Spring 2008

1. Spring 2008 Case-Control Studies and Odds Ratio STAT 6395 Filardo and Ng

2. Lopez-Carrillo et al. Chili pepper consumption and gastric cancer in Mexico • Hypothesis: chili pepper consumption increases the risk of gastric cancer • Source population: residents of Mexico City metropolitan area

3. Lopez-Carrillo et al. Chili pepper consumption and gastric cancer in Mexico • Cases: Cases of stomach cancer diagnosed between September 17, 1989 and June 30, 1990 in 15 Mexico City metropolitan area hospitals (about 80% of the stomach cancer cases) • Controls: Age-stratified random sample of residents of the Mexico City metropolitan area selected from the household sampling frame of the 1986-87 Mexican National Health Survey

4. Measurement of exposure: interview (structured questionnaire) • Cases were queried about their dietary habits during the 12-month period prior to the onset of symptoms. • Controls were queried about their dietary habits during the 12-month period preceding the interview. • Cases and controls were asked “Do you eat chili peppers or chili sauces with your meals?”

5. Case-control study of stomach cancer and chili pepper consumption Odds ratio = (204x145)/(552x9) =5.95

6. Data layout for case-control study with multiple levels of exposure

7. Calculation of odds ratio in case-control study with multiple levels of exposure No exposure group →‘reference’ OR for high exposure group →(a1d)/(b1c) OR for low exposure group →(a2d)/b2c)

8. Hypothesis: HPV infection greatly increases the risk of CIN, a precursor of cervical cancer • Source population: Women receiving Pap smears at the Kaiser Permanente prepaid health plan in Portland, Oregon between 4/1/1989 and 11/2/1990 Schiffman et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia

9. Cases: women found to have CIN on Pap smear • Controls: a random sample of women with normal Pap smear and no known history of CIN • Measurement of exposure • Cervicovaginal lavage, as part of the Pap smear screening, for HPV testing Schiffman et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia

10. Schiffman et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia

11. Matched-pair case-control study with a dichotomous (yes/no) exposure 4 possible combinations of matched pairs: • Pairs in which both the case and control were exposed (concordant) • Pairs in which neither the case nor the control were exposed (concordant) • Pairs in which the case was exposed but the control was not (discordant) • Pairs in which the control was exposed but the case was not (discordant)

12. Data layout for matched-pair case-control study with a dichotomous exposure q and t are concordant pairs (uninformative) r and s are discordant pairs Odds ratio = r/s

13. Hypothesis: Infection of genital tract with Chlamydia trachomatis increases the risk of ectopic pregnancy • Source population: Surrounding area of several hospitals • Cases: Women admitted to the participating hospitals for ectopic pregnancy • Controls: women attending prenatal clinics at those hospitals Chow et al. The association between Chlamydia trachomatis and ectopic pregnancy

14. Controls were individually matched to cases on age (within 1 year), ethnicity, and hospital • Measurement of exposure: blood drawn for antibody titer Chow et al. The association between Chlamydia trachomatis and ectopic pregnancy

15. Odds Ratio = 109/36 = 3.0 Chow et al. The association between Chlamydia trachomatis and ectopic pregnancy

16. Advantages of case-control studies • Take considerably less time to conduct than concurrent cohort studies • If the exposures of interest are relatively common, require a much smaller sample size than cohort studies

17. Advantages of case-control studies • Considerably less costly to conduct than concurrent cohort studies • Can test hypotheses about the relationship between many different exposures and the disease of interest in a single study • Useful for studying rare diseases

18. Disadvantages of case-control studies • Past exposures are ascertained after the onset of disease • Uncertainty (exposures preceded onset of disease?) • Exposure information is less accurate • Possibility of recall bias -- differential recall of exposures by those who develop the disease compared to those who do not

19. Disadvantages of case-control studies • Prone to biases in selection of controls • Can’t calculate actual incidence rates; can only estimate relative risks from the odds ratio • Case-control studies are observational studies

20. Smoking and Lung Cancer • Dramatic increase in reported mortality rates from lung cancer in Great Britain and other countries from 1920s to 1950 • Four major hypotheses about the cause of these increases • Improved diagnosis • Air pollution • Occupational exposures • Tobacco smoking • Several small case-control studies pointed to smoking Smoking and Lung Cancer

21. Landmark Studies in 1950 • Hypothesis: smoking increases the risk of lung cancer • Wynder and Graham: United States • Doll and Hill: Great Britain • Large hospital-based case-control studies • Landmark studies: • Importance of the result • Thoughtfulness of the methodology and interpretation Smoking and Lung Cancer

22. Smoking: Attributable risk percent (population) in Canada Smoking and Lung Cancer

23. Smoking is a risk factor for: • Other cancers: larynx, oral cavity, esophagus, bladder, pancreas, kidney, cervix • Peripheral artery occlusive disease • Peptic ulcers • Periodontal disease • Low birth weight, preterm delivery, neonatal death • …and fires in homes Smoking and Lung Cancer

24. Environmental Tobacco Smoke • Lung cancer • Coronary heart disease • Eye irritation • Respiratory symptoms • Aggravates allergic symptoms Smoking and Lung Cancer

25. Doll and Hill study: Cases • Provisonal cases: all patients presumed to be newly diagnosed with carcinoma of the lung admitted to 20 London hospitals between April 1948 and October 1949 • Notification about new cases: admitting clerk, physician, cancer registrar, or radiotherapy department Smoking and Lung Cancer

26. Doll and Hill study: Cases • Authors believed they missed some cases, but there was no reason to believe that the missed cases smoked more or less than the reported cases • Interviewer visited the hospital to interview the patient Smoking and Lung Cancer

27. Doll and Hill study: Controls • For each lung cancer case, the interviewer chose a noncancer control patient matched to the case on: • Sex • Age (within the same 5-year age group) • Hospital (in the same hospital at or about the same time) Smoking and Lung Cancer

28. Doll and Hill study: Controls • At 2 hospitals (Brompton and Harefield), it was not always possible to find a control. In these instances, controls were selected from one of the 2 neighboring hospitals. • Even this didn’t always work for Brompton Hospital, so used patients as controls who had been interviewed as cancer patients and were later determined not to have cancer. Smoking and Lung Cancer

29. Doll and Hill study: Confirmation of diagnoses • Initial diagnoses were provisional • Generally the hospital discharge diagnosis was accepted as the final diagnosis • Later evidence (autopsy, biopsy) taken into account • Final diagnosis based on best available evidence Smoking and Lung Cancer

30. Doll and Hill study: Flow Diagram of Case Selection Notification of provisional cancer cases (including stomach and colorectal cancers) (2,370) Cases > age 75 (150) Diagnosis changed before interview (80) (2,140) Provisional cancer cases eligible for interview Smoking and Lung Cancer

31. (2,140) Provisional cancer cases eligible for interview Discharged before interview (189) Too ill to be interviewed (116) Died before interview (67) Too deaf (24) Unable to speak English (11) Patient unreliable (1) Patient refused (0) (1,732) Provisional cancer cases interviewed Smoking and Lung Cancer

32. Interviewed study subjects (1,732 provisional cases and 743 original controls) after confirmation of diagnoses *Provisional cancer cases found not to have cancer on final diagnosis and original non cancer controls whose paired provisional lung carcinoma cases were found not to be lung carcinoma &due to doubts about their true category Smoking and Lung Cancer

33. Subjects included in this study • 709 cases of carcinoma of the lung • 649 men • 60 women • 709 non cancer controls, matched to the cases by sex, age, and hospital • 649 men • 60 women Smoking and Lung Cancer

34. Subjects included in this study • Social class distribution of cases and controls was similar • A higher proportion of lung cancer cases lived outside of London Smoking and Lung Cancer

35. Measurement of smoking –Patients were asked: • If they had smoked at any period of their lives • The ages at which they had started and stopped • The amount they smoked before the onset of their illness • The main changes in their smoking history • The maximum they had ever smoked Smoking and Lung Cancer

36. Measurement of smoking –Patients were asked: • The proportion of their smoking that was cigarettes vs. pipes • Whether or not they inhaled Definition of a smoker: A person who had smoked as much as one cigarette a day for as long as one year Smoking and Lung Cancer

37. Reliability sub-study • Reliability is the reproducibility or repeatability of a measurement • Validity is the degree to which a measurement measures what it purports to measure (accuracy) • 50 controls were re-interviewed about their smoking histories 6 months or more after the initial interview • Found fairly good agreement between the 2 interviews Smoking and Lung Cancer

38. Male Smokers and Non-smokers (2x2 table) Odds ratio = (647x27)/(622x2) = 14.0 Smoking and Lung Cancer

39. Lung cancer and amount smoked immediately before the onset of illness* *If the subject had given up smoking before then, he was classified by the amount smoked immediately prior to giving up smoking. Smoking and Lung Cancer

40. Lung cancer and other measures of cigarette smoking • Maximum amount ever smoked regularly • Total amount of tobacco smoked in lifetime (number of cigarettes) • Results similar to those obtained for amount smoked immediately before onset of illness Smoking and Lung Cancer

41. Alternative explanations of results • Smoking is a major risk factor for lung cancer • Selection of an inappropriate control group (selection bias) Smoking and Lung Cancer

42. Alternative explanations of results • Exaggeration of smoking habits by lung cancer cases who thought they had an illness that they could attribute to smoking (recall bias) • Exaggeration of smoking habits of lung cancer cases by interviewers who believed that smoking caused lung cancer (interviewer bias) Smoking and Lung Cancer

43. Selection of controls: place of residence • A higher proportion of cases than controls lived outside London • There was no difference in place of residence between cases and controls from the district hospitals, which did not have special cancer treatment facilities Smoking and Lung Cancer

44. Selection of controls: place of residence • A strong association between smoking and lung cancer was observed when the analysis was restricted to the district hospitals • Persons residing outside London smoked less than London residents Smoking and Lung Cancer

45. Selection of controls: did the hospital-based control group smoke less than the source population? • Would result in an overestimation of the association between smoking and lung cancer • Many of the subjects in the control group were hospitalized for non-malignant respiratory disease and cardiovascular disease Smoking and Lung Cancer

46. Selection of controls: did the hospital-based control group smoke less than the source population? • Both diseases have a strong association with cigarette smoking • If anything, the selection of controls was biased toward choosing controls who smoked more than the source population Smoking and Lung Cancer

47. Selection of controls: Did the interviewers select a disproportionate number of light smokers to be control patients from among the patients available for selection? • The smoking habits of the patients who the interviewers selected for interview did not differ from the smoking habits of the patients (other than lung cancer) whose names were notified by the hospitals (stomach and colorectal cancer patients) Smoking and Lung Cancer

48. Did the lung cancer cases exaggerate their smoking habits? (recall bias) • Having respiratory symptoms may have influenced their replies to the smoking questions • However, patients with nonmalignant respiratory diseases, who would also have respiratory symptoms, did not give smoking histories appreciably different from patients with nonrespiratory diseases Smoking and Lung Cancer

49. Did the lung cancer cases exaggerate their smoking habits? (recall bias) • Smoking was not thought to be related to lung cancer at the time, so there would be no reason for lung cancer cases to overstate or understate their smoking because they knew they had lung cancer Smoking and Lung Cancer

50. Did the interviewers overstate the smoking habits of the lung cancer cases? (interviewer bias) • Interviewers could not be blinded to diagnoses • 209 patients thought to have lung cancer at the time of interview later had their diagnoses disproved Smoking and Lung Cancer