Designing and PerformingCohort Studies

Edward A. Panacek, MD, MPH

Professor of MedicineUniversity 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 haslargely been arguing about the wrong things.

n The question being asked (usually) determinesthe appropriate research strategy, not tradition.

n Each method should flourish, because each hasfeatures that overcome the others limitations.

n Which way of answering the question provides uswith the most valid, useful answer?

Performing Clinical Research

n There are many different “jobs” in clinicalresearch– 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 designsn Do not confuse scientific accuracy with clinical

relevance

n Well done cohort and case-control studies can bemuch more valuable than irrelevant clinical trials

n There is much confusion regarding the definitionof a “cohort study”– Has one core definition– Multiple actual study applications– Often used erroneously in presentations

Goals of this lecturen 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 sometrait and move forward together as a unit

Epidemiology definition of “cohort”

n Cohort: A group of individuals that share acommon 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 orwork

– Exposure cohort: individuals assembled as a groupbased 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), overtime, 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:– Cohort: no– RCT: yes

n Intervention:– Cohort: no, just the

passage of time(observational)

– RCT: yes

n Prospective:– Cohort: usually– RCT: yes

n Control of initial studyconditions– Cohort: no– 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 morethan 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 somefactor. 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 acommunity: 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, annualupdated population lists

n Allowed calculation of incidence rates and otherdescriptive measures for many outcomes

Retrospective versus prospective cohort studies

n Classification is based on the temporalrelationship 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 enrollingsubjects based upon the presence or absence ofthe exposure (IV) of interest, without knowing theoutcome 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 2groups

n Measures: Incidence ratios, Relative risks, Oddsratios ( can do single univariate comparison)

Example: Retrospective (nested) cohort studywith internal controls

Belanger CF, Hennekens CH. The nurses’ health study.Am J Nurs. 1978;78:1039

n 12,000 nurses surveyed at baseline andperiodically thereafter

n Collected information on many factors andoutcomes over many years

n Later, split group into those using oralcontraceptives vs. not to compare outcomes– Compared rates of CA, AMI, etc– Addressed questions not formulated at study initiation

Example: Retrospective cohort studywith external controls

Enterline PE. Mortality among asbestos productworkers in the US. Ann NY Acad Sci.1965;132:156

n Exposed : Asbestos workers identified from IRStax 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 beforeexposure 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 withinternal controls

Doll R, Hill AB. Mortality in relation to smoking: 10 yearsobservation 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 athleticismand 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 questionnairesat baseline and 10 years

n Outcome: CHD data from questionnaires and deathcertificates

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 haverandomization of study subjects

n Therefore, they are more vulnerable to selectionbias

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 partiallyhelp address the issue

Example: Prospective cohort study with“external” comparison control group

Selikoff IJ, et al. Latency of asbestos dz among insulationworkers in the US and Canada. CANCER. 1980;46:736+

n Exposed: 17,800 males in Asbestos InsulationWorkers union in North America as of 1-1-67

n Unexposed: General population of malesmatched by age

n Outcome: F/U for lung cancer rates through 1975

n Results: Positive assoc. between asbestos andlung CA

Ambispective cohort studies

Two types:

n Cohort created at time of study initiation butexposure in the past and outcomes both past andfuture– Ideal for evaluating exposures that may have both

short-term and long-term effects

n Cohort assembled part retrospectively and partprospectively– Allows enrollment of more subjects/less time, using

prospective evaluation to check for data completeness

Example: Ambispective cohort with bothshort-term and long-term outcomes

Gunby P. Military looks toward 1985 in ongoing defoliantstudy. JAMA.1984;85:383.

n Question: Are there deleterious effects of exposure toagent 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 andprospective enrollment

White RH, et al. Bleeding complications related toINR level in patients on warfarin. JAMA.

n UC Davis anticoagulation clinic patients, since1993, 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 orproportions 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 andlook 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 andthen follow the cases through time, for theoutcomes– 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 “prospectiveobservational 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 inthe analysis

Decisions about matching

n Current statistical techniques allow adjustment forconfounders, so matching not as important as before

n If have a known powerful confounder or one that is difficultto measure precisely– Pair match on that confounder

n For most other possible confounders, better to just adjustin the analysis

n If match on a factor, less able to study its role in the dz.

n Use frequency matching to prevent gross imbalancesbetween groups that would decrease the power of thestudy

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-upstudies, 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 studiesn 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 toEM 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 anexposed group to an unexposed group

n However, that is simply an extreme case ofdifferences 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 longF/U periods

n However, that is because the outcomes ofinterest were usually cancer and other conditionswith long exposure-outcome timeframes

n When the outcome follows closely after theexposure (or factor or intervention), the length ofthe “F/U” period is likewise short

EM example: Retrospective cohortwith internal control group

n Braun BL, et al. Marijuana use and medially attendedinjury events. Ann Emerg Med.1998;32:353

n Cohort: Kaiser members undergoing multiphasic exams1979-86 in SF or Oakland, aged 15-49

n Groups: Self-reported marijuana use (prior, current) asexposed vs. the “never” category as the comparison group

n Outcomes: Injury related clinic visits, hospitalizations andfatalities

n Results: Rate ratios not different between groups

EM example: Retrospective cohort study

Tran P, Panacek EA. A comparison of norepinephrine anddopamine for treating TCA OD associated hypotension. AcadEmer Med. 1997;4:864-8.

n Cohort: All TCA OD pts requiring vasopressorsExposure 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 withinternal 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. in1988, 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 purchasedassault-type handgun

EM example: Prospective cohort study(single group)

Minogue MF, et al. Pts hospitalized after initial outpttreatment for CAP. Ann Emerg Med. 1998;31:376-80.

n Cohort: all patients with CAP initially treated asoutpatients 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 torocuronium 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 exceptrecovery 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 ofexposure

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 resourceexpensive as RCTs

n If retrospective, is dependent upon the adequacyof records

n Because these are “follow-up” studies, validity ofresults 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 theoutcome(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 theunavailable 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 importantones

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