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Eyal Shahar, MD, MPH Professor (credit to Doron Shahar, BS) December 5, 2013

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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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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

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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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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

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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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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

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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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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

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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