Retrospective & Prospective Studies Case Studies

1. Retrospective & Prospective StudiesCase Studies ICRI Delhi

2. Hierarchy of Evidence • Anecdotal case reports • Case series without controls • Series with literature control • Analyses using computer databases • Case control studies • Cohort studies • Randomized control trials (RCTs) • Meta-analysis with original data

3. Evidence Pyramid

4. Experimental Study (Controlled Assignment) RCT (randomized person assignment) Cluster trial (randomized cluster assignment) Observational Study (Uncontrolled Assignment) Cohort studies (sampling with regard to exposure) Cross-Sectional Case-Control (sampling with regard to disease or effect) Study Design

5. Study Designs Observational Experimental (RCTs) Analytical Descriptive Case-Control Cohort + cross-sectional & ecologic

6. Purpose of Studies Descriptive studies Examine patterns of disease Analytical studies Studies of suspected causes of diseases Experimental studies Compare treatment modalities

7. Algorithm for classification of types of clinical research

8. Observational Studies (no control over the circumstances) - Descriptive: Most basic demographic studies - Analytical: Comparative studies testing an hypothesis * Cross-sectional (a snapshot; no idea on cause-and-effect relationship) * Cohort (prospective; cause-and-effect relationship can be inferred) * Case-control (retrospective; cause-and-effect relationship can be inferred)

9. Types of clinical research • Descriptive studies do not feature a comparison (control) group. • Descriptive studies are often the first foray into a new area of medicine. • They describe the frequency, natural history, and possible determinants of a condition. • Hypothesis generation about the cause ot the disease. Case report Case-series reports

10. Descriptive studies Good descriptive reporting answers the five basic W questions: Who, what, why, when, where And a sixth: so what ? Who has the disease in question ? What is the condition or disease being studied ? Why did the condition or disease arise ? When and Where does or does not the disease or condition arise ? Case report Case-series reports Surveillance studies / Surveys / Cross-sectional studies

11. Case reports and series • Case report: describes an observation in a single patient. • “I had a patient with a cold who drank lots of orange juice and got better. Therefore, orange juice may cure colds.” • Case series: same thing as a case report, only with more people in it. • “I had 10 patients with a cold who drank orange juice….”

12. Value of case reports/series • May generate a hypothesis: “maybe orange juice cures colds….” • Weakness: cannot test the hypothesis • no control group • often too few people to make generalizations

13. Analytical Studies

14. Retrospective & Prospective Studies

15. Analytical Studies (comparative studies testing an hypothesis) * Cohort (prospective) Begins with an exposure (smokers and non-smokers) * Case-control (retrospective) Begins with outcome (cancer cases and healthycontrols) * Cross-sectional (concurrent) Exposure & outcome co-exist

16. Cross-sectional Study Exposure Outcome at the same time 300 men MI Next door neighbour Mean S-cholesterol Mean S-cholesterol 256 mg/dl 202 mg/dl

17. Cross-Sectional Study • Select a study sample. • Ask each person about both exposure and disease at that point in time. • Disease rate in exposed group is compared to disease rate in unexposed group. • Investigator gathers data only at that one point in time. Data Gathering Approaches -Person-to-person interviews or surveys, mailed questionnaires, telephone interviews etc.

18. Cross-Sectional Study Advantages • One stop, one time • Less expensive • Useful for planning services • Shows relative distribution of conditions • Shows interrelatedness of attributes and conditions • Does not rely on individuals who present for medical treatment • No one exposed to harmful causal agent because of study

19. Cross-Sectional Study Disadvantages • Only representative of participants • Not effective if disease is rare • May not be representative of all cases • Cause and effect uncertain because exposure and disease are measured simultaneously • Cannot be used for hypothesis testing

20. Case Control & Cohort Studies Ovarian cancer Use of oral contraceptives Control group

21. Case-control study Exposed Cases Non-exposed Study Population Exposed Controls Non-exposed

22. Schematic diagram of a case control study design

23. Bias in Case-Control studies • Selection bias • Confounding bias • Berkesonian bias • Observation bias • Recall Bias: Cases are more likely to remember exposure than controls • Non response

24. Question • In a study on the association between smoking and CHD, 200 CHD patients were selected from a hospital OPD and 400 similar controls were enrolled. History of patients revealed that there were 112 smokers in the CHD group as compared to 176 in the control (non CHD) group. Comment on the association between smoking and CHD.

25. Calculating the Odds Ratio Disease Status No CHD (Controls) CHD cases (Cases) Exposure Status Smoker 112 176 Non-smoker 88 224 Total 200 400 AD 112 x 224 Odds Ratio = = = 1.62 BC 176 x 88

26. Interpreting the Odds Ratio The odds of exposure for cases are 1.62 times the odds of exposure for controls. or Those with CHD are 1.62 times more likely to be smokers than those without CHD or Those with CHD are 62% more likely to be smokers than those without CHD

27. Disease + Exposed Disease - Study population Disease + Non-exposed Disease - Cohort study / Follow-up study

28. Cohort Studies

29. Study starts Study starts Disease occurrence Exposure time Prospective cohort study Disease occurrence Exposure time

30. Radiation Leak in Nuclear Plant Cohort Workers 1969 Workers disease status 1999 12 workers on site at time of the leak 24 workers off duty at home at time of the leak Exposed 4 withleukemia 8 no leukemia Unexposed 4 with leukemia 20 not leukemia

31. Study starts Retrospective cohort studies Disease occurrence Exposure time

32. Radiation Leak in Nuclear Plant Cohort of Workers 1999 collect info from1969 Workers disease status 1999 12 workers on site at time of the leak 24 workers off duty at home at time of the leak Exposed 4 withleukemia 8 no leukemia Unexposed 4 with leukemia 20 not leukemia

33. Nested case-control studies • Cases and controls come from a well-defined population. • Combine many of the strengths of retrospective cohort and case-control studies.

34. Prospective vs. Retrospective Cohort Studies • Prospective Cohort Studies • Time consuming, expensive • More valid information on exposure • Measurements on potential confounders • Retrospective Cohort Studies • Quick, cheap • Appropriate for examining outcomes with long latency periods • Difficult to obtain information of exposure • Risk of confounding

35. The Framingham Study • Since 1948, samples of residents of Framingham, Massachusetts, have been subjects of investigations of risk factors in relation to the occurrence of heart disease and other outcomes

36. The Framingham Study • Hypotheses: • Persons with hypertension develop CHD at a greater rate than those who are normotensive. • Elevated blood cholesterol levels are associated with an increased risk of CHD. • Tobacco smoking and habitual use of alcohol are associated with an increased incidence of CHD. • Increased physical activity is associated with a decrease in development of CHD. • An increase in body weight predisposes a person to CHD.

37. The Framingham Study • Study population consisted of 5,127 men and women between ages 30 and 62 years and were at the time of entry free of cardiovascular disease (1948-1952) • Cohort was examined every 2 years and by daily surveillance of hospitalizations at Framingham Hospital

38. The Framingham Study • Exposures included: • Smoking • Alcohol use • Obesity • Elevated blood pressure • Elevated cholesterol levels • Low levels of physical activity, etc.

39. Comparison (Control) Groups • With a one-sample (population-based) cohort, exposure is unknown until after the first period of observation • Example: • Select the cohort (all residents of Framingham) • All members of the cohort are given questionnaires, and/or clinical examinations, and/or testing to determine exposure status • The cohort is then divided into exposure categories based on those results

40. Comparison (Control) Groups • The nonexposed become the internal controls • For continuous variables, such as caloric intake or amount of exercise, multiple levels of exposure are constructed • It is common to break exposure into quantiles (equally ordered subgroups) and to use the extremes as the comparison (referent) group

41. Question How does the design of a cohort study change if everybody in the cohort is exposed (special exposure cohort)? Example: All persons exposed to radiation from the Chernobyl accident.

42. Answer • You need to select a separate control cohort people as similar as possible to the exposed cohort (income, age, gender, employment) but with no exposure • If you cannot find a comparison group, you may use available population incidence rates under certain circumstances

43. Question • In a study on association between smoking and CHD, 288 smokers and 312 nonsmokers, i.e a total of 600 subjects were enrolled. selected from a hospital OPD and 400 similar controls were enrolled. The subjects were followed up and 112 smokers developed CHD while 88 nonsmokers also developed CHD. Comment on the association between smoking and CHD.

44. Example: Calculating the Relative Risk Disease Status TOTAL CHD No CHD Smoker 112 176 288 Exposure Status Non-smoker 88 224 312 A/(A+B) 112 / 288 Relative Risk = = = 1.38 B/(C+D) 88 / 312

45. Relative Risk 1.38 = Example: Interpreting the Relative Risk The risk of developing CHD is 1.38 times higher for a smoker than for a nonsmoker. or The risk of developing CHD is 38% higher for a smoker than for a nonsmoker.