 88.4 African-American (%) 7.8 9.0 6.5 8.6 7.0 6.7 8.9 8.4 7.2 9.3 6.4 Hispanic (%) 3.9 4.5 3.1 4.7 4.2 3.5 3.2 5.1 2.8 Health System A (%) 59.4 59.9 54.5 56.8 57.8 61.1 53.6 60.9 54.1 Cigs/day (mean, SD) 17.7 (8.2) 17.5 (8.4) 17.9 (7.9) 18.1 (8.0) 17.2 (8.4) 17.8 (8.4) 17.5 (8.1) 17.9 (8.2) 17.4 (8.2) 18.1 (8.4) 17.3 (7.9) 17.8 (7.8) 17.6 (8.5) Baseline carbon monoxide (mean, SD) 20.3 (11.4) 20.3 (11.7) 20.4 (11.0) 20.6 (10.7) 20.0 (12.1) 20.6 (11.3) 20.0 (11.4) 20.3 (11.6) 20.4 (11.1) 20.2 (11.4) 20.4 (11.3) 19.6 (10.8) 21.0 (11.9) FTND (mean, SD) 4.8 (2.2) 4.8 (2.1) 4.8 (2.3) 4.9 (2.2) 4.7 (2.1) 4.9 (2.1) Heaviness of Smoking Index (mean, SD) 3.1 (1.4) (1.4) 3.0 (1.4) 3.1 (1.5) 3.2 (1.4) 3.0 (1.5)

ClinicalTrials.gov Not set up for factorial designs Describe each intervention – minimal and intensive Study Arms = 32

ClinicalTrials.gov Outcomes by intervention condition

Factorial Design Results Treatment engagement in each component How components do or do not work together Main and interaction effects on: Outcome Mechanisms Effects for different types of smokers

Treatment Engagement Intensive Cessation In-Person Counseling condition completed 2.13 (SD=1.13) out of 3 sessions Significantly more than the Intensive Cessation Phone Counseling condition (M=1.74 out of 3 sessions, SD=1.19, p<.01).

Analytic Approach General linear models 6 main effects 15 2-way interactions using effect coding Levels are coded -1 and +1

Cessation Outcome Tables   Percent Abstinent at 2 Weeks Percent Abstinent at 16 Weeks Percent Abstinent at 26 Weeks Factor On Off Preparation Patch 44.1 43.2 36.5 32.5 29.8 26.0 Preparation Gum 43.4 44.0 36.3 32.6 25.8 Preparation Counseling 44.5 42.8 38.2 30.9 30.3 25.6 Cessation In-Person Counseling 47.5 39.9 32.8 27.7 28.2 Cessation Phone Counseling 43.1 44.2 35.6 33.4 Medication Duration 36.2 33.0 28.5 27.3

  2 Weeks Post-TQD 16 Weeks Post-TQD 26 Weeks Post-TQD Unadjusted Adjusted** Variable b p-value Intercept -.26 .001 .43 .45 -.70 <.001 -.69 .25 -1.04 -.34 .59 Preparation Patch .01 .87 .04 .66 .08 .34 .11 .22 .09 .24 Preparation Gum -.01 .95 -.00 .96 .21 .12 .19 .20 .23 Preparation Counseling .03 .69 .60 .18 Cessation In-Person Counseling .14 .10 .15 .07 .05 .54 .06 .48 -.04 .68 -.03 .80 Cessation Phone Counseling .72 .75 Medication Duration .02 .78 .91 .39 .46 -.02 .73 Preparation Patch x Preparation Gum .56 .65 .53 Preparation Patch x Preparation Counseling .16 .050 .17 Preparation Patch x Cessation In-Person Counseling Preparation Patch x Cessation Phone Counseling .047 .13 Preparation Patch x Medication Duration -.06 .50 -.07 .00 .97 .84 Preparation Gum x Preparation Counseling .52 -.11 -.05 .61 -.09 .35 Preparation Gum x Cessation In-Person Counseling Preparation Gum x Cessation Phone Counseling .37 -.08 .93 .51 Preparation Gum x Medication Duration .99 .89 .67 Preparation Counseling x Cessation In-Person Counseling -.10 .26 -.17 -.16 Preparation Counseling x Cessation Phone Counseling 1.00 -.18 -.19 -.14 Preparation Counseling x Medication Duration .58 .29 .27 Cessation In-Person Counseling x Cessation Phone Counseling .47 -.28 .002 -.23 Cessation In-Person Counseling x Medication Duration -.13 .40 Cessation Phone Counseling x Medication Duration .81

What To Do With Interactions? Not powered for simple effects Graph outcomes

In-Person x Pre-quit Gum Interaction 26-week point-prevalence abstinence Similar trends at 8 and 16 weeks

In-Person x Phone Counseling Interaction 26-week point-prevalence abstinence Similar trends at 8 and 16 weeks

Main Findings 2 promising treatments Pre-quit nicotine patch + intensive in-person cessation counseling Pre-quit nicotine gum + intensive in-person cessation counseling Likely redundant treatment combination Intensive in-person cessation counseling + intensive phone cessation counseling

For Whom Do Treatments Work? Determine whether easily assessable demographic and tobacco dependence variables predict a differential response to these 6 intervention components Demonstrates stability of effects Determine whether a treatment with no significant main effect may actually be effective for a specific sub-group

Possible Moderators Gender: 55% women Race: 89% White Education: 41% high school or less Psychiatric comorbidity: 41% ≥ 1 diagnosis Dependence: 34% smoke within 5 min Living with a smoker: 21% live with smoker

Moderation Models Using GLM Base model 6 main effects + 3 significant 2-way interactions Demographic moderator model Base model + gender + race + education + psychiatric history + 24 2-way moderator x intervention interactions + 12 3-way moderator x intervention x intervention interactions Smoking moderator model Base model + time to first cigarette + cigarettes per day + living with a smoker + 18 2-way moderator x intervention interactions + 9 3-way moderator x intervention x intervention interactions

Demographic Moderators Psychiatric history moderated the effects Precessation Counseling In-Person Counseling Medication Duration In-Person x Phone Counseling interaction

Psychiatric History x In-Person Counseling Interaction

Psychiatric History x In-Person Counseling Interaction

Cigarettes Per Day Moderator

Cigarettes Per Day Moderator

Moderation Conclusions Psychiatric and dependence indicators can predict differential response to specific intervention components

What Do These Treatments Do? Understanding how treatments work can: Guide treatment choice Guide treatment combination Identify the need for treatments to address specific mechanisms Mechanism Treatment/ Action Model Conceptual/ Outcome Model Treatment Outcome

Hypothesized Mechanisms Reduced prequit smoking rate Prequit Patch, Prequit Gum, Prequit Counseling Increased post-quit medication use Prequit Patch, Prequit Gum, Prequit Counseling, InPerson Counseling, Phone Counseling, Maintenance Medication Reduced withdrawal Prequit: Prequit Patch, Prequit Gum, Prequit Counseling Postquit: Prequit Patch, Prequit Gum, Prequit Counseling, InPerson Counseling, Phone Counseling

Hypothesized Mechanisms Increased use of coping skills Prequit Counseling, InPerson Counseling, Phone Counseling Avoiding smoking temptation and cues Increased motivation

Hypothesized Mechanisms Increased intra-treatment social support Prequit Counseling, InPerson Counseling, Phone Counseling Decreased long-term withdrawal Maintenance Medication Increase self-efficacy All components

Analytic Approach General linear models and generalized linear regression models 6 main effects and 15 2-way interactions Effect coding -1 and +1 Included all main effects and two-way interactions so that the influence of all factors could be controlled in statistical tests Two-way interactions evaluated only if significant main effect for one or more of the contributing factors Standard p < .05 and Benjamini-Hochberg p-value (for the 21 effects in each hypothesis test) to control for false discovery rate

Main Effects Interaction Effects* Reduced prequit smoking Increased postquit gum use Interaction Effects* Increased prequit coping Preparation Gum x Preparation Counseling Preparation Patch Increased postquit coping Preparation Gum Preparation Gum x Cessation In-Person Counseling Increased prequit motivation Preparation Counseling Intratreatment social support Preparation Counseling x Cessation In-Person Counseling Cessation In-Person Counseling Increased prequit self-efficacy Increased postquit self-efficacy Cessation Phone Counseling Reduced withdrawal Reduced cue exposure Not significant after controlling for postquit smoking *See Figures 4-7 for the nature of the interaction effects Increased postquit motivation

Mechanisms Inform Optimization Pre-quit Patch vs. Gum Patch didn’t influence post-quit coping or post-quit medication use; no interactions No components reduced withdrawal or increased post-quit self-efficacy Intervention component selection would be similar for cessation and mechanism outcomes Pre-quit Gum Intensive In-Person Counseling Preparation Counseling

Conclusions New methodology let us answer important questions Significant treatment interactions Not everyone responds the same way to treatments Treatments may not be doing what we think they are doing We need to know more

Next Steps P01 – RCT Abstinence-Optimized Cessation treatment Pre-quit Mini-lozenge Intensive In-Person Counseling Maintenance Counseling cCalls 26 weeks Combination NRT Automated Adherence Calls Modern Usual Care 8 weeks Nicotine Patch 1 In-Person Counseling session Referral to Quitline and Quitline app

RCT Outcomes Treatment Engagement Effectiveness Cost-effectiveness

Funding Grant 9P50CA143188 from the National Cancer Institute to the University of Wisconsin- Center for Tobacco Research and Intervention Grants 1K05CA139871 and T32HP10010 from NIH The Wisconsin Partnership Program. Collaborative team effort between the UW- CTRI, University of Illinois at Chicago, and Penn State University

Acknowledgements Michael Fiore (PI) Timothy Baker (PI) Daniel Bolt Linda Collins Douglas Jorenby Robin Mermelstein Bruce Christiansen Jessica Cook Kathi Diviak Meg Feyen David Fraser Todd Hayes-Birchler Chris Hollenback Paul Kohn Madeline Oguss Megan Piper Holly Prince Tanya Schlam Stevens Smith Nick Wiley 14 Health Counselors 34 Undergraduates