designing clinical research 2009 confounding and causal inference warren browner

Designing Clinical Designing Clinical Research 2009Research 2009

Confounding and Causal Inference

Warren Browner

ConfoundingConfounding

Guaranteed to be confusing.Guaranteed to be confusing.

If you think you understand it, you If you think you understand it, you probably don’t. probably don’t.

I often revert to an analogy involving I often revert to an analogy involving smoking, carrying matches, and lung smoking, carrying matches, and lung cancer.cancer.

Confounding, Round OneConfounding, Round One

A problem in understanding what the A problem in understanding what the associationassociation between two variables between two variables means.means. No association, no confounding to worry No association, no confounding to worry

aboutabout

Example: A study which finds that people Example: A study which finds that people who carry matches are more likely to get who carry matches are more likely to get lung cancer.lung cancer.

Confounding, Round TwoConfounding, Round Two

Confounding only matters in studies Confounding only matters in studies that attempt to show that an that attempt to show that an association between a predictor and association between a predictor and an outcome is an outcome is causal.causal.

Is the association between carrying matches Is the association between carrying matches and lung cancer causal?and lung cancer causal?

Or is the association confounded by Or is the association confounded by something else?something else?

Confounding, Round Confounding, Round ThreeThree

Confounding is irrelevant in…Confounding is irrelevant in… Diagnostic and prognostic test studiesDiagnostic and prognostic test studies

Is cough a useful sign for the diagnosis of lung Is cough a useful sign for the diagnosis of lung cancer?cancer?

Risk assessmentRisk assessment You’re trying to determine whether people who You’re trying to determine whether people who

carry matches are at greater risk of lung cancer.carry matches are at greater risk of lung cancer.

Confounding, A PictureConfounding, A Picture

Lung cancer(outcome)

Carrying matches(predictor?)




Smoking cigarettes(confounder)




Smoking cigarettes(confounder)

Carrying matches does not cause lung cancer; smoking does.

Huh, Aren’t All Associations Huh, Aren’t All Associations Causal?Causal?

Nope. Most aren’t!Nope. Most aren’t!

Hard for us to believe. We excel at Hard for us to believe. We excel at ascribing causes. ascribing causes.

Think about the last time you “just Think about the last time you “just knew” someone who wronged you did knew” someone who wronged you did so intentionally.so intentionally.

What are Some Other What are Some Other Explanations?Explanations?

The Big FiveThe Big Five ChanceChance BiasBias Effect-causeEffect-cause ConfoundingConfounding

Cause-effectCause-effect

Five Potential Explanations for Five Potential Explanations for Associations Made in Associations Made in Observational StudiesObservational Studies

Spurious (not real)Spurious (not real)

1) Chance1) Chance Bottled water and lung Bottled water and lung cancercancer

(tested 100 exposures, P < (tested 100 exposures, P < 0.05)0.05)

2) Bias2) Bias Coffee and lung cancerCoffee and lung cancer (controls had GERD)(controls had GERD)


Real, but not causalReal, but not causal

3) 3) Effect – causeEffect – cause Cough and Cough and lung cancerlung cancer

4)4) ConfoundingConfounding Carrying matches andCarrying matches and lung cancer lung cancer


CausalCausal

5) Cause – effect5) Cause – effect Cigarettes Cigarettes and lung and lung

cancercancer

Surely This is a Mistake Surely This is a Mistake that Pros Don’t Makethat Pros Don’t Make

They do.They do.

Famous “proof” that smoking causes Famous “proof” that smoking causes cervical cancer (i.e., that confounding cervical cancer (i.e., that confounding was unlikely).was unlikely).

But confounding can result in strong But confounding can result in strong associations.associations.

An Example of ConfoundingAn Example of Confounding

CA

OR = ???

NO CA

MATCHES

NO MATCHES

Case-control study:1000 cases of lung cancer, 82% carry matches (or a lighter)1000 controls (no cancer), 34% carry matches

An Example of ConfoundingAn Example of Confounding

CA

OR = = 8.84

820x660180x340

34018

0

820 66

0

NO CA

MATCHES

NO MATCHES

Carrying matches increases the risk (odds) of lung cancer almost 9-fold!

What’s the Problem?What’s the Problem?

It is ABSOLUTELY true that people It is ABSOLUTELY true that people who carry matches are at increased who carry matches are at increased risk of lung cancerrisk of lung cancer

But it is NOT true (right?) that But it is NOT true (right?) that carrying matches carrying matches causescauses lung cancer. lung cancer.

What is going on? (Duh…)What is going on? (Duh…)

What’s Going On?What’s Going On?

90% of lung cancer patients smoke90% of lung cancer patients smoke 30% of controls smoke30% of controls smoke

90% of smokers carry matches90% of smokers carry matches 10% of non-smokers carry matches10% of non-smokers carry matches

Smoking Smoking confoundsconfounds the association the association between carrying matches and lung between carrying matches and lung cancercancer

Still Skeptical?Still Skeptical?

I mean, the odds ratio was I mean, the odds ratio was almost 9!almost 9!

Let’s Work This OutLet’s Work This Out

1000 cases, 820 carry matches 900 smoke, 90% of whom carry matches900 smoke, 90% of whom carry matches 100 don’t smoke, 10% of whom carry 100 don’t smoke, 10% of whom carry

matchesmatches

1000 controls, 340 carry matches 300 smoke, 90% of whom carry matches300 smoke, 90% of whom carry matches 700 don’t smoke, 10% of whom carry 700 don’t smoke, 10% of whom carry

matchesmatches

All You Need to KnowAll You Need to Know

SStratify by tratify by EExposure to the xposure to the CConfounder (SEC)onfounder (SEC)

In this case, smoking is the In this case, smoking is the confounderconfounder (“Smoking confounds the association between (“Smoking confounds the association between carrying matches and lung cancer.”)carrying matches and lung cancer.”)

The analyses should be stratified by smoking.The analyses should be stratified by smoking. Look separately among smokers and non-smokersLook separately among smokers and non-smokers

SStratify by tratify by EExposure to xposure to CConfounder (SEC)onfounder (SEC)

NO CA

NO MATCHES

CA

MATCHES

ORsmokers = ??

SMOKERS

CA

MATCHES

ORnon-smokers = ??

NON-SMOKERS

NO CA

NO MATCHES

1000 cases, 820 carry matches900 smoke, 90% of whom carry 900 smoke, 90% of whom carry matchesmatches100 don’t smoke, 10% of whom 100 don’t smoke, 10% of whom carry matchescarry matches

1000 controls, 340 carry matches300 smoke, 90% of whom carry 300 smoke, 90% of whom carry matchesmatches700 don’t smoke, 10% of whom 700 don’t smoke, 10% of whom carry matchescarry matches

SStratify by tratify by EExposure to xposure to CConfounder (SEC)onfounder (SEC)

NO CA

NO MATCHES

CA

90810MATCHES

ORsmokers = ??

SMOKERS

CA

9010MATCHES

ORnon-smokers = ??

NON-SMOKERS

NO CA

NO MATCHES

1000 cases, 820 carry matches900 smoke, 90% of whom carry 900 smoke, 90% of whom carry matchesmatches100 don’t smoke, 10% of whom 100 don’t smoke, 10% of whom carry matchescarry matches

1000 controls, 340 carry matches300 smoke, 90% of whom carry 300 smoke, 90% of whom carry matchesmatches700 don’t smoke, 10% of whom 700 don’t smoke, 10% of whom carry matchescarry matches

Stratify by Exposure to Stratify by Exposure to Confounder (SEC)Confounder (SEC)

NO CA

NO MATCHES

CA

27090

81030

MATCHES

ORsmokers = = 1.0

810x3090x270

SMOKERS

CA

709010

630MATCHES

ORnon-smokers = = 1.0

NON-SMOKERS

NO CA

NO MATCHES

10x63090x70

After Stratifying by After Stratifying by Smoking…Smoking…

There is no association between carrying There is no association between carrying matches and lung cancer in smokers (OR = 1).matches and lung cancer in smokers (OR = 1).

There is no association between carrying There is no association between carrying matches and lung cancer in non-smokers (OR = matches and lung cancer in non-smokers (OR = 1).1).

Thus the association between carrying matches Thus the association between carrying matches and lung cancer is completely confounded by and lung cancer is completely confounded by smoking.smoking.

Confounding and Confounding and ConfoundersConfounders

Confounding occurs when the Confounding occurs when the association between two variables (a association between two variables (a predictor and an outcome) is due to predictor and an outcome) is due to a third variable (the confounder).a third variable (the confounder).

The confounder must also be The confounder must also be causally related to the outcome.causally related to the outcome. Subtle point, but trueSubtle point, but true

Subtle DigressionSubtle Digression

One would NOT say that the One would NOT say that the association between carrying matches association between carrying matches and lung cancer was confounded by and lung cancer was confounded by having ashtrays in the home.having ashtrays in the home.

Though the same kind of arithmetic Though the same kind of arithmetic might hold.might hold.

My RulesMy Rules

Never assume “it can’t be Never assume “it can’t be confounding” in an observational confounding” in an observational study. study.

Be humble and skeptical.Be humble and skeptical.

Dealing with ConfoundingDealing with Confounding

Does carrying matches cause lung Does carrying matches cause lung cancer?cancer?

Design phase strategiesDesign phase strategiesSpecificationSpecificationMatchingMatching

Analysis phase strategiesAnalysis phase strategiesStratificationStratificationAdjustmentAdjustment

Specification and Specification and MatchingMatching

Both terms refer to the confounderBoth terms refer to the confounder

SpecifySpecify: only study those with (or without) : only study those with (or without) the confounderthe confounder Look at carrying matches and lung cancer only in Look at carrying matches and lung cancer only in

non-smokersnon-smokers

MatchMatch: make sure that a case who does : make sure that a case who does (not) smoke is matched to a control who (not) smoke is matched to a control who does (not).does (not). Then compare the frequency of carrying matchesThen compare the frequency of carrying matches

Stratification and Stratification and AdjustmentAdjustment

Again, both terms refer to the Again, both terms refer to the confounderconfounder

StratifyStratify the analyses by exposure to the analyses by exposure to the confounderthe confounder

AdjustAdjust the analyses for exposure to the analyses for exposure to the confounderthe confounder

It’s Not Just Ruling It’s Not Just Ruling Things OutThings Out

Even if you eliminate (or make Even if you eliminate (or make unlikely) chance, bias, confounding, unlikely) chance, bias, confounding, and effect-cause, it’s nice to have and effect-cause, it’s nice to have “positive evidence” of causality“positive evidence” of causality

““Positive” Evidence of CausalityPositive” Evidence of Causality

TemporalityTemporality

ConsistencyConsistency

Dose-Dose-responseresponse

PlausibilityPlausibility

I Misled You BeforeI Misled You Before

There can be confounding when There can be confounding when there’s no association.there’s no association. If a confounder weakens the association If a confounder weakens the association

between the predictor and the outcome.between the predictor and the outcome. Sometimes called suppression or Sometimes called suppression or

reverse confounding.reverse confounding.

Don’t lose sleep about this for all Don’t lose sleep about this for all (and often any) of your null findings.(and often any) of your null findings.

Interaction and Effect Interaction and Effect ModificationModification

Almost nobody understands these Almost nobody understands these (they’re the same thing!)(they’re the same thing!)

But what it means is not that But what it means is not that complicated. complicated.

The effect of one predictor on an The effect of one predictor on an outcome varies by the presence of outcome varies by the presence of another predictor.another predictor.

Interaction, Example from Interaction, Example from the 70’sthe 70’s

The effect of social class on survival The effect of social class on survival depended on country.depended on country.

In Viet Nam, higher social class was In Viet Nam, higher social class was associated with better survival.associated with better survival.

In Cambodia, higher social class was In Cambodia, higher social class was associated with worse survival.associated with worse survival.

Interaction, Example from Interaction, Example from the 70’sthe 70’s

The effect of country on survival The effect of country on survival depended on social class.depended on social class.

Among the rich, being in Viet Nam Among the rich, being in Viet Nam was associated with better survival.was associated with better survival.

Among the poor, being in Cambodia Among the poor, being in Cambodia was associated with better survival.was associated with better survival.

That’s the End…That’s the End…

Confounded?Confounded?

designing clinical research 2009 confounding and causal inference warren browner

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