Cohort and Case-Control Studies

September 2013

Alexander M. Walker MD, DrPHWith Sonia Hernández-Díaz MD, DrPH

Cohort Study

If you have People Observed for a health event For some amount of elapsed time in every oneYou have a cohort study

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Graphical Representation

Randomized Trial Cohort Study

Person-Time Person-Time

People People

Risks

Yes No

Yes a b n1

no c d n0

Outcome

Exp

osu

re

Risk Ratio = RR = [a/n1] / [c/n0]

Risk(exposed) r1 = a/n1

Risk(not exposed) r0 = c/n0People

Incident cases

Counts of people in different exposure/outcome categories

›

Rashkind Occluder

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Outcome N=185

Successful closure 160 (86.5%)

Embolization of occluder 18 (9.7%)

Transfusion 26 (14.1%)

Average cost per patient $11,466

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

Rates

Yes PT

Yes a t1

No c t0

Outcome

Exp

osu

re

Rate Ratio = RR = [a/t1] / [c/t0]

Person-Time

Incident cases

Rate(exposed) r1 = a/t1

Rate(not exposed) r0 = c/t0

Sum up all the individual times of observation

›

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BMI and Seizures

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Seizure Incidence and BMI

9

BMI

Seiz

ure

s p

er

100,0

00 p

ers

on

-years

95% Confidence

Interval

Time-Varying Exposures

Crossover Trial Cohort Study

Person-Time Person-Time

People

Rates with Time-Varying Exposures

Yes PT

Yes a t1

No c t0

Outcome

Exp

osu

re

Incident cases

Sum up all the individual times of observation

Person-Time

Rate Ratio = RR = [a/t1] / [c/t0]

Rate(exposed) r1 = a/t1

Rate(not exposed) r0 = c/t0

›

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

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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

Sampling Person-Time

Yes PT

Yes a st1

No c st0

Outcome

Exp

osu

re

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.

The Odds Ratio with Cases and Sampled Person-Time

CasesControl

s

Yes λ1t1 st1

No λ0t0 st0

Outcome

Exp

osu

re

Person-Time

Consider the table of expected values, below. The odds ratio of this case-control table of expected values is

OR

1t1st1

0t0st0

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From which it follows that an estimate of the OR is an estimate of ρ . Note that there is no “rare disease” assumption.

A Case-Control Study with Sampled Person-Time

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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.

Random Sampling of Person-Time

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Cases, Controls, OR

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Risk Sets

Persons over TimeRisk Set

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.”

Risk Set Sampling in Case-Control Studies

Proportional Hazards analysis

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

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

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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

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Risk set sampling

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

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Matching in risk-set sampling is equivalent to sampling from strata, where the strata definitions are the levels of the matching factors.

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

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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.

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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

Thank You!