Causal diagrams, the placebo effect, and the expectation effect

Causal diagrams, the placebo effect, and the expectation effectEyal Shahar, MD, MPHProfessor(credit to Doron Shahar, BS)

December 5, 2013OutlinePrinciples of causal diagramsWhat is placebo?What is the placebo effect?The expectation effect rather than the placebo effectPrevious study designsSuggested study designPrinciples of causal diagramsName the variablesTOFFEREDTTAKEND

Draw postulated arrows (from cause to effect)Depict theories of confounding biasDepict theories of effect modification

ExampleDQRqrTOFFEREDTTAKENCConfounderModifierModifierExample: an elaborated diagram*TOFFEREDDERBbt (taken)t (offered)bTTAKENeBlinding statusExpectationAll possible causes of the offered treatment*Note theories of effect modificationA successful double-blinded randomized trialTOFFEREDDERBt (taken)t (offered)B=blinded: null effectB=blinded: null effectTTAKENe= blindedOutlinePrinciples of causal diagramsWhat is placebo?What is the placebo effect?The expectation effect rather than the placebo effectPrevious study designsSuggested study designWhat is placebo?Too many definitions to coverAll allude to effect or lack of effectYet, most cannot be encoded in a causal diagramA VERY BAD SIGN!

What is placebo?A treatment that does not objectively affect the outcome

A meaningless adverbNo such thing as objectively affectNo such thing as subjectively affectCant depict in a diagramNot rigorous enough for scienceWhat 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 diagramNot rigorous enough for scienceWhat is placebo?A treatment that on its own has no beneficial effect

What exactly is on its own?Cant depict in a diagramNot rigorous enough for sciencePlacebo: a possible definitionA 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. t0 below (a value of TTAKEN) is placeboTOFFEREDTTAKEND=dEtE=indifference: null effect t0 vs. nothing So, what is the desired definition of placebo?Who cares?Definitions are much less important than we tend to thinkWe dont really need the term to acquire knowledgeOutlinePrinciples of causal diagramsWhat is placebo?What is the placebo effect?The expectation effect rather than the placebo effectPrevious study designsSuggested study designThe placebo effectAt least 6 definitionsAll are clear (for a change)Can be depicted in a causal diagramSome refer to placeboWhich requires a clear definition of placeboSome do not refer to placebo at all!Can be organized in two groups

Group 1: Some effect of a treatment variable on some value of the outcome variableTTAKEND=dEplacebo vs. nothing TTAKEND=d E = eplacebo vs. nothing D=dplacebo vs. nothing TOFFEREDtTAKENGroup 2: Some effect of the expectation variable on some value of the outcome variableED=dED=dTTAKENTTAKEN = placeboED=dTTAKEN = tTTAKENOutlinePrinciples of causal diagramsWhat is placebo?What is the placebo effect?The expectation effect rather than the placebo effectPrevious study designsSuggested study designThe expectation effectTOFFEREDDERBt (taken)t (offered)B=blinded: null effectB=blinded: null effectTTAKENe= blindedThe expectation effectNo need to mention the word placeboED=dTTAKEN = tTTAKENeThe effect of expectation might vary according to the treatment takenThe effect of the treatment taken might vary according to the level of expectationExpectation: two kinds of questionsCauses of expectationEffects of expectationEABCDEWXYZAnd dont forget the possibility of effect modification for each arrowOutlinePrinciples of causal diagramsWhat is placebo?What is the placebo effect?The expectation effect rather than the placebo effectPrevious study designsSuggested study designPrevious study designsClaim to estimate the placebo effect

Dont estimate the same effect

Dont estimate well the expectation effectPrevious study designsDrug or placeboDrug or placeboNeither drug nor placeboDrugNothingDrugDrugPlaceboDrugPlaceboPlaceboDrugDrugDrugTreatmentPatient toldTreatmentTreatmentPatient toldPatient toldPlaceboNothingThree armsConcealed treatmentBalanced placebo designWhats the problem?TELLING and EXPECTING are different variablesTelling the patient something affects expectation, but does not fully determine expectationThere are other causes of expectation:TrustPrior beliefsEducationNone of these designs estimates well the expectation effectOutlinePrinciples of causal diagramsWhat is placebo?What is the placebo effect?The expectation effect rather than the placebo effectPrevious study designsSuggested study designMeasure expectation!TOFFEREDDERBt (taken)t (offered)B=blinded: null effectB=blinded: null effectTTAKENe= blindedE*What is expectation?A single variable or multiple variables?Dont knowHave psychologists figured it out?Maybe (or maybe not)How do we measure the variable(s)?I am no expert in psychology and mental state variablesConclusions (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)

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

Thank you

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