Causal diagrams, the placebo effect, and the expectation effect

1. Causal diagrams, the placebo effect, and the expectation effect Eyal Shahar, MD, MPH Professor (credit to Doron Shahar, BS) December 5, 2013

2. Outline • Principles of causal diagrams • What is “placebo”? • What is the “placebo effect”? • The expectation effect rather than the placebo effect • Previous study designs • Suggested study design

3. Principles of causal diagrams • Name the variables • TOFFERED • TTAKEN • D • … • … • … • Draw postulated arrows (from cause to effect) • Depict theories of confounding bias • Depict theories of effect modification

4. Example Modifier Q r D TTAKEN TOFFERED q R C Modifier Confounder

5. Example: an elaborated diagram* Blinding status B t (offered) Expectation E b t (taken) All possible causes of the offered treatment e R D TTAKEN TOFFERED b *Note theories of effect modification

6. A successful double-blinded randomized trial B = blinded t (offered) E t (taken) B=blinded: null effect e R D TTAKEN TOFFERED B=blinded: null effect

7. Outline • Principles of causal diagrams • What is “placebo”? • What is the “placebo effect”? • The expectation effect rather than the placebo effect • Previous study designs • Suggested study design

8. What is “placebo”? • Too many definitions to cover • All allude to “effect” or “lack of effect” • Yet, most cannot be encoded in a causal diagram A VERY BAD SIGN!

9. What is “placebo”? • “A treatment that does not objectively affect the outcome” • A meaningless adverb • No such thing as “objectively affect” • No such thing as “subjectively affect” • Can’t depict in a diagram • Not rigorous enough for science

10. What is “placebo”? • “An inert/inactive/ineffective treatment” • Really?How do you know, in advance, that something doesn’t have an effect? • And what about the “placebo effect”? • Can’t depict in a diagram • Not rigorous enough for science

11. What is “placebo”? • “A treatment that on its own has no beneficial effect” • What exactly is “on its own”? • Can’t depict in a diagram • Not rigorous enough for science

12. Placebo: a possible definition • “A treatment is called placebo if the effect of that treatment (versus no treatment) is null when the patient has no particular expectation about the outcome.”

13. t0 below (a value of TTAKEN) is “placebo” E t E=indifference: null effect t0 vs. nothing D=d TOFFERED TTAKEN

14. So, what is the desired definition of placebo? • Who cares? • Definitions are much less important than we tend to think • We don’t really need the term to acquire knowledge

15. Outline • Principles of causal diagrams • What is “placebo”? • What is the “placebo effect”? • The expectation effect rather than the placebo effect • Previous study designs • Suggested study design

16. The placebo effect • At least 6 definitions • All are clear (for a change…) • Can be depicted in a causal diagram • Some refer to placebo • Which requires a clear definition of placebo… • Some do not refer to placebo at all! • Can be organized in two groups

17. Group 1: Some effect of a treatment variable on some value of the outcome variable TTAKEN D=d placebo vs. nothing E tTAKEN E = e placebo vs. nothing D=d TTAKEN D=d TOFFERED placebo vs. nothing

18. Group 2: Some effect of the expectation variable on some value of the outcome variable E D=d TTAKEN = placebo E D=d TTAKEN TTAKEN = t E D=d TTAKEN

19. Outline • Principles of causal diagrams • What is “placebo”? • What is the “placebo effect”? • The expectation effect rather than the placebo effect • Previous study designs • Suggested study design

20. The expectation effect B = blinded t (offered) E t (taken) B=blinded: null effect e R D TTAKEN TOFFERED B=blinded: null effect

21. The expectation effect • No need to mention the word “placebo” E TTAKEN = t D=d e TTAKEN • The effect of expectation might vary according to the treatment taken • The effect of the treatment taken might vary according to the level of expectation

22. Expectation: two kinds of questions • Causes of expectation • Effects of expectation A W B X E E C Y D Z And don’t forget the possibility of effect modification for each arrow

23. Outline • Principles of causal diagrams • What is “placebo”? • What is the “placebo effect”? • The expectation effect rather than the placebo effect • Previous study designs • Suggested study design

24. Previous study designs • Claim to estimate the “placebo effect” • Don’t estimate the same effect • Don’t estimate well the expectation effect

25. Previous study designs Three arms Concealed treatment Patient told Patient told Drug Drug Treatment Placebo Treatment Drug Nothing Balanced placebo design Patient told Drug Treatment Placebo

26. What’s the problem? • “TELLING” and “EXPECTING” are different variables • Telling the patient something affects expectation, but does not fully determine expectation • There are other causes of expectation: • Trust • Prior beliefs • Education • None of these designs estimates well the expectation effect

27. Outline • Principles of causal diagrams • What is “placebo”? • What is the “placebo effect”? • The expectation effect rather than the placebo effect • Previous study designs • Suggested study design

28. Measure expectation! B = blinded t (offered) E* E t (taken) B=blinded: null effect e R D TTAKEN TOFFERED B=blinded: null effect

29. What is “expectation”? • A single variable or multiple variables? • Don’t know • Have psychologists figured it out? • Maybe (or maybe not) • How do we measure the variable(s)? • I am no expert in psychology and mental state variables

30. Conclusions (1) • “Placebo” and “placebo effect” are vague terms • Stop using them; they are poorly defined • Stop using them; neither is needed to advance knowledge • The “placebo” pill is made up of something. Call it by its name (its chemical composition)

31. Conclusions (2) • Measure expectation! • Study the causes and effects of expectation!! • Use an observational cohort within a blinded randomized trial!!! • Deal with confounding bias and explore effect-modification

32. Causal diagrams, the placebo effect, and the expectation effect. Shahar E, Shahar DJ. Int J Gen Med. 2013 Sep 27;6:821-8 PMID: 24101881 [PubMed] Free PMC Article Thank you