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Case-Control Studies

Case-Control Studies . EPI 200A October 29 and November 3, 2009. Case-Control study; the history A disease looking for a cause. Vincent Memorial Hospital: 8 women of 15-22 years of age with vaginal cancer between 1966-1969 A very rare disease, especially in young women

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Case-Control Studies

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  1. Case-Control Studies EPI 200A October 29 and November 3, 2009

  2. Case-Control study; the historyA disease looking for a cause Vincent Memorial Hospital: 8 women of 15-22 years of age with vaginal cancer between 1966-1969 • A very rare disease, especially in young women • No common exposure to tampons or drugs; none used oral contraceptives (OCs) • 1 case to 4 controls without the disease matched on age, born in the same hospital • Similar data on X-rays, maternal smoking, pregnancy complications, childhood diseases, etc.

  3. Case-Control study; the historyA disease looking for a cause • 7 of 8 case mothers had used diethyl-stilbesterol (DES); none of the 32 mothers for controls had used DES. • Herbst et al. N Engl J Med 1971; 284: 878-81.

  4. a/c > b/d if a cause a/c and b/d are exposure odds

  5. The idea of a case-control study dates back to Hippocrates …..

  6. Hippocrates in first epidemics ”By paying attention to what was common to every case, and particular to each case,to the patient; the prescriber and the prescription,to the epidemic constitution generally, and its local mood,to the habits of life and occupation of each patient,to his speech, conduct, silences, thought, sleep, wakefulness,and dreams – their content and incidence,to his pickings and scratchings, tears, stools, urine, spit and vomit,to earlier and later forms of illness during the same prevalence,to critical or fatal determinations,to sweat, chill, rigor, hiccup, sneezing, breathing, belching,to passage of wind, silently or with noise;to bleedings, andto piles.”

  7. The philosophy of the case-control study was taken from JSM as stated in MacMahon, Pugh and Ipsen: Epidemiologic Methods. London: Churchill, 1960. • John Stuart Mill’s logic of causation • Method of difference • Method of agreement • Only qualitative estimates

  8. Broders 1920: JAMA; 74: 656-64.Cancer of the lip; 537 cases and 500 controls; similar smoking habits (80%), 78% of cases smoked the pipe; 38% among controls. • Schreck and Lenowitz 1947: Cancer Research; 7: 180-187.Cancer of the penis; circumcision as a protective factor. • 1950s smoking and lung cancer

  9. Doll and Hill on Smoking & Carcinoma of the Lung. BMJ September, 1950 / UK, Mortality Rates • This increase was also seen in USA, Canada, Australia, Denmark, Switzerland.

  10. Doll and Hill on Smoking & Carcinoma of the Lung. BMJ September, 1950 • Better diagnostic tools? • Hypotheses: Air pollution (cars, industries) or tobacco smoking • Reports from Germany 1939, 3 out of 86 lung cancer patients were non-smokers. Similar reports from the U.S. in 1950 (Schrek, Wynder, Graham)

  11. Methods • 20 London Hospitals were asked to notify all patients with cancer of the lung, stomach, colon, and rectum. Interviewers were also asked to select non-cancer patients of the same sex, age and from the same hospital. • Hospital diagnosis on discharge accepted • 2370 cancer cases identified • > 75 years (150) • Wrong diagnosis (80) • No interview (too late (189)) (too ill (116)) (dead (67)) (too def, etc. (37))

  12. Methods, cont. • No patients refused • Study population • Carcinoma of lung: 709 • Carcinoma of stomach: 206 • Carcinoma of colon/rectum: 431 • Other malignant diseases 81 • Controls (other patients) 709 • Other cases 335 • Excluded 4 • All 2475 • Other cases – interviewed as cancer cases but the diagnosis was not confirmed or redundant non-cancer controls – without a match

  13. Assessment of smoking • Smoking habit change as a function of e.g. price (duty raised in 1947) and disease • Were asked: 1. smoked any period of their life 2. age at which they started or stopped 3. current intensity 4. changes in smoking habits 5. type of tobacco smoking 6. inhaled or not • A smoker = at least 1 cigarette per day at least 1 year

  14. Assessment of smoking, cont. • Two interviews done 6 months apart

  15. Assessment of smoking, cont. • Then they showed • Lung cancer patients smoked more, had smoked for a longer time period, smoking a pipe carried less risk • Inhaling: Assessing 688 living cancer patients, 61.6% said they inhaled. 650 other patients, 67.2% said they inhaled.

  16. Assessment of smoking, cont. • Interpretation • Selection bias = more lung cancer patients from rural areas restriction to greater London – same results = control patients – did they have a disease that prevented them from smoking or was prevented by smoking? - different patient control groups – same results • Information bias interviewed before they were diagnosed blinding of interviewers – did not work compared smoking data for patients suspected for lung cancer but who did not have the disease

  17. Assessment of smoking, cont. • It is not reasonable, in our view, to attribute the results to any special selection of cases or to bias in recording… there is a real association between carcinoma of the lung and smoking. • This is not necessarily to say that smoking causes lung cancer. The association would occur if carcinoma of the lung caused people to smoke or if both attributes were end-effects of a common cause. • Only carcinogenic substance found in tobacco smoke is arsenic. Because carcinogenic testing at this time was based upon a skin-rat-test.

  18. a/N+ c/N- b/N+ d/N- a/ND b/ND c/ND d/ND a/b c/d a/c b/d Closed Cohort • Disease ORs and exposure ORs are similar Disease odds = = ratio Exposure odds = = ratio a/b = axd = a/c c/d cxb b/d

  19. a/b a/c OR ; = c/d b/d CI+ CI+ / (1- CI+ ) RR = ~ CI- CI- / (1- CI -) • So the exposure odds ratio is equal to the disease odds ratio and RR is closed to the disease OR when the disease is rare 1-CI close to 1, if the disease is rare.

  20. Advantages of the Case-Control Method • Well suited to the study of rare diseases or diseases with long latency periods • Allows study of multiple potential causes of a disease • Relatively quick to mount and conduct • Relatively inexpensive • Requires comparatively few subjects • Existing records can occasionally be used • Often no risk to subjects

  21. Disadvantages of the Case-Control Method • Relies often on recall or records for information on past exposures • Validation of information is difficult or sometimes impossible • Control of extraneous variables may be incomplete • Selection of an appropriate control group may be difficult • Vulnerable to selection bias • Rates of disease in exposed and unexposed individuals cannot be determined (not always true)

  22. Advantages of the cohort method • In principle, provides a complete description of experience subsequent to exposure, including rates of progression, staging of disease, and natural history • Allows study of multiple potential effects of a given exposure, thereby obtaining information on potential benefits as well as risks • Allows for the calculation of rates of disease in exposed and unexposed individuals • Permits flexibility in choosing variables to be systematically recorded • Allows for thorough quality control in measurement of study variables (not time in historical cohorts)

  23. Disadvantages of the cohort method • Large numbers of subjects are required to study rare diseases • Potentially long duration for follow-up • Current practice, usage, or exposure to study factors may change, making findings irrelevant • Relatively expensive to conduct • Maintaining follow-up is difficult • Control of extraneous variables may be incomplete

  24. A disease “looking” for a cause • Case-control study • A cause “looking” for a disease • Follow-up study

  25. Modern case-control methods • The terminology is still confusing. You will find terms such as retrospective studies, TROHOC studies, case-referent studies, case-base studies, case-cohort studies, case-non-case studies and case-control studies. • If we forget John Stuart Mill and start with a cohort and the estimates of effect measures this study provides, we have:

  26. A cohort study of CS2 exposure and AMI RR = 400/10,000) / (200/10,000) = 2.0IRR = (400/9,800) / (200/9,900) = 2.02OR = (400/9,600) / (200/9,800) = 2.04

  27. 400/200 296.9/303.1 If we for some reason would reconstruct OR by using a more economic sampling approach, we would do a case-non-case study: OR = = 2.04

  28. A cohort study of CS2 exposure and AMI RR = 400/10,000) / (200/10,000) = 2.0IRR = (400/9,800) / (200/9,900) = 2.02OR = (400/9,600) / (200/9,800) = 2.04

  29. If we wanted to estimate RR, we would select a different sampling strategy: The case-cohort study OR = (400/200) / 300/300) = 2.0 This is a study for a fixed cohort with no loss to follow up.

  30. A cohort study of CS2 exposure and AMI RR = 400/10,000) / (200/10,000) = 2.0IRR = (400/9,800) / (200/9,900) = 2.02OR = (400/9,600) / (200/9,800) = 2.04

  31. In a cohort with loss to follow-up or in a dynamic population, one would aim at estimating the IRR. As it is seen in the cohort example, we need to sample controls to estimate the distribution of exposed and unexposed observation time. OR = 2.02

  32. To obtain this estimate, we sample from the population at risk at the time of the onset of the disease (incidence density sampling). In a small population like this: D 12345678 D D time t 3 is our case at time t, and the population at risk is number 1, 4, 5, 6 and 7. All selected controls that get the disease during recruitment should also become cases and controls may be selected more than once.

  33. Summary: Assume an underlying follow-up study like RR = (a/N+) / (c/N-) or (a/c) / (N+/N-)IRR = (a/t+) / (c/t-) or (a/c) / (t+/t-)OR = (a/b) / (c/d) or (a/c) / (b/d) The right-hand figures are what we want controls to estimate.

  34. Food poisoning: diarrhea and fever within 48 hours following a picnic How would you get data? How would you analyze data? How would you do a case-control study?

  35. 18/183 6/297 18/(480x0.10-0.10N-) 6/0/10N- 18x0.10N- 6x(48-0.10N-) 1.8N- 288-0.6N- Cohort RRB-chicken = = 4.869 Case cohort approach Sampling fraction, r, 48/480 = 0.10 4.869 = 4.869 = 4.869 = 1402.27 – 2.921N- = 1.8N- N- = 297

  36. Summary: Assume an underlying follow-up study like RR = (a/N+) / (c/N-) or (a/c) / (N+/N-)IRR = (a/t+) / (c/t-) or (a/c) / (t+/t-)OR = (a/b) / (c/d) or (a/c) / (b/d) The right-hand figures are what we want controls to estimate.

  37. In a case control study we get estimates of relative effect measure. We usually cannot estimate absolute measures of association, why not? • In some situations we can

  38. We sample a fraction r then r+N+/r-N- = N+/N- if r+ = r- r+t+/r-t- = t+/t- if r+ = r- r+b/r-d = b/d if r+ = r- Since we in a study with a known source population, N, get data on RR and have data on a and c, we get: RR = That equation can be solved for N- given r is known and absolute risks can be estimated a/(rN-rN-) c/rN-

  39. A+ T+ A- T- Or in the book (ME3) terminology: Follow-up I+ = I- = We sample a rate r of controls per unit time B+/T+ = B-/T- = r or B+/r = T+ and B-/r = T-

  40. A+ /B+ A-/B- Pseudo rate+ Pseudo rate- A+ /((B+ /T+)T+) A-/((B-/T-)T-) A+/T+ A-/T- A+ /(rxT+) A-/(r xT-) In the case-control study, we have the following pseudo rate: A+/B+ and A-/B- To get incidence rates I+ = A+/T+ We: I+ = A+/B+ x r or I+ = A+/B+ x B+/T+ = A+/T+ If r is not known we still get: = = = = = requires incidence density sampling IRR

  41. Case-control studies are not conceptually retrospective. They do not compare cases with non-cases, but exposed with not exposed. They apply a specific sampling strategy to provide the relative effect measures in the underlying cohort. • They provide estimates with far less observations than in the cohort study. Given the necessary exposure data and sampling data are available, they are equivalent in quality to the cohort approach. In fact they represent just a different approach to obtain the cohort result. • Case-control studies are the studies of choice if you can reconstruct exposure data back in time (for the exposure of interest as well as for confounders). They represent often the design of choice in genetic studies

  42. If you want to study if bacterial vaginoses causes preterm birth, how would you sample cases and controls?

  43. If you want to study if antibiotics prevent preterm births, what is the source population (study base)? • If you want to study if use of bicycle helmets prevents head injuries, what is the source population (study base)?

  44. The described type of case-control study is a study with a primarily defined study base. • Cases come from a well-defined cohort and we may sample controls from this cohort. • Or • Cases come from a well-defined population. We have complete ascertainment and we may sample controls from this population at given points in time. • Be careful if these conditions are not met. • Sometimes cases are prevalent cases.

  45. Since prevalence is a function of incidence and duration (D) P/I-P= I x D • Determinants of prevalence reflect aetiologic as well as prognostic factors.

  46. Example: Exercise and AMI RR = (30/1,000) / (30/1,000) = 1.0 OR = (20/10) / (15/15) = 2.0

  47. The same rules as for risks will apply for estimating effect measures based on prevalence data. • A case-non-case study will estimate Control sampling from the entire population (including prevalent cases) will estimate:

  48. Controls are ideally randomly sampled from the same population that gave rise to the cases. • Controls will then estimate the exposure distribution in the source population but this estimate will be subject to random sampling variation.

  49. It will often be difficult to make random sampling and: If the selected sampling strategy produces exposure estimates that are interchangeable with the exposure distribution in the study base, results will be unbiased. If not, effect estimates will be biased.

  50. If all cases cannot be ascertained (no registry, not all come to the health care system), a case-control study should be designed to take this lack of ascertainment into consideration. This type of case-control study is usually ”weak”. Our source population definition will be: • All potential cases define the source population. • The conditions that actually led to case identification should lead to identification of all member of the source population. (those who would enter the case group if they have the conditions that were seen for cases – may depend upon disease characteristics, insurance conditions, financial means etc)

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