1. Bias Due to Unmeasured Covariates Alec Walker Confounding by Indication

2. TD U

3. TD

4. Confounders TD U

5. TD U Randomization

6. Confounders TD U Randomization Self-matching

7. 7 A “Classic” Example: Cimetidine and Gastric Cancer

8. 8 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

9. 9 Excess cases during follow-up 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 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 Number of cases Colin-Jones et al. Cimetidine and gastric cancer: preliminary report from post-marketing surveillance study. Brit Med J 1982;285:1311-1313

10. Hypotheses to account for excess cancers Colin-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.

11. 11 Excess persisted for years Deaths from Year1234 Ex- pected Malignant neoplasm of the stomach 4512533.5 Malignant neoplasm of the trachea, bronchus and lung 3525172212.5 Diseases of the digestive system 332120105.0 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

12. Hypotheses to account for excess deaths  Stomach cancer – The as-yet undetected disease caused the use of cimetidine and led to detected disease.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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