Designing and Performing

Cohort Studies
Edward A. Panacek, MD, MPH
Professor of Medicine
University of California-Davis
Medical Center
(SAEM meeting sylabus: May, 2000)
Choosing the best design for each research question:
It is time to stop squabbling over the “best” methods
Sackett DL, Wennberg JE. BMJ. 1997;3315:1636.
n Focusing on methods rather than questions has
largely been arguing about the wrong things.
n The question being asked (usually) determines
the appropriate research strategy, not tradition.
n Each method should flourish, because each has
features that overcome the others limitations.
n Which way of answering the question provides us
with the most valid, useful answer?
 Performing Clinical Research
n There are many different “jobs” in clinical
research
– Prevalence proportion, incidence rates
– Measures of association (RR, OR)
– Effectiveness versus efficacy evaluation
– Benefits versus safety
– Endpoints versus outcomes
– Outcomes versus cost-effectiveness

n Should have many tools in your “research tool-

box”
 Points regarding study designs
n Do not confuse scientific accuracy with clinical
relevance
n Well done cohort and case-control studies can be
much more valuable than irrelevant clinical trials
n There is much confusion regarding the definition
of a “cohort study”
– Has one core definition
– Multiple actual study applications
– Often used erroneously in presentations
 Goals of this lecture
n Be able to define the term “Cohort”
n Describe different types of cohort studies
n Contrast cohort to case-control studies and RCTs
n List the advantages & disadvantages
n List the main outcome measures used
n Cite examples of classic cohort studies
n Cite examples of cohort studies in EM literature
 Dictionary definition of “cohort”
n Latin: cohors
– Enclosed yard or company of soldiers
– All were the same type of soldier (e.g. calvary)
– In the Roman armies, a band of 300-600 soldiers,
constituting 1/10th of a Legion

Concept:
A group of individuals that are all similar in some
trait and move forward together as a unit
 Epidemiology definition of “cohort”
n Cohort: A group of individuals that share a
common characteristic
– Birth cohort : all individuals in a certain geographic
area born in the same period (usually a year)
– Inception cohort: all individuals assembled at a given
point based on some factor, e.g. where they live or
work
– Exposure cohort: individuals assembled as a group
based on some common exposure
• e.g. radiation exposure during desert testing
• e.g. asbestos exposure in the shipyards
 Definitions of “cohort study”
n The observation of a cohort (or cohorts), over
time, to measure outcome(s)
– AKA: Longitudinal, follow-up studies

They have 2 primary purposes:

n Descriptive (measures of frequency)
– To describe the incidence rates of an outcome over
time, or simply describe the natural history of disease

n Analytic (measures of association)

– To analyze associations between the rates of the
outcomes and risk factors or predictive factors
Cohort studies versus Clinical trials (RCTs)
n Randomization: n Prospective:
– Cohort: no – Cohort: usually
– RCT: yes – RCT: yes
n Intervention: n Control of initial study
– Cohort: no, just the conditions
passage of time – Cohort: no
(observational) – RCT: yes
– RCT: yes
Why use cohort studies instead of RCTs?
n Unable to randomize
– Impossible: genetic traits
– Unethical: desperate disease (CA)
– Illegal: effect of cocaine use during pregnancy

n Interested in incidence rates or predictors more

than the effects of interventions
– e.g. predictive role of initial BP in field in blunt trauma

n Field of investigation is immature

n Limited research resources
– time, money, subjects
 Types of cohort studies
n Single group (inception cohort)
n Multiple groups (Double or Comparison cohort)
– From the same inception cohort (internal controls)
– Assembled separately (external controls)

n Prospective
n Retrospective
n Ambispective
– Both prospective and retrospective components
 Single group cohort study
n AKA: Inception cohort
n Structure: Assemble cohort based on some
factor. Follow them over a set period of time.
– Usually multiple observations for outcome(s) of interest

n Time frame: Usually prospective

n Purpose: descriptive
n Measures: Incidence rates, point prevalence
 Example: Single group cohort
Dawber TR, et al. An approach to longitudinal studies in a
community: The Framingham study. Ann NY Acad Sci.
1963;107:539.
n Began in 1948 with 5,209 participants
n 5,123 spouses and children added in 1971
n Selected not based on exposures, but on stable pop.,
wide spectrum of occupations, single hospital, annual
updated population lists
n Allowed calculation of incidence rates and other
descriptive measures for many outcomes
Retrospective versus prospective cohort studies
n Classification is based on the temporal
relationship between the initiation of the study
(sample defined) and occurrence of the outcome
– i.e., outcome before initiation = retrospective

n However, both start by identifying and enrolling

subjects based upon the presence or absence of
the exposure (IV) of interest, without knowing the
outcome at the time (even if retrospective)
– i.e. subjects are free of the outcome (e.g. disease) at
the time their exposure status is defined
Double group cohort study: Retrospective
n If from within prior inception cohort;
– AKA: “nested cohort study”

n Structure: Select exposed group and non-

exposed group from pre-existing data base.
– Obtain F/U information on numbers of outcomes

n Purpose: Compare the outcome rates in the 2

groups
n Measures: Incidence ratios, Relative risks, Odds
ratios ( can do single univariate comparison)
Example: Retrospective (nested) cohort study
with internal controls
Belanger CF, Hennekens CH. The nurses’ health study.
Am J Nurs. 1978;78:1039
n 12,000 nurses surveyed at baseline and
periodically thereafter
n Collected information on many factors and
outcomes over many years
n Later, split group into those using oral
contraceptives vs. not to compare outcomes
– Compared rates of CA, AMI, etc
– Addressed questions not formulated at study initiation
 Example: Retrospective cohort study
with external controls
Enterline PE. Mortality among asbestos product
workers in the US. Ann NY Acad Sci.1965;132:156
n Exposed : Asbestos workers identified from IRS
tax returns (1948-51)
n Unexposed:1. Cotton textile workers form IRS
2. General US matched population
n Outcome: Death rates (from state health depts. )
n Measure: Death incidence rates in each group
– overall and cancer specific → calculated rate ratios
 Prospective cohort (double group) studies
n The “classic” cohort study design
n Sample defined prospectively during or before
exposure and before outcome occurrence
– “Exposure” can be many things (e.g. predictor variable)
– Allows for more accurate measure of exposure/factor
– Also allows for more accurate measure of potential
confounding variables
– Can have multiple measurements over time
– Groups followed over time for development of the
outcome
Example: Prospective (double) cohort study with
internal controls
Doll R, Hill AB. Mortality in relation to smoking: 10 years
observation of British docs. Br Med J.1964;1:1399-1410.
n Cohort: British doctors responding to a survey in 1950
– 65% response rate
n Exposed: smokers ( and quantified amount)
n Unexposed: non-smokers
n Outcome:Lung Ca and death
– Periodic F/U surveys and review of death records
n Results: Increased risk with any smoking and a dose-
response relationship
 Example: Prospective cohort study with
“internal” comparison control group
Paffenberger RS, et al. A natural history of athleticism
and CV health. JAMA.1984;252:491-5.
n Cohort: 16,936 Harvard alumni
n Groups: high vs. low exercise groups
n Measurements: college records and questionnaires
at baseline and 10 years
n Outcome: CHD data from questionnaires and death
certificates
n Results: RR for CHD = 1.5 if sedentary vs. if active
 Example: Prospective cohort study with
“external” comparison control group
British Journal of Audiology. 1980s
n Question: Is living under flight path hazardous?
n Study group: Those living next to LAX airport
n Controls: Other angelinos in different LA zip code
n Outcome: Death rates in each zip code zone
– From county health records

n Results: Higher per capita mortality rates by LAX

– Problems???
Cohort studies: Importance of the comparison group
n Unlike RCTs, cohort studies do not have
randomization of study subjects
n Therefore, they are more vulnerable to selection
bias
n This is usually not as issue with the exposure
n Often a serious problem in terms of confounders
n Increasing the size of the study can only partially
help address the issue
 Example: Prospective cohort study with
“external” comparison control group
Selikoff IJ, et al. Latency of asbestos dz among insulation
workers in the US and Canada. CANCER. 1980;46:736+

n Exposed: 17,800 males in Asbestos Insulation

Workers union in North America as of 1-1-67
n Unexposed: General population of males
matched by age
n Outcome: F/U for lung cancer rates through 1975
n Results: Positive assoc. between asbestos and
lung CA
 Ambispective cohort studies
Two types:
n Cohort created at time of study initiation but
exposure in the past and outcomes both past and
future
– Ideal for evaluating exposures that may have both
short-term and long-term effects

n Cohort assembled part retrospectively and part

prospectively
– Allows enrollment of more subjects/less time, using
prospective evaluation to check for data completeness
 Example: Ambispective cohort with both
short-term and long-term outcomes
Gunby P. Military looks toward 1985 in ongoing defoliant
study. JAMA.1984;85:383.
n Question: Are there deleterious effects of exposure to
agent orange in servicemen?
n Exposed: 1264 exposed to defoliant spraying in Vietnam
n Unexposed: 1264 who flew cargo missions at same time
n Outcomes(retro): Medical problems during exposure time
– e.g. dermatologic conditions, birth defects, liver problems
n Outcomes (prospective): cancer rates up to 25 years later
Example: Ambispective cohort study with retro and
prospective enrollment
White RH, et al. Bleeding complications related to
INR level in patients on warfarin. JAMA.
n UC Davis anticoagulation clinic patients, since
1993, with continuing enrollment into the future
n Exposed: those with elevated INRs
n Unexposed: Pts with normal INRs
n Outcomes: Bleeding complications
Cohort studies: Principal outcome measures
n Crude: simple univariate comparison of rates or
proportions between the 2 groups
– Gives statistical but not clinical significance

n Descriptive: Incidence rates in the group(s)

– Gives absolute measure of association but not
comparisons

n Comparisons: Relative measures of association

– Compares incidence rates between groups
– Relative risk
– Risk ratio (sometimes estimated by Odds Ratios)
 Cohort versus case-control studies
n Case-control studies start with the outcome and
look back for exposures/factors
– Outcome present = case
– Outcome absent = control ( or referent subject)
– Almost always are retrospective studies

n Cohort studies generally start with exposures and

then follow the cases through time, for the
outcomes
– Exposure present = study subject
– Exposure absent = control subject
 Terminology confusion
n Case-control studies often simply called
“retrospective observational studies”
– can occasionally be done prospectively
– Best name = “Case-control (referent) study”

n Cohort studies often called “prospective

observational studies”
– Often performed retrospectively
– Better name = “Exposed-unexposed study”
• Unfortunately, this name has not caught on
 Cohort studies: Matching
n Pair matching
– Each study subject is closely matched with a control
subject on some specific factor
– Requires special statistical tests in the analysis to
adjust for the confounding effects of the matching

n Frequency matching
– Each study subject or group of subjects are matched
with controls on some category of a factor
• e.g. by gender, or age within 5 years, smoker
– Generally does not require special statistical tests in
the analysis
 Decisions about matching
n Current statistical techniques allow adjustment for
confounders, so matching not as important as before
n If have a known powerful confounder or one that is difficult
to measure precisely
– Pair match on that confounder
n For most other possible confounders, better to just adjust
in the analysis
n If match on a factor, less able to study its role in the dz.
n Use frequency matching to prevent gross imbalances
between groups that would decrease the power of the
study
Cohort studies in Emergency Medicine
n Not as commonly used in EM as in primary care,
occupational medicine, and cancer research
n In EM, don’t usually perform long-term follow-up
studies, unless doing epidemiologic research
n However, very useful option for selected issues
– Injury patterns and prevention research
– When unable to randomize
– When unable to get informed consent
– When the “F/U” period can be very short or can all be
retrospective
 The evolution of cohort studies
n The classic cohort studies involved two
components:
– Exposed and unexposed groups
– Longitudinal F/U over long time periods

n Neither of these elements seem well suited to

EM research
n However, cohort studies have evolved:
– design components more flexibly applied
– application of cohort studies expanded
Cohort studies: The element of “exposure”
n The “classic” cohort studies compared an
exposed group to an unexposed group
n However, that is simply an extreme case of
differences between two groups.
n Other “differences” are also possible:
– High exposure vs. low exposure
– Exposure 1 vs. exposure 2
– Presence of factor 1 vs. factor 2
– Intervention 1 vs. 2
Cohort studies: The element of “follow-up”
n The original “classic” cohort studies involved long
F/U periods
n However, that is because the outcomes of
interest were usually cancer and other conditions
with long exposure-outcome timeframes
n When the outcome follows closely after the
exposure (or factor or intervention), the length of
the “F/U” period is likewise short
 EM example: Retrospective cohort
with internal control group
n Braun BL, et al. Marijuana use and medially attended
injury events. Ann Emerg Med.1998;32:353
n Cohort: Kaiser members undergoing multiphasic exams
1979-86 in SF or Oakland, aged 15-49
n Groups: Self-reported marijuana use (prior, current) as
exposed vs. the “never” category as the comparison group
n Outcomes: Injury related clinic visits, hospitalizations and
fatalities
n Results: Rate ratios not different between groups
 EM example: Retrospective cohort study
Tran P, Panacek EA. A comparison of norepinephrine and
dopamine for treating TCA OD associated hypotension. Acad
Emer Med. 1997;4:864-8.

n Cohort: All TCA OD pts requiring vasopressors

Exposure 1: Dopamine as first vasopressor
Exposure 2: Norepinephrine as first vasopressor

n Outcomes: BP response to normal range

n Results: Norepi effective in all, dopamine in 60%
– Relative risk for persistent hypotension with dopa= 4.8
EM example: Retrospective cohort study with
internal control group
Wintemute GJ. Criminal activity and assault-type handguns:
A study of young adults. Ann Emerg Med.1998;32:44-50.
n Cohort: 5,360 legal purchasers of handguns in Calif. in
1988, under age 25
n Group 1: purchased assault-type handguns
n Group 2: purchased other types of handguns
n Outcome: criminal activity during subsequent 3 years
n Results: RR = 1.5-3.0 for criminal activity if purchased
assault-type handgun
 EM example: Prospective cohort study
(single group)
Minogue MF, et al. Pts hospitalized after initial outpt
treatment for CAP. Ann Emerg Med. 1998;31:376-80.
n Cohort: all patients with CAP initially treated as
outpatients at 5 study centers
n Outcomes: Hospitalization within 30 days
n Results: Descriptive
– % hospitalized
– % CAP related
– Identification of factors that may be predictive
EM example: Prospective cohort study
Sakles JC... Panacek EA. Comparison of succinylcholine to
rocuronium for RSI in ED. Acad Emer Med.1999;6:518.
n Cohort: All ED pts undergoing RSI
– Group 1: those receiving rocuronium as the NMB drug
– Group 2: receiving succinylcholine as the NMB drug

n Outcomes:
– Time to full relaxation & intubating conditions
– Time to recovery and complications

n Results: Very similar in all parameters except

recovery time. RR for complications = 1
 Cohort studies: Strengths
n The best way to study incidence of the outcome
n Ideal for studying rare exposures (or initial conditions)
n Unlike case-control studies:
– The temporal sequence is clear
– Can examine multiple effects from a single exposure
n If prospective, minimizes bias in the measurement of
exposure
n Much less expensive than RCTs

n Sometimes the best or only ethical way to do the study

– e.g. cannot or should not randomize
 Cohort studies: Weaknesses
n Inefficient for study of rare outcomes
– Unless the attributable-risk is high for the exposure

n If prospective, can be nearly as resource

expensive as RCTs
n If retrospective, is dependent upon the adequacy
of records
n Because these are “follow-up” studies, validity of
results is highly sensitive to losses to F/U
Cohort studies: Strategies to minimize “lost to F/U”
n Exclude those likely to become “lost”
– Planning to move
– Unwilling to return

n Obtain complete tracking info

– Address, phone #, SSN
– Same for friend or close relative
– Primary MD

n Maintain periodic contact

– Reminders, updates

n Use secondary data sources for critical info

– Death registries, Medicare records, voter/driver registration
 Cohort studies: Follow-up issues
n Is the duration of F/U appropriate for the
outcome(s) of interest
n How is the outcome of interest measured?
– Validity and reliability of measure addressed?

n Is a high F/U rate (85%) been achieved?

n Is there a comparison of the characteristics of the
unavailable group to the followed group?
– Not needed if very high F/U rates achieved
 Cohort studies: Selecting the design
n Retrospective cohort design
– Can the question be answered with data that already exists?
– If yes, this is by far the most economical approach
n Prospective single cohort design
– If goal is descriptive, measure incidence rates
n Prospective double cohort design
– When exposures need to be measured precisely
– Outcomes are relatively common
n Ambispective cohort study
– Could study prospectively but would take too long to get
enough data. Can use prospective data to QA the retro data
 Cohort studies: final comments
n Your research tool-box should have many tools
n Cohort studies are one of the most important
ones
n Become a research conservationist
– Don’t conspicuously consume research resources
unless absolutely necessary
– Save the RCTs for when the target is known precisely
and the expense is warranted