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

2. Overview Planning Grant writing Implementation Analyses
Publishing the findings
Next grants

3. 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

4. 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

5. 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

6. 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

7. 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.

8. 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.

9. 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.

10. 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

11. 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!

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

13. Setting Up Study Schedule

14. Schedule

15. Setting Up Database Flowsheets

16. Database Flowsheets

17. 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

18. 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

19. 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

20. 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.

21. 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

22. 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

23. 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

24. 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)

25. CONSORT Diagram

26. 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)

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

28. ClinicalTrials.gov
Outcomes by intervention condition

29. 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

30. 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).

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

32. 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

33. 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

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

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

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

37. 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

38. 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

39. 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

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

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

42. Psychiatric History x In-Person Counseling Interaction

43. Psychiatric History x In-Person Counseling Interaction

44. Cigarettes Per Day Moderator

45. Cigarettes Per Day Moderator

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

47. 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

48. 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

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

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

51. 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

52. 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

53. 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

54. 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

55. 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

56. RCT Outcomes
Treatment Engagement
Effectiveness
Cost-effectiveness

57. Funding
Grant 9P50CA from the National Cancer Institute to the University of Wisconsin- Center for Tobacco Research and Intervention
Grants 1K05CA and T32HP10010 from NIH
The Wisconsin Partnership Program.
Collaborative team effort between the UW- CTRI, University of Illinois at Chicago, and Penn State University

58. 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