Bias Due to

Unmeasured Covariates

Alec Walker

Confounding by Indication

T D

U

T D

Confounders

T D

U

Confounders

T D

URandomization

Confounders

T D

URandomization

Self-matching

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A “Classic” Example:Cimetidine and Gastric Cancer

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Does cimetidine cause stomach cancer?

Case reports of de novo appearance in 1982 Colin-Jones et al looked at data from ongoing work

Persons treated with cimetidine in a 12-month window

Matched to a comparison person General practitioner Age Sex Seen for another condition

Examined the incidence of stomach cancer

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Excess cases during follow-upDiagnosed before cimetidine treatment started

Diagnosed within six months of starting cimetidine treatment

Diagnosed more than six months after starting cimetidine treatment

Controls

Cases of “early” cancer

Before study | Study period | After study

Diagnosed before cimetidine treatment started

Diagnosed within six months of starting cimetidine treatment

Diagnosed more than six months after starting cimetidine treatment

Controls

Cases of “early” cancer

Nu

mb

er

of

cases

Colin-Jones et al. Cimetidine and gastric cancer: preliminary report from post-marketing surveillance study. Brit Med J 1982;285:1311-1313

Hypotheses to account for excess cancersColin-Jones and his coauthors suggested that Stomach cancer incidence was only an artifact

of treatment having come before diagnosis in disease was already present – The as-yet undetected disease caused the use of cimetidine and led to detected disease.

They hypothesized that the effect would disappear with longer follow-up.

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Excess persisted for years

Deathsfrom Year 1 2 3 4

Ex-pected

Malignant neoplasm of the stomach 45 12 5 3 3.5

Malignant neoplasm of the trachea, bronchus and lung

35 25 17 22 12.5

Diseases of the digestive system 33 21 20 10 5.0

Colin-Jones DG. Postmarketing surveillance of the safety of cimetidine: mortality during second, third, and fourth years of follow up. Brit Med J 1985;291:1084-8

Hypotheses to account for excess deaths Stomach cancer – The as-yet undetected disease

caused the use of cimetidine and led to detected disease.

Hypotheses to account for excess deaths Stomach cancer – The as-yet undetected disease

caused the use of cimetidine and led to detected disease.

Lung cancer – Shared determinants. Cigarette smoking predisposes to persistence of stomach ulcer, which in turn leads to cimetidine use. The smoking also causes lung cancer.

Hypotheses to account for excess deaths Stomach cancer – The as-yet undetected disease

caused the use of cimetidine and led to detected disease.

Lung cancer – Shared determinants. Cigarette smoking predisposes to persistence of stomach ulcer, which in turn leads to cimetidine use. The smoking also causes lung cancer.

GI disease – Conditions that motivated cimetidine use led to death.

Hypotheses to account for excess deaths Stomach cancer – The as-yet undetected disease

caused the use of cimetidine and led to detected disease.

Lung cancer – Shared determinants. Cigarette smoking predisposes to persistence of stomach ulcer, which in turn leads to cimetidine use. The smoking also causes lung cancer.

GI disease – Conditions that motivated cimetidine use led to death.

Under each of these hypotheses, cimetidine use was driven by unmeasured factors that also led to the outcomes. The argument was that cimetidine did not cause the deaths from GI disease, stomach cancer or lung cancer, but confounding created associations and the false appearance of causal relations.

But were any of these hypotheses correct? Stomach cancer – The as-yet undetected disease

caused the use of cimetidine and led to detected disease.

Lung cancer – Shared determinants. Cigarette smoking predisposes to persistence of stomach ulcer, which in turn leads to cimetidine use. The smoking also causes lung cancer.

GI disease – Conditions that motivated cimetidine use led to death.

Colin-Jones and colleagues could not know for sure. Had they used a different study design, an answer might have been clear.

Mechanisms that underlie confounding by indication

Prognosis Doctors act in patients’ interest

Protopathic bias Treatment for symptoms of an undiagnosed disease

Shared risk factors The disease points back to its own risk-filled origins