Cohort and Case-Control Studies

1. Cohort and Case-Control Studies September 2013 Alexander M. Walker MD, DrPH With Sonia Hernández-Díaz MD, DrPH

2. Cohort Study If you have • People • Observed for a health event • For some amount of elapsed time in every one You have a cohort study

3. Graphical Representation Randomized Trial Cohort Study People People Person-Time Person-Time

4. Risks Incident cases Risk(exposed) r1 = a/n1 Risk(not exposed) r0 = c/n0 People › Outcome Risk Ratio = RR = [a/n1] / [c/n0] Counts of people in different exposure/outcome categories Exposure

5. Rashkind Occluder Gray DT, Fyler DC, Walker AM, Weinstein MC, Chalmers TC. Clinical outcomes and cost of transcatheter vs. surgical closure of patent ductus arteriosus. N Engl J Med 1993;329:1517-1523

6. Rates Incident cases Rate(exposed) r1 = a/t1 Rate(not exposed) r0 = c/t0 Person-Time › Outcome Rate Ratio = RR = [a/t1] / [c/t0] Sum up all the individual times of observation Exposure

8. BMI and Seizures

9. Seizure Incidence and BMI 95% Confidence Interval Seizures per 100,000 person-years BMI

10. Time-Varying Exposures Crossover Trial Cohort Study People Person-Time Person-Time

11. Rates with Time-Varying Exposures Incident cases Person-Time Rate(exposed) r1 = a/t1 Rate(not exposed) r0 = c/t0 › Rate Ratio = RR = [a/t1] / [c/t0] Outcome Sum up all the individual times of observation Exposure

12. Walker et al. J Am Soc Nephrol 17: 2293–2298, 2006

14. Case-Control Studies • Cohort studies with sampling • Instead of the full population denominator, we take a sample, called the “controls” • At random from the cohort members with no event • At random from the cohort members • At random times from random members • Or optionally matched to cases • Personal characteristics • Time of follow-up • Captures covariates that would be too expensive to ascertain for the full cohort • Time-varying • Resource intensive data collection

15. Sampling Person-Time Take a person at random and take a day at random. If the person is under observation on the selected date, that person-day is a control. The sampling rate of person-days (controls sampled divided by the number of person-days eligible) is the rate of control generation. It is a rate in the same sense that disease incidence is a rate, except that the control-sampling rate is by construction unrelated to exposure. Call this sampling rate s. Person-Time Outcome Exposure

16. The Odds Ratio with Cases and Sampled Person-Time Consider the table of expected values, below. The odds ratio of this case-control table of expected values is Person-Time Outcome From which it follows that an estimate of the OR is an estimate of ρ . Note that there is no “rare disease” assumption. Exposure

17. A Case-Control Study with Sampled Person-Time The question at hand was whether inhaled corticosteroids had the effect of weakening bone to the point of making women more susceptible to fracture. Nonvertebral fracture was chosen because vertebral fracture is so often asymptomatic.

18. Random Sampling of Person-Time

19. Cases, Controls, OR

20. Risk Sets Each case is compared to all the people who were at risk to become cases at the time the case occurred. This collection of persons at risk is called the “Risk Set.” Persons over Time Risk Set

21. Risk Set Sampling in Case-Control Studies Each case is compared to a sample of the people who were at risk to become cases at the time the case occurred. This sampled persons called matched controls. They have been matched on time and possibly other factors. Matched case-control analysis Proportional Hazards analysis

22. Graham et al. 2005 For every case, we randomly selected four controls from individuals under observation in the study cohort on the date of the case event (index date), and matched them for age (year of birth), sex, and health plan region (north or south). A given cohort member selected as a control for a case on one date could become a control for another case occurring on a later index date, as long as he or she remained in the study cohort and was therefore also at risk of becoming a case. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365475-81

23. Graham et al. 2005 For every case, we randomly selected four controls from individuals under observation in the study cohort on the date of the case event (index date), and matched them for age (year of birth), sex, and health plan region (north or south). A given cohort member selected as a control for a case on one date could become a control for another case occurring on a later index date, as long as he or she remained in the study cohort and was therefore also at risk of becoming a case. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365475-81 Risk set sampling

24. Graham et al. 2005 For every case, we randomly selected four controls from individuals under observation in the study cohort on the date of the case event (index date), and matched them for age (year of birth), sex, and health plan region (north or south). A given cohort member selected as a control for a case on one date could become a control for another case occurring on a later index date, as long as he or she remained in the study cohort and was therefore also at risk of becoming a case. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365475-81 Matching in risk-set sampling is equivalent to sampling from strata, where the strata definitions are the levels of the matching factors.

25. Graham et al. 2005 For every case, we randomly selected four controls from individuals under observation in the study cohort on the date of the case event (index date), and matched them for age (year of birth), sex, and health plan region (north or south). A given cohort member selected as a control for a case on one date could become a control for another case occurring on a later index date, as long as he or she remained in the study cohort and was therefore also at risk of becoming a case. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365475-81

26. Take Home Lessons: Cohort Sampling • All case-control studies can be seen as being samples drawn from specifiable cohorts. • Different modes of cohort analysis give rise to corresponding case-control designs. • Closed cohort, fixed folow-up  Sample noncases • Variable follow-up time, time-varying exposure, stable baseline incidence  Sample person-time • Variable baseline incidence  Sample risk sets • Case-control analysis are directly tied to the corresponding cohort analysis, with further allowance for sampling • “Case-control” studies that do not use cohort sampling are valid only to the extent that the procedures used approximate cohort sampling.

27. Case-Control Advantages • Relatively inexpensive • Relatively quick • Particularly useful for rare outcomes • Closely logical connection to cohort designs However, you have to bear in mind that • Focus on a single outcome can be very misleading when overall cost and benefit is the real questions • Poorly conceptualized studies can taint the field • Negative attitudes that are a holdover from old hierarchies of evidence that do not reflect modern understanding

28. Thank You!