1. Case Control Study: An example Depression and the Risk of Out-of-hospital cardiac arrest July, 2005

2. Background - OOH Cardiac Arrest Sudden pulseless condition due to heart disease. Critical confluence of chronic substrate & acute trigger Chronic Acute Accounts for up to 400,000 deaths annually in the US.

3. Theme of Research How do common non-cardiac clinical conditions and treatments influence the risk of cardiac arrest? Depression alters autonomic tone, increases platelet aggregation, and affects health behaviors and compliance with care.

4. Hypothesis Depression is associated with an increased risk of cardiac arrest.

5. Study Design? Must consider the exposure, outcome, and potential populations when choosing a study design. Randomized trial Cohort Study Case control

6. Study Design? Exposure cannot be randomized. Outcome is ~ 1/1000 person years Randomized trial Cohort Study Case control

7. Exposure, Outcome, and Population Exposure ascertainment - De novo subject evaluation/interview - Other informational resource Exposure definition - Ideal versus practical

8. Exposure, Outcome, and Population Exposure ascertainment De novo subject interview/evaluation Medical record Health Plan Enrollees Definition – Medical record review - Clinical assessment, measures of severity

9. Exposure, Outcome, and Population Outcome ascertainment - Emergency Medical Services Records - Death Records of the Health Plan Outcome definition - Validation of a sample of events - Agreement between EMS and death records

10. Exposure, Outcome, and Population Progress (definition and ascertainment) Population- Health Plan Enrollees Exposure- Medical record review Outcome- EMS and death Records

11. Controls The goal is to simulate a randomized trial to try and best examine the exposure of interest. If possible incorporate what is already known about risk factors for the outcome and the study’s goals when choosing controls.

12. Controls Using a random sample would result in substantial confounding. Overcome confounding in the design and sampling stage. Cardiac arrest risk factors Older age ~ 65 years Male gender ~67% Clinical heart disease ~ 67% Random sample of Enrollees Age ~ 45 years Male gender ~50% Clinical heart disease ~ 15%

13. Controls Cardiac arrest risk factors Older age ~ 65 years Male gender ~67% Clinical heart disease ~ 67% Selected sample of Enrollees Match on age Match on gender Match on heart disease status

14. Planning data collection Exposure - Temporal relationship to outcome - Dose response Account for potential confounders - Specific type of heart disease - Established risk factors for cardiac arrest - Medication use

15. Study Process Interface and coordination with the Health Plan and Emergency Medical Services

16. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding

17. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval

18. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval Case (and then) control identification

19. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval Case (and then) control identification Medical record review and abstraction

20. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval Case (and then) control identification Medical record review and abstraction Data entry and cleaning

21. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval Case (and then) control identification Medical record review and abstraction Data entry and cleaning Data analysis

22. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval Case (and then) control identification Medical record review and abstraction Data entry and cleaning Data analysis Draft manuscript - Interpretation

23. Study Process Interface and coordination with the Health Plan and Emergency Medical Services Funding Human Subjects review and approval Case (and then) control identification Medical record review and abstraction Data entry and cleaning Data analysis Draft manuscript - Interpretation Publication

24. Results Outcome Exposed? Yes No Yes No ab cd

25. Data Layout Cardiac Arrest Depression? Yes No Yes No ab cd

26. Results Cardiac Arrest Depression? Yes No Yes No 300327 19283837 Odds ratio = aXb/cXd = 300X3837/327X1928 Unadjusted odds ratio = 1.83 Adjusted odds ratio = 1.43

27. Results Evidence of dose response Restriction and adjustment to account for confounding. OR No depress1º Care Specialty Care 2 1.5 1

28. Strengths Outcome is rare Relatively quick and inexpensive Study > 1 exposure

29. Weaknesses Cannot estimate incidence directly ~2000 cases and 4000 controls Choice of controls is challenging Recall bias

30. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line

31. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months

32. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months

33. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months

34. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 36 months

35. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 36 months 48 months

36. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 36 months 48 months

37. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 57 months 36 months 48 months

38. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 57 months 60 months 36 months 48 months

39. Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 57 months 60 months 72 months 36 months 48 months

40. Permutations of Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 57 months 60 months 72 months 36 months 48 months

41. Permutations of Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 15 months 18 months 30 months 36 months 48 months Research accelerator 9 months

42. Permutations of Study Process Research idea Interface with HP/EMS Funding Human Subjects Subject identification Medical record abstraction Data entry and cleaning Data analysis Draft manuscript Publication Time line 6 months 24 months 30 months 54 months 15 months 18 months 30 months 36 months 48 months 9 months Young investigator Fortunate investigator Wise investigator

43. Summary When choosing study design, consider issues of exposure, outcome, and population. Understand the strengths and weaknesses of case control studies and attempt to address during the design and then in analysis Regardless of study design, recognize the hidden/logistic challenges and their time requirements.

44. Thanks to David Siscovick, Bruce Psaty, and Mickey Eisenberg Contact information Tom Rea Division of General Internal Medicine Box 359945 Pager 540-8048 E-mail rea123@u.washington.edu