Eyal Shahar, MD, MPH Professor (credit to Doron Shahar, BS)
December 5, 2013
Slide 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
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Principles of causal diagrams Name the variables T OFFERED T
TAKEN D Draw postulated arrows (from cause to effect) Depict
theories of confounding bias Depict theories of effect
modification
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Example D Q R q r T OFFERED T TAKEN C Confounder Modifier
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Example: an elaborated diagram* T OFFERED D E R B b t ( TAKEN )
t ( OFFERED ) b T TAKEN e Blinding status Expectation All possible
causes of the offered treatment *Note theories of effect
modification
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A successful double-blinded randomized trial T OFFERED D E R B
t ( TAKEN ) t ( OFFERED ) B =blinded: null effect T TAKEN e =
blinded
Slide 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
Slide 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!
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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 Cant depict in a
diagram Not rigorous enough for science
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What is placebo? An inert/inactive/ineffective treatment
Really? How do you know, in advance, that something doesnt have an
effect? And what about the placebo effect? Cant depict in a diagram
Not rigorous enough for science
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What is placebo? A treatment that on its own has no beneficial
effect What exactly is on its own? Cant depict in a diagram Not
rigorous enough for science
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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.
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t 0 below (a value of T TAKEN ) is placebo T OFFERED T TAKEN
D=d E t E=indifference: null effect t 0 vs. nothing
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So, what is the desired definition of placebo? Who cares?
Definitions are much less important than we tend to think We dont
really need the term to acquire knowledge
Slide 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
Slide 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
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Group 1: Some effect of a treatment variable on some value of
the outcome variable T TAKEN D=d E placebo vs. nothing T TAKEN D=d
E = e placebo vs. nothing D=d placebo vs. nothing T OFFERED t
TAKEN
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Group 2: Some effect of the expectation variable on some value
of the outcome variable E D=d E T TAKEN T TAKEN = placebo E D=d T
TAKEN = t T TAKEN
Slide 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
Slide 20
The expectation effect T OFFERED D E R B t ( TAKEN ) t (
OFFERED ) B =blinded: null effect T TAKEN e = blinded
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The expectation effect No need to mention the word placebo E
D=d T TAKEN = t T TAKEN e 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
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Expectation: two kinds of questions Causes of expectation
Effects of expectation E A B C D E W X Y Z And dont forget the
possibility of effect modification for each arrow
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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
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Previous study designs Claim to estimate the placebo effect
Dont estimate the same effect Dont estimate well the expectation
effect
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Previous study designs Drug or placebo Neither drug nor placebo
Drug Nothing Drug Placebo DrugPlacebo Drug Treatment Patient told
Treatment Patient told Placebo Nothing Three arms Concealed
treatment Balanced placebo design
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Whats 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
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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
Slide 28
Measure expectation! T OFFERED D E R B t ( TAKEN ) t ( OFFERED
) B =blinded: null effect T TAKEN e = blinded E*E*
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What is expectation? A single variable or multiple variables?
Dont 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
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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)
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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
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Thank you 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 ArticleFree PMC
Article